Drug development against tuberculosis: Impact of alkaloids

European Journal of Medicinal Chemistry 137 (2017) 504e544

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Drug development against tuberculosis: Impact of alkaloids* Shardendu K. Mishra a, b, 1, Garima Tripathi a, 2, 1, Navneet Kishore a, 3, Rakesh K. Singh c, Archana Singh a, Vinod K. Tiwari a, * a

Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India c Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 4 April 2017 Received in revised form 26 May 2017 Accepted 2 June 2017 Available online 3 June 2017

Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have generated extended research interest in natural products in the hope of devising new antitubercular leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards various resistant strains of M. tuberculosis. Extensive applications of alkaloids in the field of therapeutics is well-established and nowday's researches being pursued to develop new potent drugs from natural sources for tuberculosis. Alkaloids are categorized in quite a few groups according to their structures and isolation from both terrestrial and marine sources. These new drugs might be a watershed in the battle against tuberculosis. This review summarizes alkaloids, which were found active against Mycobacteria since last ten years with special attention on the study of structure-activity relationship (SAR) and mode of action with their impact in drug discovery and development against tuberculosis. © 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Alkaloids Tuberculosis Mycobacterium tuberculosis Antimycobacterial agents Multi drug resistant tuberculosis Natural products Drug development

Contents 1. 2.

3. 4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505 Clinical manifestations and pathogenesis of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 2.1. Clinical manifestations of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 2.2. Pathogenesis of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 Existing therapies and tools to combat tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3.1. Pioneer drugs in the treatment of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Resistance to current antimycobacterial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 4.1. Multi drug resistance tuberculosis (MDR-TB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 4.2. Extensively drug resistant tuberculosis (XDR-TB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 4.3. Totally drug resistant tuberculosis (TDR-TB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 Novel antituberculosis drugs in pipeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 Common molecular targets for antimycobacterial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 6.1. Protein synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 6.2. Nucleic acids biosynthesis and DNA gyrase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 6.3. Nucleotide biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 6.4. Cell wall macromolecule biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 6.5. Fatty acid biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

*

This manuscript is dedicated to Prof. (Dr) Rama P. Tripathi, Senior Scientist at CSIR-Central Drug Research Institute, Lucknow, India. * Corresponding author. E-mail address: [email protected] (V.K. Tiwari). 2 Present address: Department of Chemistry, Indian Institute of Technology, Kanpur, India. 3 Present address: Department of Plant Science, University of Pretoria, Pretoria-0002, South Africa. 1 Author contributed equally.

http://dx.doi.org/10.1016/j.ejmech.2017.06.005 0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

7.

8. 9.

10.

505

6.6. 6.7. Assay 7.1.

Isocitrate lyase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 ATP biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 and diagnostic tools for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Assays for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 7.1.1. In vivo assay for Mycobacterium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 7.1.2. In vitro assay for Mycobacterium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 7.1.3. Toxicity and selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 7.2. Diagnostic tools for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 7.2.1. Sputum investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 7.2.2. Tuberculin test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 7.2.3. Radiographic investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 7.2.4. Nucleic acid techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 Plants: a harry potter stick for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 Alkaloids with significant antimycobacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 9.1. Indole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 9.2. Pyrrole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520 9.3. Carbazole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522 9.4. Indoloquinoline alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522 9.5. Manzamine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523 9.6. Quinoline alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523 9.7. Isoquinoline alkaloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 9.8. Pyrrolo [2,1-b]quinazoline alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 9.9. Cyclostelletamine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 9.10. Pyridoacridone alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 9.11. Aza-anthraquinone alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528 9.12. Pyrrolidine alkaloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529 9.13. Imide alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530 9.14. Piperidine alkaloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530 9.15. Cyclopeptide alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 9.16. Agelasine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 9.17. Polycyclic guanidine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532 9.18. Oxazole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532 9.19. Diterpenoid b-lactam alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 9.20. Miscellaneous alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534 Conclusion and future purspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536

1. Introduction Since inception tuberculosis (TB) has been the most challenging disease in human era that is caused by Mycobacterium tuberculosis (M.Tb), an acid-fast bacillus, which persists in host body for the longer period without any indication of disease [1e3]. The primary cause for the survival of this bacillus is its unique property to develop resistance against the drugs discovered till today [4,5]. In immunocompromised patient, this bacillus start a silent warfare, which eventually transformed into an assault leading to the uncontrolled growth of bacteria (nearly 1013 organisms) [6,7]. The period of tuberculosis drug discovery and current researches in pipeline has been associated with multilateral agencies and various non-governmental organizations for technical assistance as well as pharmaceutical companies developed new strategy to alleviate tuberculosis [8e10]. It has been considered a sickness of death for many years with relatively rare cases in the developed countries. Tuberculosis remains a huge problem in economically weaker section (below poverty line) in developing countries [11]. This “White Plague” is a critical challenge not only for medical but also from the social point of view for the current situation, too. Virtually, every year about 1.5 million people dies all over the world, and around 9e9.5 million of new TB patient's registration are observed. Recently, World Health Organization (WHO) has declared as a worldwide catastrophe due

to the sudden rise of new TB cases supported by the introduction of Human Immunodeficiency Virus (HIV) resulting in millions of deaths every year [12]. Around one-third of the world's population is presently informed to be infected with M. tuberculosis. World Health Organization, 2014 survey, revealed on TB patients that the estimated 85% cases happened in Asia (58%) and Africa (28%), while around 14% cases arised in the rest of the world [13e15]. According to the WHO (2016) annual report on TB, 2.84 million Indians contracted the disease in 2015 alone and thus India bears the maximum number of TB patients with an estimated 79,000 persons becoming sick with this disease each year [16]. Immuno deficiency due to HIV clears the path for tuberculosis persistence by leading towards an immunocompetent person transformation into a horrifying assault [17,18]. HIV prevalence with tuberculosis is marked increasing from last two decades and fueled tuberculosis outbreak. The available regimen for the tuberculosis was discovered in between 1950 and 1975 resulting in a drastic decrease in the disease, but the emergence of multi-drug resistant (MDR) leads to a sudden increase in disease graph which is alarming statistics [19,20]. Today's treatment is more problematic to the clinicians due to resistance to more than two antimycobacterial drugs leading to development of multi-drug resistant tuberculosis (MDR-TB) [21,22]. However, owing to the advent of drug-resistant TB strains, new drugs are immediately required and thus efforts have been twisted

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towards natural sources to finding of new TB leads. The bioactive moiety from natural origin and their derivatives have been described to display significant inhibition of the causative agent and few of them have been selected as lead molecules for the development of new mechanisms based antitubercular drugs [2,23,24]. It's pre-requisite to mention here that compounds can be classified as strong, weak and of middle class based on their minimum inhibitory concentrations (MICs) values, i.e. considered as good with an MIC value of < 10 mg/mL or moderate up to 50 mg/mL, respectively [25]. The antitubercular medicinal preparations have been classified in different ways and as they exhibit different mechanisms of action and also adept of exerting adverse effects on a human body. There has been an immense improvement in new methods to evaluate the antimycobacterial potential of several chemical entities, reported throughout the last few decades [26,27]. The control on the tuberculosis has been extremely dependent on the resistance developed by M. tuberculosis against the short term antimycobacterial agents. Hence, a tough approach is required to abolish these drug resistant pathogens by the discovery of novel scaffolds as potent antitubercular candidates that can acts through novel mechanism of action with minimum or no cross resistance [28]. Despite the engagement of academic institutions and efforts of the scientists from many pharmaceutical companies in the development of antitubercular programmes, the current TB therapy is static and weak [29]. The search for new antitubercular metabolites from natural sources still represents a great challenge for researchers in spite of their rising efforts to determine effective antitubercular molecules of plant origin [30]. Moreover, many scientists have become attentive in the search for new leads from micro-organisms such as fungi, yeasts, and bacteria [31e33]. In this context, the search for new chemical entities (NCE's) from natural sources to combat tuberculosis is high priority objective. Therefore, in the extension of our review on bioactive alkaloids against tuberculosis from natural origin [3], we compiled the antitubercular alkaloids up to date from natural sources. This review covers the alkaloids with significant antimycobacterial activity and their synthetic analogues possessing the same activity. Diverse alkaloids amongst others phytochemicals have been presented on the basis of their chemical class type. The chemical structure of compounds with their minimum inhibitory concentrations, molecular targets for comparing the effectiveness were mentioned also along with special attentive glimpses of clinical manifestations, pathogenesis, resistant types, different assay and diagnostics tools for tuberculosis. This review also highlighted the existing therapies for TB and novel leads in pipeline, which includes pre-clinical and clinical phase-I, II, III molecules. Furthermore, why phytochemicals lead over the synthetic compounds considered for the possible treatment and prophylaxis of tuberculosis along with molecular targets for antimycobacterial agents have also been described.

based on ethnic background, age, race and immunity [35]. HIV contamination poses precise challenges to clinical administration in patients with active tuberculosis. The threat of tuberculosis rises quickly after contamination with HIV, and the symptoms of pulmonary tuberculosis at this stage are just like those in HIV negative patients [36]. In patients with cluster of differentiation-4 (CD4) counts below 200 mm3, tuberculosis was manifested by atypical infiltrates, hilar lymphodenopathy and pleural effusion whereas patients having CD4 count less than 75 mm3 indicated with non specific chronic febrile disease, mycobacteremia and multiple organ involvement [36]. This type of condition led to misinterpretation of other diseases and later described after post mortem [37]. In endemic regions 10% tuberculosis cases are sub-clinical tuberculosis or aymptomatic with negative sputum result, X-ray and associated with HIV infections [34,38,39]. Around 25e30% patient with HIV treatment are never diagnosed for tuberculosis [40]. Therefore, intense screening for tuberculosis is suggested in endemic region to highlight the patient with HIV associated tuberculosis or non-communicable diseases such as diabetes or chronic lung diseases [41,42].

2.2. Pathogenesis of tuberculosis The infection by pathogenic strains of tuberculosis occurs mainly in the oxygen-rich macrophages of the lungs. M. tuberculosis infection happens when few air-dispersed tubercle bacilli from the sufferer with active pulmonary tuberculosis reach the alveoli of the host. Here, Mycobacterium is quickly phagocytized through alveolar macrophages that can kill the entering bacteria due to the innate immune response (Fig. 1) [43]. If, infection persists, bacilli start replicating in macrophages and dispersed to epithelial and endothelial cells. Due to exponential growth of Mycobacteria in few weeks, it spreads to other organs through lymph and blood which affects other cells as well [44,45]. Toll like receptors (TLR) mediated production of cytokines and other chemical mediators act as signal for mycobacterial infection and pathogenesis [46]. This results in movement of monocytes associated macrophages and dendritic cells to infection site in lungs. There, itself dendritic cells engulf bacilli and migrate to lymph nodes to present Mycobacterium antigens to CD4 and CD8 T-cells, which functionally activate these cells [47e49]. Many studies established the involvement of CD4þ Tcells against M. Tb protection, the evidence is reinforced by the depletion of CD4þ T-cells, which is accountable for recurrence of M. Tb in HIV-infected persons. There are different subsets of CD4þ cells like T-helpers and regulatory T cells, which are co-operate or hinder with each other to regulate infection. Developed T-cells

2. Clinical manifestations and pathogenesis of tuberculosis 2.1. Clinical manifestations of tuberculosis The clinical appearances of tuberculosis mainly defined as the primary TB and secondary (reactivation) TB. Primary TB basically considered as the disease of childhood with new TB infections whereas the secondary TB designated as multiple terms like chronic TB, recrudescent TB, endogenous reinfection, and adulttype progressive TB. There are some other manifestations related to especially pulmonary TB which includes Laryngeal TB, Lower lung field TB and Tuberculoma. Pulmonary TB is characterized by the sputum production, night sweats, chronic cough, anorexia and hemoptysis [34]. About 45% of patients suffer from extra-pulmonary tuberculosis and it varies

Fig. 1. Pathogenetic steps of M. tuberculosis.

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proliferates and migrate back to the focal point of illness within the lungs, in response to mediators produced by infected cells. These episodes of cell migration in the direction of the infection focus reach a pinnacle within the formation of granuloma, which is hallmark of tuberculosis. This granuloma formation supports bacilli dormancy for long time and prevents its disruption within macrophages. Dormant bacilli housed within granuloma can released during favorable conditions and triggers relapsing of infection. Entry of Mycobacteria into macrophages occurred through cholesterol domains of plasma membrane that was mediated by binding to receptor and phagocytosis [50]. In vitro studies elucidated the role of different receptor, which involve Mycobacterium uptake by macrophages whereas in vivo studies nullify the evidence in support of in vitro studies [51e53]. The in vivo Mycobacteria uptake involves various other receptors such as complement receptors, scavenger receptor and C-type lectin receptors. Nearly all of the in vitro experiences point out that the bacilli favour interplay with complement and mannose receptors, which are benign, because they set off minimal superoxide production. In distinction, Mycobacteria uptake by Fc (fragment crystallizable) receptors, which play a minor function in the absence of exact antibodies, set off a vigorous host response and set up an exact intracellular trafficking pathway [54]. This is the reason for preventing internalization of receptors by Mycobacteria and depicts the little effect of receptor on its survival [55,56]. 3. Existing therapies and tools to combat tuberculosis Current therapy uses more than one drug, which involves two principles. First, to prevent development of drug resistance and second, to strengthen drugs potency. The available drugs are sometimes moderately effective due to the impermeable nature of the Mycobacterium cell wall and the inclination of M. tuberculosis to develop resistance to current TB therapies [57]. Responsible bacteria generate resistance to drugs because their chromosome undergoes random mutation. Positively, these chromosomal mutations are unlinked in terms of either location or function. Moreover, selectivity to a particular drug or its class, unplanned genesis of a species with multi-resistance, is particularly implausible. Faulty regimen always leads to acquire drug resistance [40]. Sometimes the treatment comprises more than four drugs for up to 18 months if the strain is resistant to multiple antibiotic forms and if treatment fails due to drug resistance than surgery is essential to eliminate infected tissue. Moreover, the patients associated with AIDS raise one more difficulty, which occurs with the routine treatment is the apparent of drug-drug interactions, likely between rifampin and other anti-retroviral drugs used for the cure of AIDS [58]. Several drugs have been passed in the clinical trials and are being used in various stages in different combination and in different conditions depending upon the new and drug resistant patients. Isoniazid, Rifampicin, Pyrazinamide, Ethambutol and Streptomycin are the five primary or first line TB drugs along with attentive spotlight on the second line, third line and the pipeline drugs for the treatment of tuberculosis are depicted with their structures (Fig. 2aed). These are Group 1 drugs except streptomycin, which comes in Group 2 with other injectables. Group 2 to 5 is termed as second line TB drugs. Drugs in fifth group are not commonly used; they are prescribed only when others fail [40,59,60]. 3.1. Pioneer drugs in the treatment of tuberculosis Since 1952, first line antimycobacterial drugs are the standard regimen to initiate the treatment for tuberculosis. These drugs are the first one which are clinically used and found to be effective at

507

that time. Later on, due to emergence of resistance to these first line therapies, the Centre for Diseases Control (CDC) and World Health Organization (WHO) launched the new class of drugs designated as second and third line drugs for the resistant tuberculosis. Isoniazid (INH, 1) is chemically known as pyridine-4-carboxy hydrazide and was firstly synthesized in 1912, but clinically approved as antimycobacterial drugs in 1952. INH cured many patients in New York hospital and recognized as a ‘magic drug’ [61]. INH discovery lead a milestone and addition of new molecule in antitubercular armamentarium. INH contains hydrazide and pyridine group, which is essential for antimycobacterial activity [62]. As a prodrug, INH transformed into INH-NAD conjugation with the assistance of M. Tb catalase-peroxidase kat G enzyme that inhibits the mycolic acid biosynthesis of M. Tb [63]. The inhibition of enoylACP reductase (encoded by inhA gene) causes an accumulation of long-chain fatty acids and cell death. Mutation in katG315 and inhA enzyme is the major cause of emergence of resistance to INH [63]. Kat G mutation in Mycobacteria was compensated by over expression of the ahpC gene [64,65]. Mutation in NADH dehydrogenase encoding gene ndh develops resistance of INH in M. bovis [66]. INH resistance due to another 16 genes mutation is also reported apart from their known mechanism of resistance [67]. Ethambutol (EMB, 2) was introduced in 1961 and chemically it is dextro-(2,2-ethylenediamino)-di-1-butanol. It has proven that S, S isomer of EMB is 600 times active than other stereoisomers. It's mode of action have different sites including phospholipid synthesis, RNA metabolism, and mycolic acid transfer [68]. Resistance to ethambutol was found to be linked to mutation in embCAB gene, which encodes molecular targets for ethambutol [69]. Pyrazinamide (PZA, 3) was firstly synthesized in 1936 by Dalmar et al. and introduced in 1952 as antimycobacterial drugs. Pyrazinamide is first line of drug in treatment of antimycobacterial agents and in addition, with rifamycin analogues, it kills tubercle bacilli and reduces the treatment regimen from 9 months to 6 months. As pyrazinamide is prodrug, it is converted into pyrazinoic acid where it transformed in protonated pyrazinoic acid, which inhibits bacterial cell and membrane transport breakage [70]. Resistance to pyrazinamide was due to mis-sense mutation in pncA gene that leads to amino acid substitutions [71e73]. Rifamycin derivatives (RMP; 4, 5, and 6) were the most potent drugs used for the treatment of tuberculosis and were reported by Lepetit Research Laboratory, Italy [74]. They consist of aromatic ring with aliphatic bridge on both sides. The substitution on rifamycin at C-1, C-8, C-21 or C-23 usually results in decrease in antimycobacterial activity. Rifamycin has three derivatives used as antitubercular viz. Rifampicin, rifabutin, rifapentine. Rifampicin also called, as rifampin, is a 3-formyl derivative; rifabutin is spiropiperidyl derivative whereas rifapentine is cyclopentyl derivative of rifampin. Rifamycin is most potent bactericidal and sterilizing chemotherapeutics in tuberculosis although its effect is lower when compared to INH in first two days of initiation of treatment [75,76]. Rifamycin analogues inhibit the DNA dependent RNA polymerase, which catalyzes the polymerization of chain. Mutation in rpoB gene that encodes for RNA polymerase beta subunit developed the resistance to rifamycin derivatives. In rifampin, there is rifampicin resistant determining region which carries 507 codons through 533 of the rpoB gene [77e79]. A drug may be classed as second-line instead of first-line if it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be effective, but unavailable in many developing countries (e.g., fluoroquinolones). Streptomycin (SM, 7) is a derivative of aminocyclitol glycoside antibiotic. It directly inhibits protein synthesis by misreading in genetic code and initiation in translation of mRNA [80,81]. Mutation in rpsL gene, which encodes ribosomal protein

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Fig. 2. a: Chemical structure of First line Antitubercular drugs. b: Chemical structure of Second Line Antitubercular drugs. c: Chemical structure of Third line Antitubercular drugs. d: Structure of Pipeline drugs for the treatment of tuberculosis.

leads to streptomycin resistance to M. Tb [82,83]. The representative example of second line drugs include aminoglycosides (e.g., streptomycin 7, amikacin 8, kanamycin 9), polypeptides (e.g., capreomycin 10, viomycin 11) fluoroquinolones (e.g., levofloxacin 12, moxifloxacin 13, gatifloxacin 14, ciprofloxacin 15, and ofloxacin 16), p-aminosalicylic acid 17, D-cycloserine 18 and less-effective secondline antituberculosis drugs like thioamides (e.g. ethionamide 19 and prothionamide 20), terizidone 21. These are only used to treat tuberculosis that is resistant to first line therapy i.e., for extensively drug-resistant tuberculosis (XDR-TB) or multidrug-resistant tuberculosis (MDR-TB) [1,2]. Third-line drugs (22-34) include the entities that may be useful, but have unproven or doubtful efficacy such as rifabutin, clarithromycin, linezolid, thioacetazone, thioridazine, bedaquiline, etc (Fig. 2c). Thus, the third-line drugs are either not very effective (e.g., clarithromycin) or their efficacy has not been proven yet (e.g., linezolid, R207910). Rifabutin is although found to be effective, but is not included in WHO list for most developing countries mainly because of its pharmaco economic factor [1]. In addition to these classes of antitubercolosis drugs, the pipeline drugs (35-46) for the possible treatment of tuberculosis are depicted in Fig. 2d. Existing drug and new chemical entities having promising antitubercular activities with their mode of action are depicted in Table 1 [84e124].

4. Resistance to current antimycobacterial agents The toxicity and serious side effects of second line drugs despite their limited use for the treatment of MDR-TB and XDR-TB, the most M. Tb resistance is attributed to the spontaneous mutation to the targeted protein that interfere the binding site of used drugs [125]. Drug resistant TB is defined as the condition whentuberculosis infection does not respond or resistant to one or more of antimycobacterial drugs. Resistance may develop due to so many factors such as failure to follow TB regimen or inadequate TB treatment or improper diagnosis. Another important point which

indicates for the development of resistant TB was transmission of resistant strain of tuberculosis from one person to another [126]. As per WHO survey, India, China and Russia are the prominent having the cases of resistant TB (MDR/XDR) comprises 45% of total world's population [127]. 4.1. Multi drug resistance tuberculosis (MDR-TB) Worldwide WHO survey reports shows 10% TB cases out of 7,00,000 treated with high quality regimen and this regimen was based on individualized in vitro drug susceptibility test [128]. MDRTB was characterized by resistance of Mycobacteria to isoniazid and rifampicin, commonly used regimen for tuberculosis [129]. MDR-TB was less responsive to six-month regimen and clinicians move the regimen for two or more years with more expensive drugs [130,131]. Xpert M. Tb/RIF assay is a diagnostic tool used for diagnosis of tuberculosis and rifampicin resistance within 2 h of test [132,133]. Currently, MDR-TB was treated with four second-line of antimycobacterial drugs under the supervision of DOT program and the total duration of treatment is 20e24 months in case of no history of MDR-TB and 28e30 months for previously detected MDR-TB. 4.2. Extensively drug resistant tuberculosis (XDR-TB) Extensively drug resistant tuberculosis is defined as resistance developed by Mycobacteria for isoniazid, rifampicin, fluoroquinolones and amikacin or kanamycin or capreomycin injectables [134]. In some cases; treatment of XDR-TB involves third line of antimycobacterial drugs that has more side effects and cost of treatment. 4.3. Totally drug resistant tuberculosis (TDR-TB) This is also known as Extremly Drug Resistant Tuberculosis (XXDR-TB), which is resistant to all first line as well as all second

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509

Fig. 2. (continued).

line drugs. After first resistance report in 2007, the increasing rate of resistant tuberculosis i.e. (MDR-TB; XDR-TB) leads to new form of total drug resistant tuberculosis, which is a major concern for public health as it indicates towards regimen failure [135]. 5. Novel antituberculosis drugs in pipeline From last few years, there is an increase in drug discovery and development of antimycobacterial agents. There is number of lead molecules for optimization, preclinical, and clinical trials (phase-II and III trials) but in phase-I trial, loopholes needs to be filled for proper screening of molecules and further advancement [136]. Effect of existing antitubercular drugs on tubercle bacilli and

physiological changes in tubercle bacilli are depicted in Fig. 3. Quinolone derivatives such as fluoroquinolones now-a-days are the established scaffold for various bacterial infections and successfully included in regimen but there is still a need to refurbish these moieties for development of antitubercular drugs for resistant strains [137,138]. New imidazooxazole derivatives Delamanid (OPC67683) and pretomanid-moxifloxacin-pyrazinamide (PA-824) are in phase-III trial and their metabolism from prodrug to active drug depends on F420-dezazaflavin-dependent nitroreductase found in Mycobacteria. Des-nitroimidazole molecule generates nitric oxide that leads to inhibition of anaerobic activity [139,140]. PA-824 was effective against both active and latent tubercular infection and

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Fig. 2. (continued).

reduces the period of regimen [141]. Delamanid acts by inhibiting mycolic acid synthesis and increased sputum production in resistant tuberculosis [142,143]. In combination with other antimycobacterial agents delamanid has shown its effectiveness with acceptable toxicity [144]. SQ-109 is under clinical phase-II trial and found active against both MDR-TB and XDR-TB (Fig. 4) [145,146]. Chemically, it is 1,2ethylenediamine {N-(2-adamantyl)-N-[(2E)-3,7 dimethyl octa-2,6dienyl] ethane-1,2-diamine} found after the screening of around 63,000 entities having skeleton similar to ethambutol (1,2ethylenediamine). SQ-109 is lead molecule for trials after screening to search new molecule for TB with more efficacy and low toxicity. Its pharmacological parameters were found different when compared to ethambutol as it targets MmpL3 transporter system, which enables movement of trehalose monomycolate into bacterial cell wall, and interfere with synthesis of mycolic acid [147]. Urea derivatives were in lead optimization stage, which also targets MmpL3 transporter and appear a novel target for antimycobacterial discovery and development. Rifamycin analogue named Rifapentine is more potent than rifampicin and acts by binding to RNA polymerase (b-subunit) in Mycobacteria [148]. In vitro and in vivo studies of rifapentine against M. tuberculosis reported MIC 0.02e0.06 mg/mL [149]. Clinically rifapentine was used with isoniazid once weekly against latent

tuberculosis for 3 months and 2 months for active tuberculosis at the dose of 600 mg twice weekly in intensive regimen and once weekly for maintenance phase as approved by USFDA [150,151]. Inhalational dosage in animals produced a good result as tubercle clearance is better and orally it might cure active as well as latent tuberculosis within 3 months. Clinical trial based on these preclinical data was not satisfactory and hence needs more concern [152]. Since last four decades, there is no affirmative result in the field of antimycobacterial drug discovery. However, in 2012 USFDA approved a new quinoline analogue Bedaquiline (TMC-207) for the cure of MDR-TB and now days it is in phase-III trials of drug approval. It inhibits ATP synthase in active and dormant stage of Mycobacteria. Human mitochondrial ATP synthase has 20,000 fold less sensitive compared to Mycobacteria ATP synthase to diarylquinoline, therefore this target is important for future implications of antimycobacterial agents [153]. During drug discovery, scientist analyzed whole genome of M. tuberculosis and M. smegmatis to find mutant gene for resistance development and hence found atpE gene encodes for ATP synthase [154,155]. QT prolongation is noticed adverse effect of bedaquiline but it effects against MDR-TB, XDR-TB and TDR-TB leads to a new addition of armor in antimycobacterial class [155]. Another semisynthetic arrangement of spectinomycin analogues (47) (Fig. 5) with particular ribosomal restraint and slender

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

O

F O N HO

N F

OH

O

N

O

H N

N H

O

511

N

N NO2

N

O

O F3CO

36 (SQ 109)

35(AZD 5847) O

O

F

37 (TBA 354)

HO

COOH

HN H2 N HO HO

O

N

N

O

OH

O

NH2

OH O

O

N

N

N

F

N C4H9

N H

N OCF3

N

OMe

43 (TBI 166)

N

NO2

N

N N H

O NH2

O

O

N

S

N

N

F3C

N

F3C

NH O O HN

O

O

S

N

N H

O

42 (SQ 641)

NO2 N

O

40 (Q 203)

38 (CPZEN 45)

O

N

OH

HO O

O

O

Cl

H N

O

41 (SQ 609)

39 (DC 159a)

O

OCF3

N

N OMe

O

O

O S

O S N

NH O

NH O

OMe

45 (BTZ 043)

44 (PBTZ 169)

46 (TCA 1)

Fig. 2. (continued).

range antitubercular action had been produced [156]. On various murine infectious models, these spectinamides were all around endured, essentially diminished lung mycobacterial load and expanded survival. Further studies suggested lack of cross resistance with existing antimycobacterial activity against multi-drug resistant (MDR) and extensively drug resistant tuberculosis (XDR). Their powerful hostile to tubercular properties is the basic alteration to avoid the Rv1258c efflux pump, which is controlled in MDR strains and is embroiled in macrophage actuated drug resilience. Synthetic changes to antimicrobial drugs results in newer treatment against intrinsic pump mediated resistance and led to explore pathway of the drug discovery and development for tuberculosis [156]. BTZ043 (45) is chemically known as 2-[(2S) 2-methyl-1,4-dioxa8-azaspiro[4.5]dec-8-yl]-8-nitro-6-trifluoromethyl-4-H-1,3benzothiazin-4-one which efficiently prevents the M. Tb cell wall synthesis by inhibiting the DprE1, essential for the synthesis of Darabinofuranose, a part of arabinogalactan and arabinomannan [157]. BTZ043 shows its potency against all M. Tb strains especially to clinical isolates from MDR and XDR patients. An in vitro study indicates MIC ranges between ~0.1e80 ng/mL and 1e30 ng/mL against M. tuberculosis. In vivo study of BTZ043 shows superior activity to isoniazid in mouse models for the duration of 2 months or more. Further toxicological studies shows that, BTZ043 was non toxic up to the dose of 180 mg/kg in rodents and have no action with cytochrome enzymes or hERG channel. As per OECD

guidelines, genotoxicity, mutagenicity and carcinogenicity of BTZ043 were also studied and implicate negative results proving its stability as well as safety profile [157]. 6. Common molecular targets for antimycobacterial agents Antimycobacterial agents have bactericidal as well as bacteriostatic properties. The former one inhibits the M.TB, whereas the later one averts the growth of M.TB. Various molecular targets are well-known for the individual existing antitubercular drugs. The targets decided for novel lead identification is specific to avert transfer of mutated gene from one generation to another. The novel molecule should active against throughout the lifecycle of M.TB [158]. Inside and outside of mammalian cells; different biosynthetic pathway was included for antitubercular drugs viz. interruption of bacterial protein synthesis, cell wall synthesis and nucleic acid synthesis (Fig. 6). Drug discovery and development of lead molecule focused on specific targets, which include both classes i.e. bactericidal and bacteriostatic. Lots of research was going on but until date, no natural lead was discovered with safety and potency profile. Apart from these, we are enlisting various molecular targets for antimycobacterial agents [159]. 6.1. Protein synthesis Generally, antimycobacterial leads target protein synthesis as it

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Table 1 List of existing and pipeline drugs useful for the treatment of tuberculosis. S Drug No.

Origin

Chemical Class

First Line of Antitubercular Drugs (Orally) 1. Isoniazid (1) Synthetic Isonicotinic acid analogue 2. 3.

Ethambutol (2) Pyrazinamide (3)

4.

Rifampicin (4)

Synthetic Synthetic

Natural/ Semi synthetic 5. Rifabutin (5) Semi synthetic 6. Rifapentine (6) Semi synthetic Second Line of Antitubercular Drugs Injectables Aminoglycosides 7. Streptomycin (7) Natural

Amino-alcohol derivative Pyrazinecarboxamide derivative Rifamycin derivative

Ansamycin derivative Rifamycin derivative

MIC (mg/mL)

Mechanism of action

0.01e0.20 mg/mL

Target gene involved

Inhibits mycolic acid synthesis, affect DNA, lipids and carbohydrates Arabinogalactanbiosynhesis inhibition 1-5 mg/mL 20-100 mg/mL Targets membrane energy metabolism; membrane transport breakage 0.05e0.50 (0.486) RNA synthesis inhibition, target NA polymerase mg/mL b sub unit

katG, inhA, ndh [84]

0.015e0.125 mg/ mL 0.03e0.06 mg/mL

RNA synthesis

rpoB (Rv0667) [86]

RNA synthesis

rpoB(Rv0667) [86]

rpsL, rrs [84] rrs (M.Tb 000019) [87]

Aminoglycosides analogues 2e8 mg/mL

embCAB [84] pncA [85] rpoB [84]

Semi synthetic Natural

Aminoglycoside derivative

0.12e0.25 mg/mL

S12 and 16S rRNA components of 30S ribosomal subunit Protein synthesis

Aminoglycosides

1-2 mg/mL

Inhibition of protein synthesis

rrs (16SrRNA) [88]

Natural

Aminoglycosides

1.25e2.25 mg/mL

Inhibition of protein synthesis

11. Viomycin (11) Synthetic Oral and injectable fluoroquinolones 12. Levofloxacin (12) Synthetic

Tuberactinomycins

4-8 mg/mL

Inhibition of protein synthesis

(rrs) 16SrRNA, 50S ribosome, rRNAmethyltransferase (TlyA) [89] vph (70S tRNA) [89]

Ofloxacin L-isomer

0.5e0.75 mg/mL

DNA replication and transcription

13. Moxifloxacin (13)

Synthetic

Quinolone analogue

1.0 mg/mL

DNA replication and transcription

14. Gatifloxacin (14)

Synthetic

Fluoroquinolone derivative 1.0 mg/mL

DNA replication and transcription

15. Ciprofloxacin (15)

Synthetic

Fluoroquinolone analogue

0.125e2 mg/mL

DNA replication and transcription

16. Ofloxacin (16)

Synthetic

Fluoroquinolone analogue

0.125e2 mg/mL

DNA replication and transcription

Synthetic

1-8 mg/mL 1.2e8 mg/mL

Inhibition of folate pathway and mycobactin genesis D-Alanine metabolism

8.

Amikacin (8)

9. Kanamycin (9) Injectables Polypeptides 10. Capreomycin (10)

gyrB (Rv0005); gyrA (Rv0006) [90] gyrB(Rv0005); gyrA(Rv0006). [91,92] gyrB(Rv0005); gyrA(Rv0006) [91,93] gyrB(Rv0005); gyrA(Rv0006) [91,94] gyrB(Rv0005); gyrA(Rv0006) [91,94]

Oral Second line drugs 16. Para amino salicylic acid (17) 17. D-Cycloserine (18)

Natural

Para aminobenzoic acid derivative Amino acid derivative

18. Ethionamide (19)

Synthetic

Nicotinamide derivative

0.6e2.5 mg/mL

Inhibition of mycolic acid synthesis

19. Prothionamide (20) 20. Terizidone (21)

Synthetic Synthetic

Thiomide derivative Analogue of cycloserine

0.3e1.2 mg/mL 8-32 mg/mL

Cell wall Peptidoglycan synthesis

0.1 mg/mL 0.5 mg/mL

Cell wall Protein synthesis

0.5 mg/mL & 0.23 e0.84 mM 10 mg/mL & 0.23 e0.84 mM 0.16 mg/mL

Peptidoglycan Synthesis

Peptidoglycan synthesis

pbpB(Rv2163c); blaC(Rv2068c) [103] ponA1 (Rv0050); blaC (Rv2068c) [104] pbpB, ftsI (Rv2163c) [105]

1 mg/mL

Protein synthesis

rplV (Rv0706) [106]

21. Thioacetazone (30) Synthetic Thio-semicarbazone 22. Linezolid (31) Synthetic Oxazolidienone analogue Third Line Antitubercular Drugs (MDR/XDR) 23. Meropenem (22) and Semi Carbapenem derivative Clavulanate (23) synthetic 24. Amoxicillin (24) and Semi Penicillin derivatives Clavulanate (23) synthetic 25. Imipenem SemiThienamycin analogue and Cilastatin (25, 27) synthetic 26. Clarithromycin (26) Semi Macrolide analogue synthetic 27. Clofazimine (28) Synthetic Riminophenazine analogue 28. Bedaquiline (29) Synthetic Diarylquinoline analogue 29. Pretomanid (32) Synthetic Nitroimidazole analogue

Peptidoglycan synthesis

thyA(Thymidylate synthase) [95] alr(Rv3423c); ddlA(Rv2981c) [96,97] inhA(Acyl carrier protein reductase) [84] inhA(Rv1484) [98] alr (Rv3423c); ddlA (Rv2981c) [99] cmaA2(Rv0503c) [100] rplC(Rv0701) [101,102]

Oxazolidienone analogue Dihydro-nitroimidazooxazole derivative

0.12e0.24 mg/mL Probably membrane transport. 0.063 mg/mL Oxidative phosphorylation 0.015e0.25 mg/mL Probably targeting cell wall, and causing respiratory poisoning 0.5e4 mg/mL Protein synthesis 0.006e0.024 mg/ Inhibiting mycolic acid synthesis mL

rv0678 [107] atpE (Rv1305) [108] Target gene is not yet known [109] rplC(Rv0701) [110,111] Rv3547 [112]

Antitubercular drugs in pipeline 32. AZD-5847 (35) Synthetic 33. SQ109 (36) Synthetic 34. TBA-354 (37) Synthetic

Oxazolidienone analogue 1,2-ethylenediamine Nitroimidazole derivative

0.25e1.0 mg/mL 0.78 mg/mL 0.34 mg/mL

rplC(Rv0701) [113] mmpl3(Rv0206c) [114] Target gene is not yet known [115]

35. CPZEN-45 (38)

Caprazamycin analogue

1.56 mg/mL

30. Sutezolid (33) 31. Delamanid (34)

Synthetic Synthetic

Natural/ Semi synthetic

Protein synthesis Cell wall Probably inhibiting cell wall synthesis, and causing respiratory poisoning Cell wall

wecA, rfe (Rv1302) [116]

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513

Table 1 (continued ) S Drug No.

Origin

Chemical Class

36. DC-159a (39)

Synthetic

37. Q203 (40) 38. SQ609 (41)

MIC (mg/mL)

Mechanism of action

Target gene involved

Fluroquinolones derivative 0.5 mg/mL

DNA replication and transcription

Synthetic Synthetic

Imidazopyridine amide Dipiperidine analogue

2.7 nM 4 mg/mL

Oxidative phosphorylation Probably cell wall biosynthesis

39. SQ641 (42) 40. TBI-166 (43)

Synthetic Synthetic

Capreomycin analogue Clofazimine analogue

0.12e0.28 mg/mL 0.016 mg/mL

Cell wall Membrane transport

41. PBTZ-169 (44)

Synthetic

42. BTZ043 (45)

Synthetic

43. TCA-1 (46)

Synthetic

Piperazinobenzothiazinone 0.0003 mg/mL derivative Piperazinobenzothiazinone 0.001 mg/mL derivative Benzothiazone analogue 0.01e0.19 mg/mL (biofilm media)

gyrB(Rv0005); gyrA(Rv0006) [117] qcrB(Rv2196) [118] Target gene is not yet known [119] mraY(Rv2156c) [120] Target gene is not yet known [121] DprE1(Rv3790) [122]

involves RNA and DNA, the nuclear elements [160,161]. Many existing drugs such as chloramphenicol, tetracyclines and others are potent inhibitor of protein synthesis but lack antitubercular activity. Streptomycin, aminoglycoside analogue inhibits protein synthesis and disrupts their metabolism [162,163].

6.2. Nucleic acids biosynthesis and DNA gyrase Tetrahydrofolate reductase is an enzyme involved in folic acid synthesis, which is a rational target for antitubercular drugs. PAS, sulphonamides inhibits tetrahydrofolate biosynthesis and block the synthesis of purine and pyrimidine, which is essential component of nucleic acid synthesis. DNA gyrase is also a target enzyme for antimycobacterial leads as it was involved in negative supercoiling of dsDNA and it keen interest of researcher for novel molecule discovery [164e166]. Fluoroquinolones such as moxifloxacin, gatifloxacin are the inhibitor of DNA gyrase and exist as good antitubercular drugs in combination with other TB drugs [167,168].

Fig. 3. Effect of antitubercular drugs on tubercle bacilli and physiological changes in tubercle bacilli.

Inhibits DprE1, an enzyme essential for the biosynthesis of key cell wall components Inhibits DprE1, an enzyme essential for the biosynthesis of key cell wall components Inhibits DprE1, an enzyme essential for the biosynthesis of key cell wall components

DprE1(Rv3790) [122] DprE1(Rv3790), katG, fdxA [123,124]

6.3. Nucleotide biosynthesis Nucleotide biosynthesis is an important link for discovery of new antitubercular drugs especially TB in HIV cases. Thymidine monophosphate kinase (dTMKase) has been indicated as molecular target to develop novel antimycobacterial drugs for TB in HIV cases, MDR-TB, XDR-TB [169,170]. dTMKase catalyzes phosphorylation of thymidine monophoshate (dTMP) to thymidine diphosphate (dTDP) which is also target of anti-HIV agent [171]. 6.4. Cell wall macromolecule biosynthesis The virulence of M. Tb is due to its cell wall, which is made up lipophilic mycolic acid, arabinogalactan, peptidoglycan and they are known to prevent entry of dyes and stains. Cell wall helps M. Tb to maintain its viability during adverse conditions. Hence, cell wall synthesis is a molecular target to kill the bacteria as enzymes involved in the biosynthesis are pathogen specific and they do not have homologues in the mammalian system [172e174]. Recently, Xin-Shan Ye Research Group reported a really challenging synthesis of an arabinogalactan (that contains 92 sugars), which is an essential cell-wall component in M. tuberculosis and is responsible to causes tuberculosis [175]. Ethambutol works by blocking the polysaccharide's biosynthesis (Arabnosyl Transferase). This may lead to a novel tuberculosis vaccines and help a better understanding of the bacterium's mechanism of cell-wall biosynthesis for the drug development against tuberculosis. Furthermore, several sugar-based promising molecules having necessary structural features as possible inhibitors of the Mycobacterial cell wall biosynthesis has been developed through the extensive research contributed by Tripathi Group [176]. Based on promising antitubercular activities associated with D-cycloserine, a cyclic analogue of alanine known to inhibit enzymes alanine racemase and alanine synthatase involved in peptidoglycan biosynthesis, a series of glycosylated b-amino ester derived from Dglucose was developed, where one compound bearing long alkyl chain at amino group has shown promising activities against Mycobacterium tuberculosis, M. avium, M. fortuitum and M. smegmatis (upto MIC 3.12 mg/mL) [177]. Mechanisms of action invisaged to be the similar to D-cycloserine and also believe to reduce the toxicity as well improve the pharmacokinetic parameter by introducing the suitably protected glycogyl residue to the amino acid skeleton. Keeping in view the structure of ethambutol for targeting the inhibition of arabinosyl transferase involved in cell wall

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Fig. 4. Pipeline drugs for tuberculosis.

biosynthesis, a series of potent glycosyl amino alcohols [178,179] and N1, Nn-bis-glycosylated diamino alcohols [180] were reported by Tripathi et al., where few of them exhibited anti-TB activity with MIC 6.25e3.12 mg/mL in virulent and avirulent strains. These compounds were designed to mimic the enzyme D-alanine racemase and glycosyl transferase involved in the biosynthesis of essential cell wall peptidoglycan and arabinogalactan. Few phenyl cyclopropyl methanones exhibit promising anti-TB activities against M. tuberculosis H37Rv (MIC upto 3.125 mg/mL), where the most active one showed activity against MDR strains [181]. From a series of galactopyranosyl amino alcohols, a N1,Nn-bis-galactopyranosyl amino alcohol showed potent activity against M. tuberculosis H37Rv in vitro and also displayed activity in MDR TB [182]. The compound was found to be superior to ethambutol clinically used anti TB drug in in vitro screening.

6.5. Fatty acid biosynthesis Mycolic acid is important components of M. Tb cell wall. Initial precursor of mycolic acid synthesis leads to molecular targets for novel antimycobacterial drugs. M. tuberculosis has type-I and typeII of fatty acid synthase (FAS-I and FAS-II respectively) pathways. In

Fig. 5. Spectinomycin analogues.

FAS-I, C16eC26 fatty acids are synthesized, whereas in FAS-II these fatty acid chains are lengthened up to C56, which serves as precursors for mycolic acids [183]. FAS-I configuration is similar to mammalian system while FAS-II system is distinct to microbes. Mycocerosic acids are branched fatty acid generated from methyl malonyl-CoA, found in the cell wall of the M. Tb. The synthesis of the precursor methyl malonyl-CoA becomes a potential drug molecular target [184]. Thus, in the alarming circumstance of the emergence of MDR, EDR, and TDR tuberculosis, understanding of the biosynthesis of mycolic acids, a specific and major lipid component of the mycobacterial cell envelope is an essential for the survival of members of the genus Mycobacterium and is a critical determinant of the mycobacterial physiology [185]. This may open an opportunity for the development of mechanism based novel antimycobacterial agents and considered as an important molecular target. Antitubercular drug isoxyl and thioacetazone are well-known inhibitor of mycolic acid biosynthesis in M. bovis during a 6-hr exposure to 10 mg/mL [186,187].

6.6. Isocitrate lyase Isocitrate lyase (ICL) converts isocitrate into succinate during glyoxalate shunt, which helps in growth of bacteria and plants by using acetate and fatty acids. During study of M. Tb it is realized that level of isocitrate lyase (ICL) increases abruptly when it infects human macrophages [188e190]. The most noticeable point is that ICL is not required for viability of tubercle bacilli in any conditions either normal or hypoxic seen in M. Tb infected mice. ICL is required for persistence and virulence of tubercle bacilli and icl gene encodes for this resistance to antimycobacterial agents [191]. icl-1 and icl-2 deletion has marked effect on M. Tb infected mice and human macrophages and inhibition of intracellular replication. ICL inhibitors could be recognized as the new possible targets for tuberculosis.

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515

Fig. 6. Molecular targets for antimycobacterial drugs [158].

6.7. ATP biosynthesis ATP is essentially required for the proper functioning of bacterial cell and it requires ATP synthase which is an essential enzyme in the process by which M. tb generates energy in the form of ATP. For the novel discovery and development of antimycobacterials a possible target is ATP synthase which directly alter the pathway and led to inhibition of bacterial cell. Well-known antitubercular drug bedaquiline targets the ATP synthase enzyme of the TB mycobacteria. Among ATP synthase inhibitors a novel diarylquinoline R207910 inhibits M. tuberculosis [192,193]. In addition to the discovery of novel drug targets, the recent development in drug development against TB has also received considerable attention in the area of antibiotic development [193]. Recently, Andries et al. have made a promising new development in the front of antibiotic development, and have successfully identified a potent diarylquinoline, R207910 that inhibits both drug-sensitive and drug-resistant M. tuberculosis in vitro with MIC 0.06 mg/mL [194]. Further more, glycosyl uriedes [195,196], amines and amino alcohol [180], enaminones [197], and glycopeptide [198] reported by Tripathi et al. after virtual screening program using the modeled domain from MtuLigA with the potential to bind to this domain, have shown to inhibit Mtu LigA with several fold specificity compared to ATP-dependent ligases including for the human DNA ligase I. Bacterial growth inhibition studies using specific LigA deficient strains suggest that their observed antibacterial activity is most likely due to inhibition of the LigA in the bacteria [199,200]. 7. Assay and diagnostic tools for tuberculosis 7.1. Assays for tuberculosis In order to establish appropriate linkage in drug discovery and development, bioassays are the most significant steps. Several assays have been discussed against Mycobacterium sp. 7.1.1. In vivo assay for Mycobacterium Virulent strain, M. tuberculosis H37Rv (ATCC 27294) is representative strain for maximum clinical isolates to check drug

susceptibility profile. Another strain was also considered by the researchers working on drug development against tuberculosis, which is mainly due to its rapid growing capacity and saprophytic nature. M. smegmatis (ATCC 607), M. tuberculosis H37Ra (ATCC 25177) and M. bovis BCG (ATCC 35743) was extensively used in place of M. tuberculosis H37Rv for drug susceptibility investigation [201]. Mice models are very common for in vivo assay in which aerosol infection of susceptible strain Mycobacterium is given to mice. Mycobacteria invades lung and divide for a long period to enter in active phase and depending on experimental design, treatment protocol was followed. 7.1.2. In vitro assay for Mycobacterium Various in vitro assays were developed to investigate antimycobacterial activity. Mycobacterium is cultured in broth, agar based media, and it takes several weeks for growth. Non-virulent species such as M. avium, M. intracellulare, M. kansasii, M. fortuitum, M. smegmatis were used for the in vitro assay. 7.1.2.1. Macro and micro agar dilution. Test compounds in agar media are allowed for determining the MIC. Middelbrook 7H11 agar media was used to culture Mycobacterium, which is supplemented with albumin, dextrose, oleic acid and catalase [202]. Test samples are cultured with media at 1% v/v and then 20 mL added to standard 150 mm diameter petri dishes, 4 mL to 6-well microplates or 1.5 mL to 24 well microplates. In case of 96 well plates 100e200 mL medium is used for assay. At 37 C sample were incubated overnight and plates can be inverted for the remainder of the incubation period. This assay takes nearly 18e20 days to visualize growth of the colonies. 7.1.2.2. Radiorespirometry. The growth or inhibition of Mycobacteria can be determined within seven days by the oxidation of palmitic acid in Middelbrook 7H12 medium to 14CO2, which can be measured in BACTEC 460 instrument [203,204]. Some nonradiometric systems have also been developed where oxygen consumption and CO2 production is determined to quantify the growth inhibition by test compound [205e207].

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Table 2 Nucleic acid techniques enduring for the diagnosis of tuberculosis [229]. Technology

Developed at

Targets

Amplification reaction Active features

EasyNAT

Ustar Biotechnologies Lts,China Cepheid Inc., USA

IS6110

Cross priming amplification PCR

Xpert NEAT RPA

rpoB

Ionia Technologies Inc.,USA/Alere, USA TwistDx, UK/Alere, USA IS6110, IS1081

Truenat

Molbio diagnostics Pvt. Ltd., India VerePLEX Lab Veredus Laboratories, On Chip Singapore Genedrive Epistem Ltd, UK

Nicking enzyme amplification reaction Recombinase polymerase PCR

Ribonucleoside diphosphate 16S RNA

PCR

REP13E1 2 rpoB

PCR

Isothermal 39.8  C Miniaturized chip based Semi automated DNA extraction Microarray technology Rifampicin and issoniazid resistance plus nne non-TB mycobacteria Paper based DNAextraction technology Rifampicin resistance

Cl

Cl

OH

OH

OH NC

Cl H

H

H

OH

NC

O

O N H

N H

52

OH

OH

NC

NC

NH

OH

51

H

OH

NC

Field trails

N H

50

Cl

Released for research use

NC

OH

N H

N H 49

48

Proof of concept study published Released to market CEmark

NC

NC

N H

H

H

H

H

H

Status of product development

Isothermal 65. 8  C instrument free visual output Released to market instrument free DNA extraction Automated sample extraction resistance to Rifampicin CE mark and US FDA approval, WHO endorsement In development Isothermal 55.8  C e 59.8  C

54

53

OH

N H 55

Cl

Cl

H

H H H

H

NC

OH

OH

NC

NC

H

NC

H NH 57

56

N H

N H

NH

58

59

Cl

Cl

H

H

OH

OH NC

N H

H OH

NC OH

OH

N H

Cl

H

O

N H 61

60

NC OH

62 Cl

H

CN

HO

O N H 63

N H

CN

64

Fig. 7. Structure of Indole alkaloids having promising antitubercular activity.

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517

Fig. 8. Structure of Indole alkaloids (Contd.).

7.1.2.3. Micro broth dilution. Sample in 96 well microplates has benefits of low cost, small sample requirement and potential for automation. Middelbrook 7H9 broth was used with glycerol, catalase, oleic acid, dextrose, albumin for the culture of Mycobacteria and quantify by turbidity in liquid medium. Redox indicators such as Alamar blue determine the sensitivity and speed of assay. It can be visualized by colorimetric method i.e. at absorbance 570 nm or fluorimetrically at 530 nm [203,208]. Hence, this allows to perform high-throughput antimycobacterial screening assays in microplates using spectrophotometer or fluorimeter. 7.1.2.4. Agar diffusion. It is well diffusion assay used in antimicrobial evaluation of natural products and indicates merely inhibition of growth at any concentration with respect to concentration gradient. Area under zone of inhibition depends on rate of growth of microbes and rate of diffusion and size of zone indicates microbial susceptibility and resistance to specific antibiotics. Agar diffusion assay was not comfortable with mycobacteria as its cell wall is lipophilic and less permeable to non-polar compounds [209]. Less polar compounds diffuse more slowly compared to polar compounds resulting in small zone of inhibition indicating less potent antimicrobial activity.

reduce nitrate into nitrite can be measured by Griess method. Colorimetric estimation of resistance or susceptibility of M. tuberculosis to natural phytoconstituents or drug has been characterized in nitrate reductase method. This technique was introduced to detect differentiation of M. tuberculosis from other Mycobacteria sp. and evaluation of medicinal plant activity as antimycobacterials [213,214]. In this method, potassium nitrate is inoculated with culture media, which leads to reduction of nitrate into nitrite by using colorimetric technique. Compared to BACTEC 460 TB system, nitrate reductase assay (NRA) has 100% and 100% results for rifampicin, 75% and 98% for ethambutol, 95% and 83% for streptomycin, 97% and 96% for isoniazid, respectively. A fresh study suggests that NRA was directly used for sputum culture. Solis and his co-workers reported the sensitivity and specificity of NRA to Lowenstein Jensen medium for resistant M. Tb for isoniazid and

7.1.2.5. Reporter gene assay. Reporter genes are used as alternative to redox dyes in which plasmids are introduced to help in determination of bacterial viability by measuring level of luminescent or fluorescent proteins. Proteins such as green fluorescent protein [210,211] or red fluorescent protein also help in easy determination of growth and inhibition kinetics [212]. 7.1.2.6. Nitrate reductase assay. The capacity of M. tuberculosis to

Fig. 9. Structure of globospiramine.

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O

C6H5 F

N H

The detection of tuberculosis was attained using this technique in less than 20 min at 39  C in treated sputum with high specificity [227].

C3H7

C6H5 F

HN

O

N

75

N H

HN

76

N

S

O

Fig. 10. Structure of synthetic indole alkaloids active against tuberculosis.

rifampicin [215]. While Musa with his colleagues indicated the evaluation of NRA for drug susceptibility test for M. tuberculosis directly on smear positive sputum having acid-fast bacilli per microscopy field [216]. These studies reflect the importance of NRA for detection of resistant M. tuberculosis in sputum [217]. 7.1.2.7. Low oxygen bioassay. In present scenario, the available antimycobacterial drugs cannot efficiently eradicate M. tuberculosis as it has a power of dormancy that lead to failed or prolonged regimen for tuberculosis [218e220]. Dormant Mycobacterium appears to be an obstacle towards new drug discovery against latent tuberculosis [221]. In this assay, hypoxia or low oxygen environment is used to test non-replicating Mycobacteria [222,223]. Wayne's hypoxic model is designed for in vitro evaluation of novel compounds in spite of its low throughput capability [221,224]. Cho et al. has resolved luminescence based, high throughput, hypoxic recovery assay for novel compounds against non-replicating mycobacteria using M. Tb H37Rv strain containing plasmid acetamidase promoter propulsive a bacterial luciferase gene [121]. 7.1.3. Toxicity and selectivity Above-mentioned techniques help a lot in lead development from natural products and following to this cytotoxicity to cells should be investigated in order to confirm sample toxicity and selectivity for Mycobacteria. In discovery of new leads for antitubercular drug, selectivity and cell toxicity studies is key factor that led to determination of mycobacterial MIC, IC50 value and selectivity index [225,226]. 7.2. Diagnostic tools for tuberculosis Various techniques were used for the detection of tuberculosis infection. Major of these includes tuberculin test performed on skin and called as skin test. To diagnose the infection of M. tuberculosis, Interferon-Gamma Release Assays (IGRAs) are convenient tools refers to whole blood test. These tests principally trials the immune reactivity of individuals infected with tuberculosis, white blood cells released interferon-gamma (IFN-g) when mixed with antigens. Sputum investigation is also a confirmatory tool for M. tuberculosis. Radiography investigation of chest is also a technique to detect impact of tuberculosis. The nucleic acid amplification tests are also one of the useful diagnostic tools for TB detection. Below are enlisted techniques as a confirmatory tool for TB. 7.2.1. Sputum investigation Sputum is thick mucus expelled from bronchi or lungs through coughing for culture and detects the presence of any pathogenic microbes. In this, sputum of infected person was cultured in appropriate nutrient media. Cultured sample is incubated for 2e3 weeks and then observe for bacterial growth. If no bacterial growth were seen, it implies negative to bacterial invasion. If colony of bacteria was observed, it confirms the presence of M. tuberculosis.

7.2.2. Tuberculin test Tuberculin is injected under the skin of patient. In case of Mycobacterium infection, area around injection site becomes red affirming tuberculosis. In case of BCG vaccinated person, tuberculin test shows positive result so confirmatory test is further required. 7.2.3. Radiographic investigation Infected lungs from M. tuberculosis present the infiltrates and cavities in upper lungs or any other region. Hilar lymphadenopathy is also characterized in case of pulmonary TB. 7.2.4. Nucleic acid techniques The nucleic acid amplification tests (NAATs) were introduced in the year 1990s and termed as a new generation diagnostic tools for detection of new TB cases in hours. In previous, nucleic acid amplification test techniques were found less sensitive in compare to culture but more sensitive than microscopy and the ability to safely detection of TB cases without relocation to a specialist laboratory [228]. Recently, some nucleic acid amplification test products for tuberculosis have been shared in the market to acquire their reduced cost, results in short time duration and enhanced strength with expediency [229]. The development of NAAT techniques have been depicted inb Table 2. 8. Plants: a harry potter stick for tuberculosis Since long back, natural product have shown enormous potential to cure different disease and widely explore to achieve a potential lead for the drug development [230]. The urge for discovery and development of new novel antitubercular drugs leading from natural resources to decrease the burden of deadly disease also known as “Captain of Death”, is highlighted by the number of researchers [230e234]. Novel scaffolds for TB from natural origin has been well mentioned and focused on some potential molecules with promising efficacy [235]. WHO targeted 2035 for complete eradication (95%) of disease or death due to tuberculosis by the means of excellent regimen keeping in mind the safety, efficacy and duration of treatment [231]. Lot of reviews proved the efficacy and importance of natural products as lead molecule for many diseases [234e238]. Mdluli et al., mentioned notable compounds from natural source which were proven as useful lead for antitubercular agents [239]. Drug discovery for TB is not only confined to plants but it also encompasses the fungi, marine, mineral, bacterial and animal source of drug. The plethoras of compounds were embarked in literature with awesome inhibitory concentration to active as well as dormant M. Tb [240e242]. Apart from number of ongoing projects in the field of natural product inspired antimycobacterial drug discovery and development, there were some notable reasons listed below, which lead to failure of novel therapeutic compounds as antimycobacterial agents: a) Structural complexity of natural product compounds, b) Low yield of active moiety from natural source,

Fig. 11. Structure of thiadiazolylhydrazones derivatives.

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Fig. 12. Structure of cyclohepta[b]indoles analogues.

c) Absence of precis raw data from academic research d) Sometimes false data provided by researchers on the name of drug development, e) Evaluating the safety profile of drug without interfering with other pathway, f) Drug-drug interactions, g) Optimization of dose for its antimycobacterial activity. Furthermore, the available literature has no sign on the safety profile of isolated compounds as shown by means of the selectivity index (SI); therefore there is an increased demand to examine the toxicological profile of purified and semi-purified compounds. This could be a rough assignment to meet the mentioned problems without improved funding for antitubercular drug discovery and development pipeline via good-coordinated global efforts. Even though combinatorial chemistry continues to be key factor in the drug development process for antimycobacterials, it is remarkable that the inclination toward the synthesis of multifaceted natural-product database has continued. To researchers, a multidisciplinary trials to drug discovery, concerning the generation of efficacious novel molecular variety from natural sources, shared with total and combinatorial synthetic procedure and including the management of biosynthetic pathways, will persist to afford the best explanation to the current output crisis facing the scientific society engaged in drug discovery and development. Antitubercular drug discovery and development from natural sources need to overcome various hurdles such as finding efficacious lead within limits of safety profile and identify the hits with preclinical stages of drug discovery. Another major challenge is to characterized novel entities for de novo structure elucidation. To fasten the drug discovery and development program for TB, we need an upgraded technology with high-throughput screening (HTS) of natural product leads [243,244]. In this review, the previously mentioned bottlenecks are assessed with different points and focus on scientific tasks to overcome in drug discovery and development program for antitubercular drugs. Hereafter, we emphasize on the recent trends in the field of mycobacteriology specifically by providing different methods available for diagnosis, assay, available treatments, possible targets and effective antimycobacterial alkaloids and their synthetic analogues to justify role of phytoconstituents in the treatment of tuberculosis.

range of pharmacological activities [245]. Indomethacin, strychnine and many others alkaloids are the well-known representative examples to justify the effectiveness of indole alkaloids for their antimycobacterial efficacy. Blue Green algae contain several secondary metabolites having potential antimycobacterial activity. All the isolated alkaloids were screened for their activities against tuberculosis, where many of them showed significant biological efficacy and may be considered lead molecule for the treatment of tuberculosis [246]. Four new indole alkaloids, including Ambiguine K (48), Ambiguine L (49), Ambiguine M (50), and Ambiguine N (51) were isolated from Fischerella ambigua, where they showed significant inhibitory activity against M. tuberculosis (H37Rv) with MIC of 6.6, 11.5, 7.5, and 46.7 mM, respectively. Six different isonitrile analogues of indole alkaloids were showed moderate action on M. tuberculosis. These are ambiguine A isonitrile (52), ambiguine C isonitrile (53), ambiguine E isonitrile (54), ambiguine I isonitrile (55), hapalindole G (56), and hapalindole H (57) with MIC value of 46.7,7.0, 21.0, 13.1, 6.8, and 58.8 mM, respectively [247]. Later on, new ambiguine isonitriles K, L, M, N, and O (58-62) were found efficacious against Mycobacterium. Ambiguine K isonitrile (58) possess the potent activity with MIC value of 2.8 mg/mL against M. tuberculosis H37Rv strain. Ambiguine L (59), ambiguine M (60) and ambiguine N (61) have moderate effect against M. tuberculosis with MIC of 4.5, 3.3 and 10.9 mg/mL respectively [247]. In further investigation, F. ambigua has been successfully isolated and reported in addition to new indole alkaloids, fischambiguine B (63), ambiguine G isonitrile (64) which showed significant inhibition to H37Rv M. tuberculosis at MIC of 2.0 and 53.7 mM, respectively. The former one has an IC50 value of 128 mM, which makes it potent antimycobacterial agent (Fig. 7) [247]. Likewise, six indole type alkaloids viz. (þ)-manilamine, Nmethyl angusilobine, 19,20- (E) vallesamine, angustilobine B Noxide, 20(S)-tubotaiwine, 6,7-seco-angustilobine (65-70) were isolated from the methanol leaves extract of Alstonia scholar isthat displayed 50e89% inhibition of M. tuberculosis H37Rv using an MIC of 50 mg/mL [248]. The root of Tabernaemontana elegans possesses indole alkaloids voacangine (71) and dregamine (72) with MIC value of 128e256 mg/ mL against Mycobacterium sp [249]. Another source for indole analogue was Chaetomium globosum, which was reported with echinuline (73) moderately active against M. tuberculosis with MIC value of 169.9 mg/mL (Fig. 8) [250]. Voacanga globosa was discovered with spiroindole alkaloid named globospiramine (74) (Fig. 9). This compound has potent activity against M. tuberculosis H37Rv with MIC value of 4e5.2 mg/ mL [251]. The antimycobacterial activity of globospiramine is depends on the presence or absence of unoxidized C-20 and hydroxyl group at C-3 on spriobisindole moiety [251]. In sight of new synthetic indole derivative Cihan et al. synthesized hydrazone (75) and spirothiazolidinone analogue (76) of 5fluoro-3-phenyl-1H-indole scaffold and evaluated for its antimycobacterial efficacy (Fig. 10). They found the efficacy of these synthesized derivatives against the M. tuberculosis H37Rv with the

9. Alkaloids with significant antimycobacterial activity 9.1. Indole alkaloids Indole-based heterocyclic compounds are identified as the 3rd most common skeleton found in drugs known to exhibit wide

519

Fig. 13. Structure of pentacyclic indole alkaloid.

520

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Fig. 17. Structure of celastramycin A. Fig. 14. Structure of Pyrrole alkaloids.

Fig. 18. Structure of banegasine. Fig. 15. Structure of vermelhotin.

MIC value of 6.25 mg/mL. The methyl or propyl group on 8th position of spiro ring is responsible for its potency as antimycobacterial agent [252]. Further studies revealed that thiadiazolylhydrazones derivatives (cyclic analogues) i.e. indole-3-carboxaldehyde 1,3,4-thiadiazol-2yl-hydrazone has potent activity against M. bovis BCG with inhibitory concentration of 7.81 mg/mL (77) (Fig. 11). Absitence of antimycobacterial activity of indole ring was resulted due to substitution of bromine at C-5 position of ring. The main possible reason for loss of antimycobacterial activity was lipophilicity and size of bromine which may cause steric hindrance [253]. Heterocyclic compounds such as pyrazolo- (78), isoxazolo- (79), pyrimido- (80) and mercaptopyrimido- (81) substitution at cyclohepta[b]indoles resulted in compounds with potent activity against M. tuberculosis (Fig. 12). These derivatives were synthesized by cyclocondesation of 7-hydroxymethylene-7, 8, 9, 10tetrahydrocyclohepta[b]indol-6(5H)-ones using nucleophiles. Resazurin microtitre assay was used to evaluate the in vitro antimycobacterial activity of these substituated analogues and the chloro substituated compound showed maximum potency against M. tuberculosis H37Rv with MIC 3.12 mg/mL [254]. Pentacyclic indole alkaloids were evaluated for their antitubercular activites although biological activities were not increased than molecules having simple heterocyclic core. Ibogaine (82) and voacangine (83) isolated from Tabernaemontana citrifolia found to inhibit the Mycobacterium sp. with MIC values of 50e100 mg/mL (Fig. 13) [255,256].

against M. tuberculosis with MIC value of 6.1 and 64 mg/mL, respectively [257,258]. The compound, Vermelhotin (86) obtained during the investigation of Hintonia latiflora fungus, displayed significant antimycobacterial activity against M. tuberculosis H37Rv with an MIC value of 3.1 mg/mL (Fig. 15) [134,259]. Solsodomine A (87), potent antimycobacterial natural compound was isolated from Solanum sodomaeum. This alkaloid ceased the growth of M. intracellulare with minimum inhibition concentration of 10.0 mg/mL [260]. Nitropyrrole analogue, pyrrolnitrin (88) did not lead to any significant improvement in the MIC values of 4e16 mg/mL against M. tuberculosis, M. avium and M. smegmatis (Fig. 16) [261]. Based on potent anitubercular activities with imidazole skeleton [260], a series of synthetic analogues of imidazole with spacer as

9.2. Pyrrole alkaloids Carribean sponge Prosuberites laughlini possesses two brominecontaining pyrrole as hymenidin (84) and monobromo isophakellin (85) (Fig. 14). These compounds have shown moderate potency

Fig. 16. Structure of solsodomine A and pyrrolnitrin.

Fig. 19. Structure of Diarylpyrrole alkaloids.

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521

Fig. 20. Structure of BM-212. Fig. 23. Structure of Dimeric alkaloid.

Fig. 21. Structure of diarylpyrrole derivatives.

well without spacer has been developed [262]. Futhermore, a series of glycosylated aminoester having imidazole were achieved and screened for antitubercular efficacy [263]. Some imidazle-based compounds have shown interesting antitubercular activity [262]. A dichloropyrrole alkaloid was isolated through fermentation of Streptomyces strain with broad-spectrum antimycobacterial activity. Celastramycin A (89) (Fig. 17) exhibited the MIC value of 0.05e3.1 mg/mL against M. vaccae, M. fortuitum, M. smegmatis

Fig. 22. Structure of cyclo-penta[b]fluorene ring type alkaloids.

strains [264]. Indian shrub named Adhatoda vasica possesses vasicine and its semi synthetic analogues bromhexine and ambroxol were found to inhibit M. tuberculosis. These alkaloids exhibited antimycbacterial activity with MIC value of 6e64 mg/mL [265]. Pyrrole analogue banegasine (90), isolated from zoobacterium Aristabacter necator possess antimycobacterial activity against M. smegmatis with MIC value of 0.5 mg/mL [23]. Similarly, another pyrrole analogue pyrrolnitrin (MIC 4e16 mg/mL) with banegasine showed potent activity against M. tuberculosis, M. smegmatis, and M. avium with inhibitory concentration of 0.075 mg/mL (Fig. 18) [261]. Three metabolites namly denigrins A-C (91-93) were isolated from the marine sponge Dendrilla nigra, displayed potent antimycobacterial activity against M. tuberculosis H37Rv with the MIC values of 16, 32 and 4 mg/mL, respectively (Fig. 19) [266]. Based on the structure and activity of denigrin A, a series of maleimide substituted derivatives were obtained by reacting anilines with maleic anhydride in presence of acetic anhydride and sodium acetate and developed molecules were evaluated for in vitro antitubercular activity against M. tuberculosis H37Rv using MABA method. Three of them e.g. PA4, PA8 and PA14 showed potent activity against M. tuberculosis H37Rv with MIC value of 6.25, 3.125, 3.125 mg/mL respectively [267]. Synthetic diarylpyrroles are well documented for antimycobacterial activity and among them BM- 212 (94) (Fig. 20) analogues shown promising efficacy against Mycobacterium with MIC value of 1.0 mg/mL. This is obvious to conclude that the presence of (thiomorpholine-4-yl) methyl at C-3 postition of 1, 5diarylpyrrole is responsible for the antitubercular activity [267]. Several diarylpyrrole derivatives such as novel analogues 95a, 95b, and 95c have most potent antitubercular activity with MIC value of 1, 0.4 and 0.5 mg/mL, respectively which was comparable to standard antimycobacterial isoniazid and Rifampicin. They are potent against intracellular M. tuberculosis with MIC value three times lesser than the standard one. Compounds 95a, 95b, 95c are very effective against other strains of Mycobacterium and resistant M. Tb [268,269]. Furthermore, synthesis of other analogues resulted in 95d-t compounds in which they shown activity against Mycobacterium as well as resistant strains. Compound 95 exert most effective inhibition against Mycobacterium 103471 with MIC value of 0.125 mg/mL similar to MIC of isoniazid. Other compounds 95d, 95 g, 95 l, 95 m, 95r, 95s have similar MIC to rifampicin i.e. 0.25 mg/ mL, whereas 95 k, 95p and streptomycin has similar MIC of 0.5 mg/ mL [267]. Compound 95t exhibits its antitubercular activity against M. tuberculosis CIP 103471, M. tuberculosis H37Rv ATCC 27294 and the rifampicin-resistant M. tuberculosis ATCC 35838 with MIC value of 0.25 mg/mL (Fig. 21) [270]. Three cyclopenta[b]fluorene type alkaloids, phomapyrrolidones A-C (96, 97, and 98) were obtained from the endophytic fungal strain Phoma sp. These compound were found to exhibit good to

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Fig. 24. Structure of Carbazole alkaloids having antitubercular activities.

Fig. 25. Structure of carbazole analogues isolated from bark of M. hirsutum.

significant antitubercular activity in blue assay with the MIC values of 20.1, 5.9 and 5.2 mg/mL, respectively (Fig. 22) [271]. Pyrrole-based dimeric alkaloid have shown promising efficacy against tuberculosis. For example, Trichoderma, a seed fungus (BCC 7579) possess hirsutellone F (99) alkaloid which exhibited antimycobacterial activity with MIC of 3.12 mg/mL (Fig. 23) [272].

the antimicrobial properties of 3-formyl-1-methoxycarbazole (100) (commonly known as murrayanine, which was isolated from the Murraya koenigii) commenced a strong interest of medicinal chemist and since then this skeleton have shown enormous potential in drug discovery and development due to their fascinating structural features and wide range of biological activities [273]. 7-Hydoxymukonal (101) was isolated from Clausena harmandiana, which inhibits the growth of M. tuberculosis (H37Ra) with MIC of 25 mg/mL [274]. Fluroclausine-A (102) and 7-hydroxy-heptaphylline (103) have been extracted from the air-dried roots of C. guillaumine and displayed week antimycobacterial activity with MIC value of 25 mg/mL (Fig. 24) [275]. Another carbazole alkaloids, such as rhizomes (104), 3-methoxycarbonyl carbazole (105), clauszoline J (106) and 2-hydroxy-3-formyl-7-methoxy-carbazole (101) were isolated from the roots and were shown moderate efficacy on M. tuberculosis with MIC value of 100, 50, 100, and 100 mg/ mL, respectively [276]. The carbazoles derivatives such as 107, 108, 109 and 110 were isolated from bark of M. hirsutum has shown potent antimycobacterial activity with MIC of 31.5, 14.3, 42.3, and 15.6 mg/mL, respectively (Fig. 25) [277].

9.3. Carbazole alkaloids 9.4. Indoloquinoline alkaloids About ninety years later the discovery of carbazole heterocycle, Cryptolepis sanguinolenta contains indoloquinoline alkaloids viz. cryptolepine (111), neocryptolepine (112), dimer biscryptolepine (113) which was have been found effective against M. fortuitum, a species alternative to M. tuberculosis with MIC value of 16 mg/mL, 31 mg/mL, 6.25 mg/mL, respectively (Fig. 26) [278,279]. Two canthin-6-one alkaloids (114 and 115) were isolated from Allium neapolitanum an ornamental flowering plant possess antimycobacterial activity against M. smegmatis and M. phlei (Fig. 27). They have shown moderate action with reported MIC value of 8e32 mg/mL. Interestingly, synthetic analogue of alkaloid 115 reported with increase in antimycobacterial activity eight folds with

Fig. 26. Structure of Indoloquinoline alkaloids.

Fig. 27. Structure of canthin-6-one alkaloid.

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Fig. 28. Structure of manzamine alkaloids.

MIC value of 2.0 mg/mL [280]. 9.5. Manzamine alkaloids Four manzamine alkaloids (-)-8-hydroxymanzamine A (116), (-)-manzamine F (117), manzamine A (118), and (þ)-8- hydroxymanzamine A (119) were tested against M. tuberculosis H37Rv. They exhibited MICs of 0.91, 12.5, 1.56, and 6.25 mg/mL, respectively [244,281]. Manazamine derivatives manazamine Y (120), mandomanazamine A (121) and mandomanazamine B (122) were isolated from Acanthostrongylophora sp. and showed potent activity against M. tuberculosis H37Rv with MICs of 1.9, 1.5 and 5.2 mg/mL respectively. The metabolite 6-hydroxymanzamine E (123) and 8hydroxymanzamine J (124), isolated from same species, exhibited an MIC of 0.4 mg/mL against M. tuberculosis H37Rv and an IC50 of 3.5 mg/mL against M. intracellulare (Fig. 28) [244,282,283].

4-Methoxy-2-phenylquinoline (125), graveolinine (126), and kokusagine (127) were isolated from Lunasia amara exhibited antitubercular activity against H37Rv strain and reported MIC of 16 mg/mL [286]. The quinoline alkaloids from Zanthoxylum wutaiense were reported g-fagarine (128) and dictamine (129). Both alkaloids showed MIC value of 30 mg/mL (Fig. 29) [287]. Based on antitubercular activity associated with quinoline scaffold, two novel series have been recently developed through conjugation of quinoline skeleton with chalcone as well pyrazoline motifs and tested for their antibacterial and anti-tubercular activities [288]. Some of them exhibited good to appreciable antibacterial activity against the tested bacterial strains. Two of them found to be the promising candidates exhibiting MIC 4 mg/mL

9.6. Quinoline alkaloids Several quinoline-based heterocyclic compounds have been explored to search out a lead against antituberculosis drug. This heterocyclic core placed important position in medicinal chemistry and several natural products possessing quinoline skeleton are well explored for their antitubercular potential. Representative examples include, Bedaquiline, the first FDA-approved new chemical entity to fight multidrug-resistant tuberculosis in the last forty years. Several modification on this drug were attempted to achieve the most promising one useful to fight against tuberculosis [284]. In order to increase the antitubercular efficacy, the quinoline ring was replaced with a naphthalene ring resulting to a new type of triarylbutanol skeleton [285].

Fig. 29. Structure of Quinoline alkaloids.

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Fig. 30. Structure of quinolines as antitubercular agent. Fig. 33. Structure of Bis-benzylisoquinoline alkaloids isolated from Tiliacora triandra.

Fig. 31. Structure of Quinolones alkaloids isolated from Evodia rutaecarpea.

against B. subtilis MTCC 121 and M. luteus MTCC 2470 and few conjugates displayed moderate anti-tubercular activity against both H37RV as well as RifR strains. The binding modes and effect of the C4 quinoline substitution on the activity was studied using computational techniques. Several quinoline derivatives, for example 3-benzyl-6-bromo-2methoxy quinolines were developed through molecular modelling techniques found to be active against M. tuberculosis H37Rv strain [289]. Some 7-chloro quinoline derivatives were effective against multi-drug resistant tuberculosis [290]. Considering mefloquine as the lead, a series of quinoline with some active pharmacophores such as hydrazones, ureas, thioureas and pyrazoles attached at the 4th position have been developed as anti-tubercular agents [291].

Fig. 32. Structure of isoquinoline alkaloids active against tuberculosis.

Interestingly, quinoline-based molecules having an isoxazole as a side chain was proven to be active against M. tuberculosis [292]. Investigation on Angostura bark (Galipea officinalis) established a series of six new alkaloids 130, 131, 132, 133, 134, and 135 which exhibited antimycobacterial activity against M. tuberculosis with MIC value of 6.25e50 mg/mL. The antitubercular activity was found due to the presence of quinoline ring and 4-methoxyl group. These alkaloids were present in ethanolic extract of G. officinalis (Fig. 30) [293] (see Fig. 31). A series of quinolone alkaloids i.e. 136, 137, 138, 139, and 140, isolated from Evodia rutaecarpea have shown good potency against M. tuberculosis. They inhibited the Mycobacteria at the MIC of 2e362 mg/mL (Fig. 32) [294].

9.7. Isoquinoline alkaloid Various alkaloids in solvent extracts of natural origin have shown moderate to strong potency against mycobacterial species. For this, alkaloids from leaves or other parts of plant were taken, purification and characterization of compound were followed by mycobacterial studies of these extract. In some cases like in the leaf of Justicia adhatoda, purification was done by crystallization. For that crude alkaloid were dissolved in the boiling methanol followed

Fig. 34. Structure of tetrandrine alkaloid.

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Fig. 35. Structure of ecteinascidin alkaloids.

by filtration and concentration until the alkaloids started crystallising out. Six different quinazoline alkaloids, for example, vasicoline, vasicolinone, vasicinone, vasicine, adhatodine and anisotine were successfully identified as lead molecules against tuberculosis [265]. Crude DCM-methanolic extract of the, Voacanga megacarpa, showed moderate inhibitory activity (MIC ¼ 64 mg/mL) against M. tuberculosis H37Rv [295e297]. Four isoquinoline alkaloids such as dioxoaporphine (141), ouregidione (142), oxoaporphine liriodenine (143), and oxostephanine (144) were isolated from CHCl3 extract of Pseuduvaria setosa. Out of four alkaloids, oxoaporphineliriodenine (143) was found to be the most active molecule against M. tuberculosis with an MIC of 12.5 mg/mL (Fig. 32) [298]. Bisbenzylisoquinoline alkaloid have been isolated from natural resources and evaluated for their antitubercular efficacy. For example, isoquinoline derivatives tiliacorinine (145), 2’- ortiliacorinine (146), and tiliacorine (147) (Fig. 33) were isolated from Tiliacora triandra and exhibited antimycobacterial activity against M. Tb with MIC value of 6.2, 3.1, and 3.1 mg/mL respectively [299]. Tetrandrine (148) (Fig. 34), isolated from Stephania tetrandra exhibited antimycobacterial activity in combination with isoniazid or ethambutol at the MIC value of 0.25e1.25 mg/mL by inhibiting drug efflux [300,301]. Ecteinascidin 743 (149) isolated from Caribbean ascidian Ecteinascidia turbinata was reported to exhibit antimycobacterial activity against M. avium with zone of inhibition at 10 mg/disc loading [302e304]. Another alkaloid ecteinascidin 770 (150) and ecteinascidin 786 (151) isolated from different species namely Ecteinascidia thurstoni native of Thailand owes antitubercular activity against M. tuberculosis H37Ra strain with MIC value of 0.1 and 1.6 mg/ mL, respectively (Fig. 35) [305]. Three aporphine alkaloids (152-154) (Fig. 36) were isolated from Colombian plants Ocotea macrophylla, exhibited the moderate

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antimycobacterial activity against the M. tuberculosis with the MIC values of 64, 128 and 4 mg/mL, respectively [306]. Similarly, an aporphine alkaloid, dicentrinone (155) was isolated from the Stephania dinklagei exhibited the moderate antimycobacterial activity with an MIC value of 50 mg/mL against M. tuberculosis H37Rv [307,308]. A novel antitubercular agent effective against M. TB (H37Ra) with MIC of 6.25 mg/mL, bidebiline E (dimericaporphine) (156), was isolated from the roots of P. cerasoides. Oxoaporphine alkaloids named liriodenine (157) and oxostephanine (158) obtained from Pseuduvaria setosa, exhibited antimycobacterial activity with MICs of 12.5 and 25 mg/mL, respectively [298]. A study of flowers of Goniothalamus laoticus revealed a known aporphine alkaloid (-)-nordicentrine (159), which showed activity against M. tuberculosis H37Ra with a MIC of 12.5 mg/mL (Fig. 36) [309]. Two benzophenanthridine alkaloid namely, decarine (160) and 6-acetonyldihydronitidine (161) were isolated from the plant Zanthoxylum capense exhibited significant antimycobacterial activity against M. tuberculosis H37Rv with the MIC values of 3.1 and 6.2 mg/ mL, respectively (Fig. 37) [310]. Extensive structure activity study revealed that the benzophenanthridine alkaloids nitidine, chelirubine and macarpine were potent inhibitor against M. tuberculosis H37Rv with MIC value of 12.5 mg/mL [311]. This is interesting to note that methoxy or methylene dioxy substitution in benzophenanthridine alkaloids plays a decisive role in the antimycobacterial activity. Furthermore, considering the antitubercular potency of alkaloids containing isoquinaline heterocyclic ring, a benzylisoquinoline alkaloids have also been evaluated to search a lead molecule suitable for drug development againd tuberculosis. Medicinal plant families such as Berberifaceae, Menispermaceae possess the active constituents, which are reported for their good antimycobacterial activities. Berberine (162), a potent antimicrobial alkaloid possesses antimycobacterial activity against M. smegmatis, and M. intracellulare with MIC value of 0.78e1.56 mg/mL. Berberine also inhibits M. tuberculosis with MIC value of 25 mg/mL (Fig. 38) [312e315]. Blood root also known as Sanguinaria canadensis, was reported with sanguinarine (163) and chelerythrine (164) (iminium salt), which has a better lipophilicity and active against M. Tb with MIC value of 24.5 and 14.3 mg/mL, respectively (Fig. 39) [316]. Few alkaloids which possess the good antimycobacterial activity were isolated from Duguetia species. For example, anonaine (165), xylopine (166), anolobine (167), and jatrorrhizine (168) exhibits potential inhibition against Mycobacterium species and observed MIC value with 12e50 mg/mL, 12e50 mg/mL, 6e25 mg/mL, <100 mg/ mL, respectively (Fig. 40) [317,318]. 9.8. Pyrrolo [2,1-b]quinazoline alkaloids Extracts from Boophone disticha herb gave three alkaloids (galanthamine, lycorine, and crinine) to treat TB [319]. Petroleum ether extracts of leaf of Arctotis auriculata resulted alkaloids with other phytochemicals and displayed MIC of 8.5 mg/mL against M. smegmatis. Antimycobacterial activity of leaf of Samanea saman was observed using radiospirometric BACTEC 460 TB assay method (two-fold dilution) [320]. The alcoholic extract of Samanea saman showed activity against M. tuberculosis at 50 mg/mL. Justicia adhatoda, also called as vasaka was investigated to have the potential antitubercular agents where a series of interesting quinazoline alkaloids were isolated which showed significant antimycobacterial activity. Six different quinazoline alkaloids, namely vasicoline (169), vasicolinone (170), vasicinone (171), vasicine (172), adhatodine (173) and anisotine (174) (Fig. 41) were extracted from the leaf of Justicia adhatoda, have shown to

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Fig. 36. Structure of Aporphine alkaloids.

Fig. 37. Structure of Benzophenanthridine alkaloids.

posses activity against M. tuberculosis [321]. Furthermore, in-silico investigation affirmed that these alkaloids hinder b-ketoacylacyltransporter protein synthase III (FabH), an enzyme required in the

first step of fatty acid biosynthesis, prompting poor cell wall development and vitality of bacilli [322]. Adhatoda vasica, which is traditionally used to cure colds, cough, and other respiratory disorders, possess antimycobacterial compounds like vasicine acetate (175) alongwith 2-acetyl benzylamine that inhibited both, sensitive and MDR strains of M. tuberculosis at MIC of 50 and 200 mg/mL, respectively [323]. Azaindoloquinazolinedione alkaloid, namely tryptanthrin (176) was isolated from Chinese Strobilanthes cusia and on nbiological screening showed active against sensitive and multiple resistant M. tuberculosis strains with MIC of 16e64 pg/mL in vitro (Fig. 41) [324]. 9.9. Cyclostelletamine alkaloids Cyclostelletamines alkaloids were isolated from sea sponge Pachychalina sp. namely cyclostelletamine A (177),

Fig. 38. Structure of berberine.

Fig. 39. Structure of sanguinarine and chelerythrine.

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8.0 mg/mL, respectively. SAR of these alkaloids indicates that the length of alkyl chain for the antitubercular activity i.e. smaller alkyl chain has excellent activity compared to larger one. Furthermore, synthetic analogues of cyclostelletamines i.e. cyclostelletamine G (183), cyclostelletamine H (184), cyclostelletamine I (185), cyclostelletamine J (186), and cyclostelletamine K (187) also possessed bactericidal effect against M. tuberculosis. The minimum inhibitory concentration for the compounds were 4.6, 9.3, 6.6, 5.3, 4.6 mg/mL, respectively (Fig. 42) [325]. 9.10. Pyridoacridone alkaloids

Fig. 40. Structure of miscellaneous alkaloids.

cyclostelletamine B (178), cyclostelletamine C (179), cyclostelletamine D (180), cyclostelletamine E (181), and cyclostelletamine F (182). These alkaloids showed significant activity against M. tuberculosis (H37Rv) with value of MIC 32.0, 4.0, 4.0, 8.0, 11.0 and

Sea squirts Lissoclinum notti and Diplosoma extracts showed the presence of ascididemin (188), diplamine (189), isodiplamine (190), lissoclinidine (191), kuanoniamine D (192) and shermilamine B (193), where these alkaloids known to inhibit M. tuberculosis growth with MIC value of 0.35, 17, 17, 17, 34 and 32 mM, respectively. The IC50 level of ascididemin is around 0.14 mM, which is highly toxic to Vero cells that make this molecule not suitable for further drug development (Fig. 43) [326]. Further investigation revealed two new marine products of ascididemin class, namely 11-hydroxyascididemin (194) and kuanoniamine A (195) (Fig. 44), which possess promising antitubercular activity against M. tuberculosis H37Rv with MIC value of >42 mM and 10.7 mM respectively [327,328]. Synthesis of tetracyclic pyrido[2,3,4-kl]acridin-6-one analogues

Fig. 41. Structure of pyrrolo [2,1-b]quinazoline-based antimycobacterial alkaloids isolated from plant extracts.

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Fig. 44. Structure of Pyridoacridone alkaloids (Contd.).

Fig. 42. Structure of Cyclostelletamine alkaloids.

(196, 197, 198, and 199) are also indicative of antimycobacterial activity as it resembles to the part of strucuture activity relationship of 11-hydroxyascididemin. These analogues have reported with minimum inhibitory concentration against M. tuberculosis H37Rv with values 9.0, 2.20, 0.34, and 1.5 mM respectively (Fig. 45) [329]. Interestingly, substitution on acridinones ring, such as thiophene (200), furan (201), 2,3,4-trisubstitued pyridine ring (202) resulted with potent antitubercular activity against Mycobacteria with MIC value of 0.58, 0.61, and 2.1 mM, respectively. Acridinone analogue 4-ethylthiopyrido[2,3,4-kl]acridin-6-one (203) was exerted most efficacious inhibition against Mycobacterium H37Rv with MIC value of 0.34 mM, which was nearby similar to ascididemin (Fig. 46) [329]. Based on the activity profile, a series of simple pyridylmethyl

O

O

N C6H4H3CS

N C6H4H3CS

N

O 196

197

O

O

N H2CH3CS

N H3CO

N

N 198

199

Fig. 45. Structure of synthetic tetracyclic pyrido[2,3,4-kl]acridin-6-one analogues.

amines have been developed and evaluated for their antitubercular activity profile. Few of them exhibited promising abtitubercular activity with MIC as low as MIC 1.56 mg/mL [330]. 9.11. Aza-anthraquinone alkaloids Cleistopholine (204) and 3-methoxy sampangine (205) from Cleistopholis patens and Sampangine (206) from Cananga odorata exhibited the potent activity against Mycobacterium sp. with MIC value of 12.5, 1.56 and 0.78 mg/mL, respectively [331,332]. Cleistopholine was also reported in D. vallicola and has same antimycobacterial activity (Fig. 47) [331,333]. In another research

Fig. 43. Structure of Pyridoacridone alkaloids.

Fig. 46. Structure of acridinone analogues.

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Fig. 47. Structure of aza-anthraquinone alkaloids.

Fig. 50. Structure of Alkamide type alkaloids.

and brachyamide B (211), and the isolated alkaloids 208-211 have exhibited moderate antitubercular activity against H37Ra strain with MIC value of 50, 25, 50, and 50 mg/mL respectively (Fig. 48) [335]. Furthermore, two alkyl amides namely pellitorine (212) and brachystamide B (213) were isolated from the same source Piper sarmentosum and possess moderate inhibitory activity against M. tuberculosis with MIC of 50 and 50 mg/mL, respectively (Fig. 49)

Fig. 48. Structure of pyrrolidine alkaloids isolated from Piper sarmentosum.

program, aza-anthraquinones alkaloid (207) was isolated from Mitracarpus scaber which on bioevaluation found to inhibit the growth of M. intracellulare at the concentration of 6.5 mg/mL [334].

9.12. Pyrrolidine alkaloid Piper sarmentosum, a potent medicinal plant showed the presence of sarmentine (208), pyrrolidine (209), sarmentosine (210),

Fig. 49. Structure of pellitorine (212) and brachystamide B (213) isolated from Piper sarmentosum.

Fig. 51. Structure of imide alkaloids.

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Fig. 55. Structure of piperine alkaloid.

Fig. 52. Structure of himanimide alkaloids isolated from Serpula himantoids.

Fig. 56. Structure of chabamide isolated from Piper chaba.

Fig. 53. Structure of epiccocarines A and b.

[335]. Pyrrolidine alkaloid based amides like Alkamide type alkaloids have also shown promising antitubercular activities. Three alkaloid amides malyngamide 4 (214), malyngamide A (215) and malyngamide B (216) were isolated from the red sea marine cyanobacterium Moorea producens, exhibited antibacterial activity against M. tuberculosis H37Rv at a concentration of 12.5 mg/mL with an inhibition of 17, 18 and 10%, respectively [336]. Likewise, an alkamide, N-isobutyl-(2E,4E)-2,4-tetradecadienamide (217) was isolated from the roots methanol extract of plant Zanthoxylum capense. The isolated metabolite displayed good antibacterial activity against M. tuberculosis H37Rv with an MIC value of 6.2 mg/mL (Fig. 50) [310]. 9.13. Imide alkaloids

Hirustellone D (221) were isolated from fungal species Hirustella nivea BCC 2594 and exhibited significant antitubercular activity against M. tuberculosis with inhibitory concentration of 0.78, 0.78, 0.78, and 3.125 mg/mL, respectively (Fig. 51) [337]. Through the extensive investigation of Serpula himantoids, fungus found in Chile, four interesting alkaloids viz. himanimide A (222), himanimide B (223), himanimide C (224), and himanimide D (225) have been isolated successfully (Fig. 52). Among these alkaloids himanimides C (224) was found more effective against M. phlei with MIC value of 25 mg/mL [338]. Tetrameric acid analogue were isolated from Myeelia extract of fungus Epicoccum sp. Epiccocarines A (226) and B (227) (Fig. 53) possess antimycobacterial activity against M. vaccae with MIC value of 6.25 mg/mL [339]. Similarly, fermentation of Streptomyces rimosus resulted a protein kinase inhibitor 228, which was also found as a potent antimycobacterial agent against M. aurum and M. phlei at loading dose of 20 mg/disc (Fig. 54) [340,341].

9.14. Piperidine alkaloid Piperine (229), an analogue of 1-piperonyl piperidine, which was isolated from Piper nigrum, exhibited the antimycobacterial activity against M. smegmatis with MIC value of 128 mg/mL. Piperine also inhibited the efflux pump (putative multidrug) M. Tb (Fig. 55)

Imide alkaloid analogue hirustellones with some structural modification known for the more potent antimycobacterial activity. Hirustellone A (218), Hirustellone B (219), Hirustellone C (220), and

Fig. 54. Structure of alkaloid 228 isolated from Streptomyces rimosus.

Fig. 57. Structure of neopetrosiamine A.

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Fig. 58. Structure of tetracyclic diamine alkaloids isolated from sea sponge Haliclona sp.

[342]. Chemical investigation of Piper chaba stem resulted to the successful isolation of methylene dioxybenzene analogue chabamide (230), which possess antitubercular activity against M. tuberculosis H37Ra strain with MIC value of 12.5 mg/mL (Fig. 56) [343]. In a research program, a series of interesting bis-piperidine alkaloid and tetracyclic bis-piperidine alkaloids were isolated with a purpose to find a potential lead molecule useful to cure tuberculosis. Thus, bis-piperidine alkaloid neopetrosiamine A (231), isolated from sea sponge Neopetrosia proxima, possesses significant antimycobacterial activity against M. tuberculosis with MIC value of 7.5 mg/mL (Fig. 57) [344]. Fractionation of sea sponge Haliclona sp. reported new tetracyclic diamine alkaloid halicyclamine A (232) with MIC value against M. tuberculosis (H37Ra) in between of 1.0e5.0 mg/mL (Fig. 58) [345]. When tested against M. smegmatis and M. bovis halicyclamine A, the observed MIC was 2.5 and 1.0 mg/mL, respectively. Halicyclamine A has potent activity against M. tuberculosis, which is resistant to isoniazid, ethambutol, rifampin and streptomycin with MIC value of 3.13e6.25 mg/mL under aerobic conditions [345].

Fig. 60. Structure of Agelasine alkaloids.

Furthermore, from the same species of Haliclona, a series of similar alkylpiperidine-based alkaloids were isolated namely, 22dihydroxy haliclonacyclamine (233) and its analogue haliclonacyclamines A (234) as well haliclonacyclamines B (235) (Fig. 58), which has potent activity against Mycobacteria (M.smegmatis and M. bovis) in both condition i.e. aerobic and anaerobic with inhibitory concentration of 12.5e25 mg/mL, 2.5 mg/mL and 1.0 mg/ mL, respectively. Haliclonacyclamines B has potency against both active and dormant growing Mycobacteria [346,347]. 9.15. Cyclopeptide alkaloids Ziziphus mauritiana was reported to be rich in antimycobacterial cyclopeptide alkaloids. Further investigation of the plant resulted to the isolation of two cyclic alkaloids and three cyclopeptide alkaloids. On biological screening, it was reported that cyclopeptide alkaloid mauritine M (236) and nummularine H (237) were found to moderately inhibition of M. tuberculosis (Fig. 59) [348]. 9.16. Agelasine alkaloids

Fig. 59. Structure of Cyclopeptide alkaloids.

Marine sponge Agelas nakamurai has been reported with Agelasine E (238), which has found to be active against Mycobacterium sp. This alkaloid and its analogues viz A (239), B (240), C (241), and D (9-methyladenine) (242) have better antitubercular activity and effective against H37Rv strain. The MIC value of compound 239, 240, 241, and 242 were found to be 3.13, 1.56, 3.0, and 6.25 mg/mL, respectively [244,349,350]. Interestingly, another species of Agelas, origin of Philippines, resulted an alkaloid Agelasine F (243) that significantly retard the growth of M. tuberculosis H37Rv strain with the MIC value of 3.13 mg/mL (Fig. 60) [351,352]. Synthetic analogue of agelasines and agelasimines for example, compound 244 and 245 were found effective against M. tuberculosis with an inhibitory concentration of 6.25 mg/mL [353]. O-Benzyl

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Fig. 61. Structure of agelasines and agelasimines analogues with antitubercular activity.

analogue 246 of agelasines showed 46% inhibition at the concentration of 6.25 mg/mL, whereas agelasine D (247), compounds 248, 249, 250, 251 and N-alkoxy derivative 252 & 253 were known to inhibits the M. tuberculosis with varying efficacy at the minimum concentration of 6.25 mg/mL respectively (Fig. 61). Compound 253 has been recognized as the potent compound with MIC 3.13 mg/mL against M. tuberculosis [354].

9.17. Polycyclic guanidine alkaloids A series of interesting antimycobacterial polycyclic guanidine alkaloids named batzelladine L (254), batzelladine M (255), batzelladine N (256), batzelladine C (257), dehydrobatzelladine C (258) and crambescidine 800 (259) has been isolated from Monanchora unguifera, a marine sponge (Fig. 62) [355]. Among these alkaloids batzelladine L and batzelladine N possess most satisfactory antimycobacterial activity with MIC value of 1.68 and 3.18 mg/mL, respectively. Batzelladine M, C, dehydrobatzelladine C and crambescidine 800 exhibited mild activity against M. tuberculosis (H37Rv strain) with MIC value of 28.5, 34.7, 37.7 and 46.5 mg/mL, respectively. Among these guanidine alkaloids, ptilomycin A (260), 16bhydroxy-crambescidin (261) and compound 262 were not shown any significant antitubercular activity [355].

9.18. Oxazole alkaloids Benzoxazole alkaloids, obtained from marine metabolites of Pseudopterogorgia elisabethae, are strong inhibitor of M. tuberculosis. Pseudopteroxazole (263), seco-pseudopteroxazole (264) and homopseudopteraoxazole (265) exhibited its antimycobacterial activity with MIC value of 12.5, 12.5 and 12.5 mg/mL, respectively (Fig. 63) [356e358]. Bicyclic nitroimidazo-oxazole (266) showed in vitro as well as in vivo antimycobacterial activity and possess mutagenicity which was later modified by substitution at 2nd position with 6-nitro-2,3dihydroimidazo [2,1-b]oxazole (267) with MIC value of 0.05 mg/mL against M. tuberculosis H37Rv. Substitution with hydrophilic group (268) increases the antitubercular activity against M. tuberculosis H37Ra and H37Rv with inhibitory concentration of 0.78 and 0.39 mg/ mL, respectively whereas lipophilic group (269) substitution led to most potent antimycobacterial compound against M. Tb H37Rv with MIC of 0.006 mg/mL (Fig. 64) [359]. Texalin (270), a tetracyclic oxazole alkaloid isolated from Amyris elemifera, inhibited M. tuberculosis, M. avium and M. kansasii with MIC 25 mg/mL (Fig. 65) [360]. Transvalenein Z (271, Fig. 66), isolated from Nocardia transvalensis, was found to be effective against acid fast bacteria M. smegmatis with MIC value of 0.125 mg/mL [361].

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533

Fig. 62. Structure of polycyclic guanidine alkaloids.

9.19. Diterpenoid b-lactam alkaloids Diterpenoid b-lactam alkaloid monamphilectine A (272) and 8,15-diisocyano-11 (20)-amphilectine (273) (Fig. 67) were isolated from marine sponge Hymenia cidon, which showed potent antimycobacterial properties with MIC value of 15.3 and 2.0 mg/mL respectively [362]. Some 2-azetidinone derivatives known for their antitubercular activity against M. tuberculosis H37Rv with 90% inhibition and then after re-evaluated at lower concentration using BACTEC 460 compared with standard antimycobacterial rifampin at 0.031 mg/ mL [363]. 2,4-Dichlorophenyl or o-chlorophenyl substitution (274 and 275) increases antimycobacterial activity of 2-azetidinone (Fig. 68) [363]. Furthermore, from a synthetic livbrary of azetidinone analogues viz. 4-aryl-3-chloro-N-(3,4,5-trihydroxy benzamido)-2azetidinones (276a-o), compounds 276f, 276 g, 276 k and 276 showed potent antimycobacterial activity against M. tuberculosis with MIC of 0.76, 0.57, 0.62 and 0.83 mg/mL, respectively. Chloro (276f, g, o) and dimethyl amino (276 k) substitution in azetidinones resulted in enhancement of antitubercular activity, while other substitutions did not exhibit any remarkable antimycobacterial activity. Substitution at m-position with chloro group indicated the

Fig. 63. Structure of Benzoxazole alkaloids isolated from marine metabolites of Pseudopterogorgia elisabethae.

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N H O N Ar

Cl

274: Ar = 2,4-dichlorophenyl 275: Ar = O-chlorophenyl OH O

HO NH N

HO O

Fig. 64. Structure of nitroimidazo-oxazole analogues.

276

R

276a: R= H 276b: 2-OH/R Cl 276c R = 2-OH-3-OCH3 276d: R = 3-OH 276e:R = 4-OH 276f: R = 2-Cl 276g: R = 3-Cl

276h: R= 2-NO2 276i: R= 3-NO2 276j: R= 4-NO2 276k: R= 4-N-(CH3)2 276l: R= 3,4,5-(OCH3)3 276m:R = 3,4-(OCH3)2 276n: R= 4-OCH3 276o: R= Cl

Fig. 68. Structure of 2-azetidinone derivatives.

Fig. 65. Structure of tetracyclic oxazole alkaloid.

Fig. 69. Structure of pyridine N-oxide alkaloid.

Fig. 66. Structure of Transvalenein Z isolated from Nocardia transvalensis.

highest antitubercular activity in all the compounds. This was envisaged that the introduction of electron withdrawing and bulky group (such as dimethyl amino) has good inhibitory property against tuberculosis and this has also been evidenced if incorporation of electron withdrawing group in the structure of simple existing antitubercular drugs, like isoniazid and pyrizinamide is considered [364]. 9.20. Miscellaneous alkaloids Allium stipitatum possess pyridine N-oxide (277) alkaloid, which has significant anti-tuberculosis effect on H37Rv strain of M. Tb with

Fig. 67. Structure of diterpenoid b-lactam alkaloid analogues.

Fig. 70. Structure of alkaloids isolated from marine invertebrates.

MIC value of 1.25 mg/mL (Fig. 69) [365]. Streptomyces sp. is a good source of antibacterial alkaloids among them one metabolite viz. metabolite-A has potent antimycobacterial activity with MIC value of 10e14 mg/mL [366,367]. Screening of marine invertebrates has led to find new species Aplysina cauliformis and Pachychalina sp. which resulted to the

Fig. 71. Structure of bis-1-oxaquinolizidine alkaloid from marine source.

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Fig. 72. Brominated fistularin derived alkaloids possess antitubercular activity.

535

effective. In another program, a very interesting alkaloid namly bis-1oxaquinolizidine was isolated from marine source. (þ)-Araguspongine C (280) was isolated from the marine sponge Xestospongia exigua, which showed to inhibit M. tuberculosis H37Rv with an MIC of 1.9 mg/mL (Fig. 71) [368]. Brominated fistularin derivative 281 and 282 (Fig. 72), possess promising activity against Mycobacteria with MIC value of 7.9 and 8.0 mg/mL, respectively [369]. The ethanolic extract of C. atratum was screened in n-hexane and the dichloromethane and showed that (-)-Deoxypergularinine (12.5 mg/mL) inhibited the growth of H37Ra M. Tb strain until 42 days, and also MICs of 12.5 mg/mL have been observed against six M. tuberculosis strains namely H37Ra- M. Tb, H37Rv- M. Tb, MDRM. Tb, XDR-M. Tb, INH resistant M. Tb, and pyrazinamide resistant M. Tb. Moreover, (-)-deoxypergularinine (283) (Fig. 73) with an MIC of 6.25 mg/mL shown effectiveness against rifampicin-resistant TB also against MDR/XDR strains, and harmonious effects with rifampicin and isoniazid for the H37Ra strain [370,371]. The alkaloid was considred as a potent drug for targeting M/XDR M. tuberculosis. Meninsporopsis theobromae, seed fungus was reported with dithioketopiperazines analogues 284, 285 and 286. These alkaloids (284-286) were exhibited antimycobacterial activity against M. tuberculosis H37Ra strain with MIC value of 100 mg/mL, 0.80 mg/ mL and 3.10 mg/mL, respectively (Fig. 74) [372]. 10. Conclusion and future purspective

Fig. 73. Structure of (-)-deoxypergularinine.

isolation of two bioactive alkaloids 278 and 279 (Fig. 70). Compound 278 was effective against M. tuberculosis H37Rv with MIC value of 15.9 mg/mL, however compound 279 was not found

Despite the introduction of cheap and effective treatment with quadruple drug therapy for tuberculosis, there is still urgency for new better drugs, less toxic treatment regimens with shorter ways of evaluating new TB drugs and regimens. We need improved directions and strong collaborative network from all the researching bodies, which are involved in drug discovery for TB. In same aforesaid, we compiled the up to date TB research and introduced the role of alkaloids in tuberculosis drug discovery. Moreover, there is also need the improved tools for the detection of tuberculosis, which can be use in laboratories to assist early case finding from the populations. Since very beginning, natural products alone or their derivatives are considered as the most valuable source for the drug candidates useful in the treatment of various diseases, and several groups have

Fig. 74. Structure of dithioketopiperazines analogues from Meninsporopsis theobromae.

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been actively involved to find a lead from natural sources to control tuberculosis. The review compiles literature up to 2016 as well as recent drugs of pipeline that may be natural, synthetic or semi synthetic. This review covers the most active naturally occurring compounds with antitubercular properties at minimum inhibitory concentrations (MICs) of 50 mg/mL or less. The biological activity of natural products provides a hope for prompt discovery of highly effective low-toxic leads, which may be a potent drug to fight against tuberculosis. Some plant-derived alkaloids having MICs in range of 0.05 mg/mL are proving alkaloids as lead to answer the community involved in search of therapeutic agents for treatment of tuberculosis those are far from satisfaction so far. Extensive studies on the alkaloids having lower MICs can formulate a good antituberculosis compound with benefit of fewer side effects. Moreover, these would serve as a useful scaffolds or templates for the development of new specific and selective antimycobacterial drugs. Celastramycin A exhibited the MIC value of 0.05e3.1 mg/mL against M. vaccae, M. fortuitum, M. smegmatis strains, which is quite a potent MIC level and some synthetic compounds like PA-824, SQ-109 etc are currently in phase II clinical trials, and TMC-207, currently in phase III clinical trials, showed MIC in the range of 0.015e0.03 mg/mL in vitro against M. tuberculosis [264]. (-)-Deoxypergularinine with an MIC of 6.25 mg/mL is a potent drug for targeting M/XDR M. tuberculosis. Although considerable effort is needed to obtain new class of optimized and safe anti-tuberculosis agents from the natural product alkaloid family, evaluation for their antimycobacterial activity both, in vitro as well in vivo, identification of mechanisms of action, their chemical and metabolic stabilities, pharmacokinetic studies to fight against tuberculosis [373]. Interestingly, ruthenium complexes with some amino acids were developed evaluated against M. tuberculosis H37Rv where MIC values of the complexes are found to be comparable to the first-line drugs ethambutol (MIC 5.61 mg/mL) and second-line drug cycloserine (MIC 12.5e50.0 mg/ mL) requires more studies [374]. Similar investigation with library of natural product inspired molecules especially alkaloids [375] identified as the most active one should be strongly encouraged. Furthermore arising from the needs of biochemists (microbiologist and molecular biologists), well-established rapid construction of large collections of alkaloid related compounds under standard coupling protocol [376] or cyclorelease strategy [377] on solid support could be even more beneficial, although little attempt is made in this direction [196,378]. The combined application of solid supported combinatorial chemistry and established diverse scaffold of identified potent antituberculosis alkaloids isolated in major amount from different natural resources, chemist may further investigate to develop library of natural product inspired molecules first in mili gram scale to find out more potent molecule and then in gram scale using solution phase chemistry for complete pharmacological studies and thus could be considered a useful way to end of with molecule useful to combat tuberculosis. Acknowledgements The authors thank Banaras Hindu University for all the support. VKT gratefully acknowledge Department of Science & Technology (DST), New Delhi for the DST fast track project for young scientist (in 2006, Project No. M-48/73) and also Science Engineering and Research Board (SERB), Department of Science & Technology, New Delhi (in 2016, Grant No. EMR/2016/001123) for the funding. Abbreviations IFN-g IGRAs

Interferon-gamma Interferon-Gamma Release Assays

PCR Polymerase Chain Reaction TB Tuberculosis HIV Human Immunodeficiency Virus SAR Strucuture Activity Relationship US FDA United States Food and Drug Administration WHO World Health Organization MDR-TB Multi-drug resistant tuberculosis XDR-TB Extensively drug resistant tuberculosis TDR-TB/XXDR-TB Totally drug resistant/extremely drug resistant tuberculosis M.Tb Mycobacterium tuberculosis MIC Minimum inhibitory concentration mg Microgram mL Millilitre mM Micromolar INH Isoniazid BACTEC Bactenecin DCM Dichloromethane sp Species pg Picogram NGO Non Governmental Organization CD4/8 Cluster of Differentiation-4/8 TLR Toll Like Receptors CNS Central Nervous System Fc-R Fragment Crystallizable Receptors AIDS Acquired Immunodeficiency Syndrome NAD Nicotinamide adenine dinucleotide ACP Acyl Carrier Protein DNA Deoxyribonucleic acid RNA Ribonucleic acid rRNA Ribosomal Ribonucleic acid mRNA Messenger Ribonucleic acid DprE1 decaprenylphosphoryl-b-D-ribose oxidase DOT Directly Observed Treatment OECD Organization for Economic Co-operation and Development dsDNA Double stranded deoxyribonucleic acid dTMKase Thymidine monophosphate kinase DTDP Thymidine diphosphate FAS Fatty acid synthase ICL Isocitrate lyase ATP Adenine triphosphate ATCC American Type Culture Collection
rin BCG Bacillus CalmetteeGue NRA Nitrate reductase assay IC50 Inhibitory Concentration NAATs Nucleic Acid Amplification Tests SI Selectivity Index HTS High-Throughput Screening CDC Centre for Disease Control References [1] D.G. Russell, Mycobacterium Tuberculosis: here today and here tomorrow, Nat. Rev. Mol. Cell Biol. 2 (2001) 1e9. [2] R.P. Tripathi, N. Tewari, N. Dwivedi, V.K. Tiwari, Fighting tuberculosis, an old disease with new challenges, Med. Res. Rev. 25 (2005) 93e131. [3] N. Kishore, B.B. Mishra, V. Tripathi, V.K. Tiwari, Alkaloids as potential antitubercular agents, Fitoterapia 80 (2009) 149e163. [4] A. Koul, E. Amoult, N. Lounis, J. Guillemont, K. Andries, The challenge of new drug discovery for tuberculosis, Nature 469 (2011) 483e490. [5] R. Shi, N. Itagaki, I. Sugawara, Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms, Mini-Rev. Med. Chem. 7 (2007) 1177e1185. [6] S.H.E. Kaufmann, A.J. McMichael, Annulling a dangerous liaison, vaccination strategies against AIDS and tuberculosis, Nat. Med. 11 (2005) S33eS44. [7] C.J. Cambier, S. Falkow, L. Ramakrishnan, Host evasion and exploitation schemes of Mycobacterium tuberculosis, Cell 159 (2014) 1497e1509. [8] D. Zhang, Y. Liu, C. Zhang, H. Zhang, B. Wang, J. Xu, L. Fu, D. Yin, C.B. Cooper,

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

[9]

[10]

[11] [12] [13] [14] [15]

[16] [17] [18] [19] [20] [21] [22] [23] [24] [25]

[26]

[27] [28]

[29]

[30] [31]

[32]

[33] [34] [35]

[36] [37]

[38]

[39]

Z. Ma, Y. Lu, H. Huang, Synthesis and biological evaluation of novel 2methoxy-pyridylamino-substituted riminophenazine derivatives as antituberculosis agents, Molecules 19 (2014) 4380e4394. J.J. Salomon, P. Galeron, N. Schulte, P.R. Morow, D. Severynse-Stevens, H. Huwer, N. Daum, C.M. Lehr, A.K. Hickey, C. Ehrhardt, Biopharmaceutical in vitro characterization of CPZEN-45, a drug candidate for inhalation therapy of tuberculosis, Ther. Deliv. 4 (2013) 915e923. Y. Ishizaki, C. Hayashi, K. Inoue, M. Igarashi, Y. Takahashi, V. Pujari, D.C. Crick, P.J. Brennan, A. Nomoto, Inhibition of the first step in synthesis of the mycobacterial cell wall core, catalyzed by the GlcNAc-1-phosphate transferase WecA, by the novel caprazamycin derivative CPZEN-45, J. Biol. Chem. 288 (2013) 30309e30319. G.K. Sandhu, Tuberculosis, current situation, challenges and overview of its control programs in India, J. Glob. Infect. Dis. 3 (2011) 143e150. C. Dye, B.G. Williams, The population dynamics and control of tuberculosis, Science 328 (2010) 856e861. World Health Organization (WHO), Global Tuberculosis Report, WHO, Geneva, 2015. L.J. McGaw, N. Lall, J.J. Meyer, J.N. Eloff, The potential of South African plants against Mycobacterium infections, J. Ethnopharmacol. 119 (2008) 482e500. G.P. Kamatou, N.P. Makunga, W.P. Ramogola, A.M. Viljoen, South African Salvia species, a review of biological activities and phytochemistry, J. Ethnopharmacol. 119 (2008) 664e672. World Health Organization, Global Tuberculosis Report, WHO, Geneva, 2016. http//www.who.int/tb/publications/global_report/en/. B. Marston, B. Miller, Tuberculosis, the elephant in the AIDS clinic, AIDS 20 (2006) 1323e1325. P. Nunn, B. Williams, K. Floyd, C. Dye, G. Elzinga, M. Raviglione, Tuberculosis control in the era of HIV, Nat. Rev. Immunol. 5 (2005) 819e826. E.D. Chan, M.D. Iseman, Current medical treatment for tuberculosis, Br. Med. J. 325 (2002) 1282e1286. D. Yu, L. Susan, M. Natschke, K.H. Lee, New developments in natural products based anti-AIDS research, Med. Res. Rev. 27 (2007) 108e132. L.A. Basso, J.S. Blanchard, Resistance to antitubercular drugs, Adv. Exp. Med. Biol. 456 (1998) 115e144. I. Bastian, R. Colebunders, Treatment and prevention of multi-drug resistant tuberculosis, Drugs 58 (1999) 633e666. B.R. Copp, A.N. Pearce, Natural product growth inhibitors of Mycobacterium tuberculosis, Nat. Prod. Rep. 24 (2007) 278e297. F. Saadat, S. Sardari, B. Maleki, Virtual screening of antimycobacterial plant compounds, Mol. Inf. 32 (2013) 802e810. K.I. Wolska, A.M. Grudniak, B. Fiecek, A. Kraczkiewicz-Dowjat, A. Kurek, Antibacterial activity of oleanolic and ursolic acids and their derivatives, Cent. Eur. J. Biol. 5 (2010) 543e553. C.L. Karp, C.B. Wilson, L.M. Stuart, Tuberculosis vaccines, barriers and prospects on the quest for a transformative tool, Immunol. Rev. 264 (2015) 363e381. T.S. Balganesh, V. Balasubramanian, S.A. Kumar, Drug discovery for tuberculosis, Bottle necks and path forward, Curr. S. C. 86 (2004) 167e176. B. Khoshkholgh-Sima, S. Sardari, K.I. Mobarakeh, R.A. Khavari-Nejad, In-silico metabolome target analysis towards panC-based antimycobacterial agent discovery, Iran. J. Pharm. Res. 14 (2015) 203e214. G.A. Chung, Z. Aktar, S. Jackson, K. Duncan, High-throughput screen for detecting antimycobacterial agents, Antimicrob. Agents Chemother. 39 (1995) 2235e2238. K.C. Chinsembu, Tuberculosis and nature's pharmacy of putative antituberculosis agents, Acta Trop. 153 (2016) 46e56. G.A. Gale, K. Kirtikara, P. Pittayakhajonwut, S. Sivichai, Y. Thebtaranonth, C. Thongpanchang, V. Vichai, In search of cyclo-oxygenase inhibitors, antimycobacterials and anti-malarial drugs from Thai flora and microbes, Pharmacol. Ther. 115 (2007) 307e351. C. Lienhardt, M. Raviglione, M. Spigelman, R. Hafner, E. Jaramillo, M. Hoelscher, A. Zumla, J. Gheuens, New drugs for the treatment of tuberculosis, needs, challenges, promise, and prospects for the future, J. Infect. Dis. 205 (2012) 241e249. S.M. Newton, C. Lau, C.W. Wright, A review of antimycobacterial natural products, Phytother. Res. 14 (2000) 303e322. S.D. Lawn, A.I. Zumla, Tuberculosis, Lancet 378 (2011) 57e72. M. Caws, G. Thwaites, S. Dunstan, T.R. Hawn, N.T. Lan, N.T. Thuong, K. Stepniewska, M.N. Huyen, N.D. Bang, T.H. Loc, S. Gagneux, D. van Soolingen, K. Kremer, M. van der Sande, et al., The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis, PLoS Pathog. 4 (2008) 1000034. C.F. von Reyn, Optimal treatment of co-disease due to HIV and tuberculosis, J. Infect. Dis. 204 (2011) 817e819. V. Mudenda, S. Lucas, A. Shibemba, J. O'Grady, M. Bates, N. Kapata, S. Schwank, P. Mwaba, R. Atun, M. Hoelscher, M. Maeurer, A. Zumla, Tuberculosis and tuberculosis/HIV/AIDS-associated mortality in Africa, the urgent need to expand and invest in routine and research autopsies, J. Infect. Dis. 205 (2012) S340eS346. L. Mtei, M. Matee, O. Herfort, M. Bakari, C.R. Horsburgh, R. Waddell, B.F. Cole, J.M. Vuola, S. Tvaroha, B. Kreiswirth, K. Pallangyo, C.F. von Reyn, High rates of clinical and subclinical tuberculosis among HIV-infected ambulatory subjects in Tanzania, Clin. Infect. Dis. 40 (2005) 1500e1507. K.P. Cain, K.D. McCarthy, C.M. Heilig, P. Monkongdee, T. Tasaneeyapan,

[40] [41]

[42]

[43] [44]

[45]

[46]

[47] [48]

[49]

[50] [51] [52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60] [61] [62]

[63]

[64]

[65]

537

N. Kanara, M.E. Kimerling, P. Chheng, S. Thai, B. Sar, P. Phanuphak, et al., An algorithm for tuberculosis screening and diagnosis in people with HIV, New Engl, J. Med. 362 (2010) 707e716. World Health Organization (WHO), Treatment of Tuberculosis Guidelines, WHO, Geneva, 2012, p. p.84. H. Getahun, W. Kittikraisak, C.M. Heilig, E.L. Corbett, H. Ayles, K.P. Cain, A.D. Grant, G.J. Churchyard, M. Kimerling, S. Shah, S.D. Lawn, R. Wood, G. Maartens, R. Granich, A.A. Date, J.K. Varma, Development of a standardized screening rule for tuberculosis in people living with HIV in resourceconstrained settings, individual participant data meta-analysis of observational studies, PLoS Med. 8 (2011) 1000391. M. Bates, J. O'Grady, P. Mwaba, L. Chilukutu, J. Mzyece, B. Cheelo, M. Chilufya, L. Mukonda, M. Mumba, J. Tembo, M. Chomba, N. Kapata, A. Rachow, P. Clowes, M. Maeurer, M. Hoelscher, A. Zumla, Evaluation of the burden of unsuspected pulmonary tuberculosis and co-morbidity with noncommunicable diseases in sputum producing adult in-patients, PLoS One 7 (2012) 40774. K.B. Urdahl, S. Shafiani, J.D. Ernst, Initiation and regulation of T-cell responses in tuberculosis, Mucosal. Immunol. 4 (2011) 288e293. A.J. Wolf, L. Desvignes, B. Linas, N. Banaiee, T. Tamura, K. Takatsu, J.D. Ernst, Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs, J. Exp. Med. 205 (2008) 105e115. V. Balasubramanian, M.S. Pavelka Jr., S.S. Bardarov, J. Martin, T.R. Weisbrod, R.A. McAdam, B.R. Bloom, W.R. Jacobs Jr., Allelic exchange in Mycobacterium tuberculosis with long linear recombination substrates, J. Bacteriol. 178 (1996) 273e279. T.K. Means, S. Wang, E. Lien, A. Yoshimura, D.T. Golenbock, M.J. Fenton, Human Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis, J. Immunol. 163 (1999) 3920e3927. K.A. Bodnar, N.V. Serbina, J.L. Flynn, Fate of Mycobacterium tuberculosis within murine dendritic cells, Infect. Immun. 69 (2001) 800e809. R.A. Henderson, S.C. Watkins, J.L. Flynn, Activation of human dendritic cells following infection with Mycobacterium tuberculosis, J. Immunol. 159 (1997) 635e643. C.J. Hertz, S.M. Kiertscher, P.J. Godowski, D.A. Bouis, M.V. Norgard, M.D. Roth, R.L. Modlin, Microbial lipopeptides stimulate dendritic cell maturation via Toll-like receptor-2, J. Immunol. 166 (2001) 2444e2450. J. Gatfield, J. Pieters, Essential role for cholesterol in entry of mycobacteria into macrophages, Science 288 (2000) 1647e1650. J.D. Ernst, Macrophage receptors for Mycobacterium tuberculosis, Infect. Immun. 66 (1998) 1277e1281. G. Sch€afer, M. Jacobs, R.J. Wilkinson, G.D. Brown, Non-opsonic recognition of Mycobacterium tuberculosis by phagocytes, J. Innate Immun. 1 (2008) 231e243. G. Sch€afer, R. Guler, G. Murray, F. Brombacher, G.D. Brown, The role of scavenger receptor B1 in infection with Mycobacterium tuberculosis in a murine model, PloS One 4 (2009) 8448. L.S. Schlesinger, C.G. Bellinger-Kawahara, N.R. Payne, M.A. Horwitz, Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3, J. Immunol. 144 (1990) 2771e2780. J.A. Armstrong, P. D'Arcy Hart, Phagosome lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual non-fusion pattern and observations on bacterial survival, J. Exp. Med. 142 (1975) 1e16. S. Zimmerli, S. Edwards, J.D. Ernst, Selective receptor blockade during phagocytosis does not alter the survival and growth of Mycobacterium tuberculosis in human macrophages, Am. J. Respir. Cell. Mol. Bio 15 (1996) 760e770. K. Dheda, T. Gumbo, N.R. Gandhi, M. Murray, G. Theron, Z. Udwadia, G.B. Miglior, R. Warren, Global control of tuberculosis from extensively drugresistant to untreatable tuberculosis, Lancet Respir. Med. 2 (2014) 321e338. M.J. Boeree, A.H. Diacon, R. Dawson, K. Narunsky, J. du Bois, A. Venter, P.P.J. Phillips, S.H. Gillespie, T.D. McHugh, M. Hoelscher, N. Heinrich, S. Rehal, D. Soolingen, J. Ingen, C. Magis-Escurra, D. Burger, G.P. van Balen, R.E. Aarnoutse, A dose ranging trial to optimize the dose of rifampin in the treatment of tuberculosis, Am. J. Respir. Crit. Care. Med. 191 (2015) 1058e1065. C. Crauste, M. Flipo, A.R. Baulard, B. Deprez, N. Willand, Tuberculosis, the drug development pipeline at a glance Baptiste Villemagne, Eur. J. Med. Chem. 51 (2012) 1e16. N. Shakya, G. Garg, B. Agrawal, R. Kumar, Chemotherapeutic interventions against tuberculosis, Pharmaceuticals 5 (2012) 690e718. L.B. Heifets, Antimycobacterial drugs, Semin. Respir. Infect. 9 (1994) 84e103. J. Bernstein, W.A. Lott, B.A. Steinberg, H.L. Yale, Chemotherapy of experimental tuberculosis. V. Isonicotinic acid hydrazide (nydrazid) and related compounds, Am. Rev. Tuberc. 65 (1952) 357e364. Y. Zhang, B. Heym, B. Allen, D. Young, S. Cole, The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis, Nature 358 (1992) 591e593. D.R. Sherman, K. Mdluli, M.J. Hickey, T.M. Arain, S.L. Morris, C.E. Barry 3rd, C.K. Stover, Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis, Science 272 (1996) 1641e1643. S. Sreevatsan, X. Pan, Y. Zhang, Mutations associated with pyrazinamide

538

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74] [75]

[76]

[77]

[78]

[79]

[80] [81] [82]

[83]

[84] [85]

[86]

[87]

[88]

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 resistance in pncA of Mycobacterium tuberculosis complex organisms, Antimicrob. Agents Chemother. 41 (1997) 636e640. C. Vilcheze, T.R. Weisbrod, B. Chen, L. Kremer, M.H. Hazbon, F. Wang, D. Alland, J.C. Saccettini, W.R. Jacobs Jr., Altered NADH/NADþ ratio mediates co-resistance to isoniazid and ethionamide in mycobacteria, Antimicrob. Agents Chemother. 49 (2005) 708e720. S.V. Ramaswamy, V.R. Reich, S.J. Dou, L. Jasperse, X. Pan, A. Wanger, T. Quitugua, E.A. Graviss, Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 47 (2003) 1241e1250. K. Takayama, E.L. Armstrong, K.A. Kunugi, J.O. Kilburn, Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis, Antimicrob. Agents Chemother. 16 (1979) 240e242. A. Telenti, W.J. Philipp, S. Sreevatsan, C. Bernasconi, K.E. Stockbauer, B. Wieles, J.M. Musser, W.R. Jacobs Jr., The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol, Nat. Med 3 (1997) 567e570. M.A. Miller, L. Thibert, F. Desjardins, S.H. Siddiqi, A. Dascal, Testing of susceptibility of Mycobacterium tuberculosis to pyrazinamide, comparison of BACTEC method with pyrazinamidase assay, J. Clin. Microbiol. 33 (1995) 2468e2470. A. Scorpio, P. Lindholm-levy, L. Heifets, R. Gilman, S. Sidiqi, M. Cynamon, Y. Zhang, Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 41 (1997) 540e543. G.P. Morlock, J.T. Crawford, W.R. Butler, S.E. Brim, D. Sikes, G.H. Mazurek, C.L. Woodley, R.C. Cooksey, Phenotypic characterization of pncA mutants of Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 44 (2000) 2291e2295. M.M. Hannan, E.P. Desmond, G.P. Morlock, G.H. Mazurek, J.T. Crawford, Pyrazinamide-mono-resistant Mycobacterium tuberculosis in the United States, J. Clin. Microbiol. 39 (2001) 647e650. P. Sensi, History of the development of rifampin, Rev. Infect. Dis. 5 (1983) S402eS406. P.R. Donald, F.A. Sirgel, F.J. Botha, H.I. Seifart, D.P. Parkin, M.L. Vandenplas, J.S. Van de Wal, B.W. Maritz, D.A. Mitchison, The early bactericidal activity of isoniazid related to its dose size in pulmonary tuberculosis, Am. J. Respir. Crit. Care Med. 156 (1997) 895e900. F.A. Sirgel, P.R. Donald, J. Odhiambo, W. Githui, K.C. Umapathy, C.N. Paramasivan, C.M. Tan, K.M. Kam, C.W. Lam, K.M. Sole, D.A. Mitchison, A multicentre study of the early bactericidal activity of antituberculosis drugs, J. Antimicrob. Chemother. 45 (2000) 859e870. M.T. McCammon, J.S. Gillette, D.P. Thomas, S.V. Ramaswamy, I.I. Rosas, E.A. Graviss, J. Vijg, T.N. Quitugua, Detection by denaturing gradient gel electrophoresis of pncA mutations associated with pyrazinamide resistance in Mycobacterium tuberculosis isolates from the United States-Mexico border region, Antimicrob. Agents Chemother. 49 (2005) 2200e2209. V. Mikhailovich, S. Lapa, D. Gryadunov, A. Sobolev, B. Strizhkov, N. Chernyh, O. Skotnikova, O. Irtuganova, A. Moroz, V. Litvinov, M. Vladimirskii, M. Perelman, L. Chernousova, V. Erokhin, A. Zasedatelev, A. Mirzabekov, Identification of rifampin-resistant Mycobacterium tuberculosis strains by hybridization, PCR, and ligase detection reaction on oligonucleotide microchips, J. Clin. Microbiol. 39 (2001) 2531e2540. A. Telenti, P. Imboden, F. Marchesi, D. Lowrie, S. Cole, M.J. Colston, L. Matter, K. Schopfer, T. Bodmer, Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis, Lancet 341 (1993) 647e650. D. Moazed, H.F. Noller, Interaction of antibiotics with functional sites in 16S ribosomal RNA, Nature 327 (1987) 389e394. G.R. Stewart, B.D. Robertson, D.B. Young, Tuberculosis, a problem with persistence, Nat. Rev. Microbiol. 1 (2003) 97e105. H. Galili, H. Fromm, E. Galun, Ribosomal protein S12 as a site for streptomycin resistance in Nicotiana chloroplasts, Mol. Gen. Genet. 218 (1989) 289e292. X.Q. Liu, N.W. Gillham, J.E. Boynton, Chloroplast ribosomal protein gene rps12 of Chlamydomonas reinhardtii. Wild-type sequence, mutation to streptomycin resistance and dependence, and function in Escherichia coli, J. Biol. Chem. 264 (1989) 16100e16108. A.S. Pym, S.T. Cole, Bacterial resistance to antimicrobials, in: Wax RG. In, K. Lewis, A.A. Salyers, H. Taber (Eds.), CRC, 2008, pp. 313e342. W. Shi, X. Zhang, X. Jiang, H. Yuan, J.S. Lee, C.E. Barry, H. Wang, W. Zhang, Y. Zhang, Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis, Science 333 (2011) 1630e1632. World Health Oraganization (WHO), Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-resistant Tuberculosis, WHO, 2014. € ttger, P.D. van Helden, F.A. Sirgel, M. Tait, R.M. Warren, E.M. Streicher, E.C. Bo N.C. Gey van Pittius, G. Coetzee, E.Y. Hoosain, M. Chabula-Nxiweni, C. Hayes, T.C. Victor, A. Trollip, Mutations in the rrs A1401G gene and phenotypic resistance to amikacin and capreomycin in Mycobacterium tuberculosis, Microb. Drug Resist 18 (2012) 193e197. S. Salian, T. Matt, R. Akbergenov, S. Harish, M. Meyer, S. Duscha, € ttger, StructurD. Shcherbakov, B.B. Bernet, A. Vasella, E. Westhof, E.C. Bo eeactivity relationships among the kanamycin aminoglycosides, role of ring I hydroxyl and amino groups, Antimicrob. Agents Chemother. 56 (2012) 6104e6108.

[89] R.E. Stanley, G. Blaha, R.L. Grodzicki, M.D. Strickler, T.A. Steitz, The structures of the antituberculosis antibiotics viomycin and capreomycin bound to the 70S ribosome, Nat. Str. Mol. Biol. 17 (2010) 289e293. [90] N. Rastogi, K.S. Goh, A. Bryskier, A. Devallois, In vitro activities of levofloxacin used alone and in combination with first and second-line antituberculous drugs against Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 40 (1996) 1610e1616. [91] Z. Ma, C. Lienhardt, H. McIlleron, A.J. Nunn, X. Wang, Global tuberculosis drug development pipeline, the need and the reality, Lancet 375 (2010) 2100e2109. [92] The Global Alliance for TB Drug Development Handbook of Antituberculosis Agents. Moxifloxacin. Tuberculosis, vol. 88, 2008, pp. 127e131. [93] The Global Alliance for TB Drug Development Handbook of Antituberculosis Agents. Gatifloxacin. Tuberculosis, vol. 88, 2008, pp. 109e111. [94] S. Vacher, J.L. Pellegrin, F. Lablanc, J. Fourche, J. Maugein, Comparative antimycobacterial activities of ofloxacin, ciprofloxacin, and grepafloxacin, J. Antimicrob. Chemother. 44 (1999) 647e652. [95] S. Chakraborty, T. Gruber, C.E. Barry 3rd, H.I. Boshoff, K.Y. Rhee, Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis, Science 339 (2013) 88e91. [96] Global Alliance for TB Drug Development. Cycloserine. Tuberculosis (Edinb.), vol. 88, 2008, pp. 100e101. [97] J.B. Bruning, A.C. Murillo, O. Chacon, R.G. Barletta, J.C. Sacchettini, Structure of the Mycobacterium tuberculosis d-alanine, d-alanine ligase, a target of the antituberculosis drug d-cycloserine, Antimicrob. Agents Chemother. 55 (2010) 291e301. [98] R. Urbanczik, On the mechanism of the antimycobacterial activity of isoniazidþprothionamideþdapsone (Isoprodian), Chemotherapy 25 (1979) 261e267. [99] B.J. Van den, G.S. Kibiki, E.R. Kisanga, M.J. Boeree, R.E. Aarnoutse, New drugs against tuberculosis, problems, progress, and evaluation of agents in clinical development, Antimicrob. Agents Chemother. 53 (2009) 849e862.
rardel, L.G. Dover, G.S. Besra, J.C. Sacchettini, [100] A. Alahari, X. Trivelli, Y. Gue R.C. Reynolds, G.D. Coxon, L. Kremer, Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria, PLoS One 2 (2007) 1343. [101] B. Ji, S. Lefrancois, J. Robert, A. Chauffour, C. Truffot, V. Jarlier, In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against Mycobacterium ulcerans, Antimicrob. Agents Chemother. 50 (2006) 1921e1926. [102] R.C. Moellering, Linezolid, the first oxazolidinone antimicrobial, Ann. Intern. Med. 138 (2003) 135e142. [103] J.E. Hugonnet, L.W. Tremblay, H.I. Boshoff, C.E. Barry III, J.S. Blanchard, Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis, Science 323 (2009) 1215e1218. [104] J.P. Nadler, J. Berger, J.A. Nord, R. Cofsky, M. Saxena, Amoxicillin-clavulanic acid for treating drug-resistant Mycobacterium tuberculosis, Chest 99 (1991) 1025e1026. [105] H.F. Chambers, J. Turner, G.F. Schecter, M. Kawamura, P.C. Hopewell, Imipenem for treatment of tuberculosis in mice and humans, Antimicrob. Agents Chemother. 49 (2005) 2816e2821. [106] M.S. Bolhuis, R.V. Altena, D.V. Soolingen, W.C. de Lange, D.R. Uges, T.S. van der Werf, J.G. Kosterink, J.W. Alffenaar, Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients, Eur. Respir. J. 42 (2013) 1614e1621. [107] Y. Lu, M.Q. Zheng, B. Wang, W.J. Zhao, P. Li, N.H. Chu, B.W. Liang, Activities of clofazimine against Mycobacterium tuberculosis in vitro and in vivo, Zhonghua Jie He He Hu Xi Za Zhi 31 (2008) 752e755. [108] A.H. Diacon, A. Pym, M.P. Grobusch, J.M. de los Rios, E. Gotuzzo, I. Vasilyeva, V. Leimane, K. Andries, N. Bakare, T. De Marez, M. Haxaire-Theeuwes, N. Lounis, P. Meyvisch, E. De Paepe, R.P. van Heeswijk, B. Dannemann, Multidrug-resistant tuberculosis and culture conversion with bedaquiline, New Engl. J. Med. 371 (2014) 723e732. [109] R. Dawson, A.H. Diacon, D. Everitt, C. van Niekerk, P.R. Donald, D.A. Burger, R. Schall, M. Spigelman, A. Conradie, K. Eisenach, A. Venter, P. Ive, L. PageShipp, E. Variava, K. Reither, N.E. Ntinginya, A. Pym, F. von Groote-Bidlingmaier, C.M. Mendel, The antituberculosis activity of the combination of moxifloxacin, pretomanid (PA-824) and pyrazinamide during the first eight weeks of therapy, a Phase 2b open label, partially randomized trial of efficacy, tolerability and safety in patients with drug-susceptible and drugresistant pulmonary tuberculosis, Lancet 385 (2015) 1738e1747. [110] R.S. Wallis, R. Dawson, S.O. Friedrich, A. Venter, D. Paige, T. Zhu, A. Silvia, J. Gobey, C. Ellery, Y. Zhang, K. Eisenach, P. Miller, A.H. Diacon, Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis, PLoS One 9 (2014) 94462. [111] D. Wang, Y. Zhao, Z. Liu, H. Lei, M. Dong, P. Gong, In vitro and intracellular activity of 4-substituted piperazinyl phenyl oxazolidinone analogues against Mycobacterium tuberculosis, J. Antimicrob. Chemother. 69 (2014), 1711e1174. [112] V. Skripconoka, M. Danilovits, L. Pehme, T. Tomson, G. Skenders, T. Kummik, A. Cirule, V. Leimane, A. Kurve, K. Levina, L.J. Geiter, D. Manissero, C.D. Wells, Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis, Eur. Respir. J. 41 (2013) 1393e1400. [113] V. Balasubramanian, S. Solapure, H. Iyer, A. Ghosh, S. Sharma, P. Kaur, R. Deepthi, V. Subbulakshmi, V. Ramya, V. Ramachandran, M. Balganesh,

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125] [126] [127]

[128]

[129]

[130] [131]

[132]

[133]

[134]

L. Wright, D. Melnick, S.L. Butler, V.K. Sambandamurthya, Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis, Antimicrob. Agents Chemother. 58 (2014) 495e502. N. Heinrich, R. Dawson, J. du Bois, K. Narunsky, G. Horwith, A.J. Phipps, C.A. Nacy, R.E. Aarnoutse, M.J. Boeree, S.H. Gillespie, A. Venter, S. Henne, A. Rachow, P.P. Phillips, Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients, J. Antimicrob. Chemother. 70 (2015) 1558e1566. A.M. Upton, S. Cho, T.J. Yang, Y. Kim, Y. Wang, Y. Lu, B. Wang, J. Xu, K. Mdluli, Z. Ma, S.G. Franzblau, In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 59 (2015) 136e144. Y. Takahashi, M. Igarashi, T. Miyake, H. Soutome, K. Ishikawa, Y. Komatsuki, Y. Koyama, N. Nakagawa, S. Hattori, K. Inoue, N. Doi, Y. Akamatsu, Novel semi-synthetic antibiotics from caprazamycins AeG, caprazene derivatives and their antibacterial activity, J. Antibiot. 66 (2013) 171e178. A. Disratthakit, N. Doi, In Vitro Activities of DC-159a, a Novel Fluoroquinolone, against Mycobacterium Species, Antimicrob. Agents Chemother. 54 (2010) 2684e2686. K. Pethe, P. Bifani, J. Jang, S. Kang, S. Park, S. Ahn, J. Jiricek, J. Jung, H.K. Jeon, J. Cechetto, T. Christophe, H. Lee, M. Kempf, M. Jackson, A.J. Lenaerts, H. Pham, V. Jones, M.J. Seo, Y.M. Kim, M. Seo, J.J. Seo, D. Park, Y. Ko, I. Choi, R. Kim, S.Y. Kim, S. Lim, S.A. Yim, J. Nam, H. Kang, H. Kwon, C.T. Oh, Y. Cho, Y. Jang, J. Kim, A. Chua, B.H. Tan, M.B. Nanjundappa, S.P. Rao, W.S. Barnes, R. Wintjens, J.R. Walker, S. Alonso, S. Lee, J. Kim, S. Oh, T. Oh, U. Nehrbass, S.J. Han, Z. No, J. Lee, P. Brodin, S.N. Cho, K. Nam, J. Kim, Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis, Nat. Med. 19 (2013) 1157e1160. E. Bogatcheva, C. Hanrahan, B. Nikonenko, G. de los Santos, V. Reddy, P. Chen, F. Barbosa, L. Einck, C. Nacy, M. Protopopova, Identification of SQ609 as a lead compound from a library of dipiperidines, Bioorg. Med. Chem. Lett. 21 (2011) 5353e5357. S. Siricilla, K. Mitachi, B. Wan, S.G. Franzblau, M. Kurosu, Discovery of a capuramycin analog that kills non-replicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors, J. Antibiot. 68 (2015) 271e278. S.H. Cho, S. Warit, B. Wan, C.H. Hwang, G.F. Pauli, S.G. Franzblau, Low-Oxygen-Recovery Assay for High-Throughput Screening of Compounds against Non-replicating Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 51 (2007) 1380e1385. V. Makarov, B. Lechartier, M. Zhang, J. Neres, A.M. van der Sar, S.A. Raadsen, R.C. Hartkoorn, O.B. Ryabova, A. Vocat, L.A. Decosterd, N. Widmer, T. Buclin, W. Bitter, K. Andries, F. Pojer, P.J. Dyson, S.T. Cole, Towards a new combination therapy for tuberculosis with next generation benzothiazinones, EMBO Mol. Med. 6 (2014) 372e383. F. Wang, D. Sambandan, R. Halder, J. Wang, S.M. Batt, B. Weinrick, I. Ahmad, P. Yang, Y. Zhang, J. Kim, M. Hassani, S. Huszar, C. Trefzer, Z. Ma, T. Kaneko, K.E. Mdluli, S. Franzblau, A.K. Chatterjee, K. Johnsson, K. Mikusova, G.S. Besra, K. Fütterer, S.H. Robbins, S.W. Barnes, J.R. Walker, W.R. Jacobs, P.G. Schultz, Identification of a small molecule with activity against drug-resistant and persistent tuberculosis, Proc. Natl. Acad. Sci. 110 (2013) E2510eE2517. D.G.N. Muttucumaru, G. Roberts, J. Hinds, R.A. Stabler, T. Parish, Gene expression profile of Mycobacterium tuberculosis in a non-replicating state, Tuberculosis 84 (2004) 239e246. S. Keshavjee, P.E. Farmer, Tuberculosis, drug resistance, and the history of modern medicine, New Engl. J. Med. 367 (2012) 931e936. H. Getahun, A. Matteelli, R.E. Chaisson, M. Raviglione, Latent mycobacterium tuberculosis infection, New Engl. J. Med. 372 (2015) 2127e2135. Drug resistance” National Cancer Institute, Global Tuberculosis Report 2016, WHO, Geneva, 2016. http://www.cancer.gov. www.who.int/tb/publications/ global_report/en. D. Falzon, E. Jaramillo, H.J. Schünemann, M. Arentz, M. Bauer, J. Bayona, L. Blanc, J.A. Caminero, C.L. Daley, C. Duncombe, C. Fitzpatrick, A. Gebhard, H. Getahun, WHO guidelines for the programmatic management of drugresistant tuberculosis, 2011 update, Eur. Respir. J. 38 (2011) 516e528. M.C.Y. Fomogne-Fodjo, S. van Vuuren, D.T. Ndinteh, R.W.M. Krause, D.K. Olivier, Antibacterial activities of plants from Central Africa used traditionally by the Bakola pygmies for treating respiratory and tuberculosisrelated symptoms, J. Ethnopharmacol. 155 (2014) 123e131. J. Crofton, P. Chaulet, D. Maher, Guidelines for the Management of Drug Resistant Tuberculosis vol. 31, WHO, Geneva, 1997, p. 7. K.E. Dooley, E.E. Bliven-Sizemore, M. Weiner, Y. Lu, E.L. Nuermberger, W.C. Hubbard, E.J. Fuchs, M.T. Melia, W.J. Burman, S.E. Dorman, Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers, Clin. Pharmacol. Ther. 91 (2012) 881e888. S.D. Lawn, A. Zumla, Advances in tuberculosis diagnostics, the Xpert MTB/RIF assay and future prospects for a point-of-care test, Lancet Infect. Dis. 13 (2013) 349e361. K. Weyer, F. Mirzayev, G.B. Migliori, W. Van Gemert, L. D'Ambrosio, M. Zignol, K. Floyd, R. Centis, D.M. Cirillo, E. Tortoli, C. Gilpin, J. de Dieu Iragena, D. Falzon, M. Raviglione, Rapid molecular TB diagnosis, evidence, policy-making and global implementation of Xpert®MTB/RIF, Eur. Respir. J. 42 (2013) 252e271. D.U. Ganihigama, S. Sureram, S. Sangher, P. Hongmanee, T. Aree, C. Mahidol,

[135]

[136] [137]

[138] [139]

[140]

[141]

[142]

[143] [144]

[145]

[146]

[147]

[148] [149] [150]

[151]

[152]

[153]

[154] [155]

[156]

[157]

539

S. Ruchirawat, P. Kittakoop, Antimycobacterial activity of natural products and synthetic agents, Pyrrolodiquinolines and vermelhotin as antitubercular leads against clinical multidrug resistant isolates of Mycobacterium tuberculosis, Eur. J. Med. Chem. 89 (2015) 1e12.
ndez, M.C. Raviglione, A. Laszlo, N. Binkin, H.L. Rieder, A. Pablos-Me F. Bustreo, P. Nunn, Global surveillance for anti-tuberculosis-drug resistance, New Engl. J. Med. 338 (1998) 1641e1649. I. Smith, Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence, Clin. Microbiol. Rev. 16 (2003) 463e496. D.T. Hoagland, J. Liu, R.B. Lee, R.E. Lee, New agents for the treatment of drugresistant Mycobacterium tuberculosis, Adv. Drug Deliv. Rev. 102 (2016) 55e72. G. Lamichhane, Novel targets in M. tuberculosis, search for new drugs, Trends Mol. Med. 17 (2011) 25e33. R. Singh, U. Manjunatha, H.I. Boshoff, Y.H. Ha, P. Niyomrattanakit, R. Ledwidge, C.S. Dowd, I.Y. Lee, P. Kim, L. Zhang, S. Kang, T.H. Keller, J. Jiricek, C.E. Barry, PA-824 kills non replicating Mycobacterium tuberculosis by intracellular NO release, Science 322 (2008) 1392e1395. U. Manjunatha, H.I. Boshoff, C.E. Barry, The mechanism of action of PA-824, novel insights from transcriptional profiling, Commun. Integr. Biol. 2 (2009) 215e218. A.H. Diacon, R. Dawson, M. Hanekom, K. Narunysky, S.J. Maritz, A. Venter, P.R. Donald, C. van Niekerk, K. Whitney, D.J. Rouse, M.W. Laurenzi, A.M. Ginsberg, M.K. Spigelman, Early bactericidal activity and pharmacokinetics of PA-824 in smear positive tuberculosis patients, Antimicrob. Agents. Chemother. 54 (2010) 3402e3407. M.T. Gler, V. Skripconoka, E. Sanchez-Garavito, H. Xiao, J.L. Cabrera-Rivero, D.E. Vargas-Vasquez, M. Gao, M. Awad, S.K. Park, T.S. Shim, G.Y. Suh, M. Danilovits, H. Ogata, A. Kurve, J. Chang, K. Suzuki, T. Tupasi, W.J. Koh, B. Seaworth, L.J. Geiter, C.D. Wells, Delamanid for multidrug-resistant pulmonary tuberculosis, New Engl. J. Med. 366 (2012) 2151e2160. A.S. Xavier, M. Lakshmanan, Delamanid: A new armor in combating drugresistant tuberculosis, J. Pharmacol. Pharmacother. 5 (2014) 222e224. Q. Zhang, Y. Liu, S. Tang, W. Sha, H. Xiao, Clinical benefit of delamanid (OPC67683) in the treatment of multidrug resistant tuberculosis patients in China, Cell biochem. Biophys. 67 (2013) 957e963. K. Tahlan, R. Wilson, D.B. Kastrinsky, K. Arora, V. Nair, E. Fischer, S.W. Barnes, J.R. Walker, D. Alland, C.E. Barry 3rd, H.I. Boshoff, SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 56 (2012) 1797e1809. K.A. Sacksteder, M. Protopopova, C.E. Barry, K. Andriesm, C.A. Nacy, Discovery and development of SQ109, a new antitubercular drug with a novel mechanism of action, Future Microbiol. 7 (2012) 823e837. C.P. Owens, N. Chim, A.B. Graves, C.A. Harmston, A. Iniguez, H. Contreras, M.D. Liptak, C.W. Goulding, The Mycobacterium tuberculosis secreted protein Rv0203 transfers heme to membrane proteins MmpL3 and MmpL11, J. Biol. Chem. 288 (2013) 21714e21728. S.S. Munsiff, C. Kambili, S.D. Ahuja, Rifapentine for the treatment of pulmonary tuberculosis, Clin. Infect. Dis. 43 (2006) 1468e1475. J.G. Chan, X. Bai, D. Traini, An update on the use of rifapentine for tuberculosis therapy, Exp. Opin. Drug Deliv. 11 (2014) 421e431. T.R. Sterling, M.E. Villarino, A.S. Borisov, N. Shang, F. Gordin, E. Bliven-Sizemore, J. Hackman, C.D. Hamilton, D. Menzies, A. Kerrigan, S.E. Weis, M. Weiner, D. Wing, M.B. Conde, L. Bozeman, C.R. Horsburgh, R.E. Chaisson, Three months of rifapentine and isoniazid for latent tuberculosis infection, New Engl. J. Med. 365 (2011) 2155e2166. K.E. Dooley, C.D. Mitnick, M. Ann DeGroote, E. Obuku, V. Belitsky, C.D. Hamilton, M. Makhene, S. Shah, J.C. Brust, N. Durakovic, E. Nuermberger, Efficacy Subgroup, Resist-TB Old drugs, new purpose, retooling existing drugs for optimized treatment of resistant tuberculosis, Clin. Infect. Dis. 55 (2012) 572e581. A.C. Haagsma, R. Abdillahi-Ibrahim, M.J. Wagner, K. Krab, K. Vergauwen, J. Guillemont, K. Andries, H. Lill, A. Koul, D. Bald, Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue, Antimicrob. Agents Chemother. 53 (2009) 1290e1292. €hlmann, J.M. Neefs, K. Andries, P. Verhasselt, J. Guillemont, H.W. Go H. Winkler, J. Van Gestel, P. Timmerman, M. Zhu, E. Lee, P. Williams, D. de Chaffoy, E. Huitric, S. Hoffner, E. Cambau, C. Truffot-Pernot, N. Lounis, V. Jarlier, A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis, Science 307 (2005) 223e227. B. Chan, T.M. Khadem, J. Brown, A review of tuberculosis, focus on bedaquiline, Am. J. Health Syst. Pharm. 70 (2013) 1984e1994. E.B. Chahine, L.R. Karaoui, H. Mansour, Bedaquiline, a novel diarylquinoline for multidrug-resistant tuberculosis, Ann. Pharmacother. 48 (2014) 107e115. R.E. Lee, J.G. Hurdle, J. Liu, D.F. Bruhn, T. Matt, M.S. Scherman, P.K. Vaddady, Z. Zheng, J. Qi, R. Akbergenov, S. Das, D.B. Madhura, C. Rathi, A. Trivedi, C. Villellas, R.B. Lee, Rakesh, S.L. Waidyarachchi, D. Sun, M.R. McNeil, € ttger, J.A. Ainsa, H.I. Boshoff, M. Gonzalez-Juarrero, B. Meibohm, E.C. Bo A.J. Lenaerts, Spectinamides, a new class of semisynthetic anti-tuberculosis agents that overcome native drug efflux, Nat. Med. 20 (2014) 152e158. €llmann, O. Ryabova, B. SaintV. Makarov, G. Manina, K. Mikusova, U. Mo Joanis, N. Dhar, M.R. Pasca, S. Buroni, A.P. Lucarelli, A. Milano, E. De Rossi,

540

[158] [159]

[160]

[161]

[162]

[163]

[164]

[165] [166]

[167] [168]

[169]

[170]

[171]

[172] [173] [174] [175]

[176]

[177]

[178]

[179]

[180]

[181]

[182]

[183]

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 M. Belanova, A. Bobovska, P. Dianiskova, J. Kordulakova, C. Sala, E. Fullam, P. Schneider, J.D. McKinney, P. Brodin, T. Christophe, S. Waddell, P. Butcher, J. Albrethsen, I. Rosenkrands, R. Brosch, V. Nandi, S. Bharath, S. Gaonkar, R.K. Shandil, V. Balasubramanian, T. Balganesh, S. Tyagi, J. Grosset, G. Riccardi, S.T. Cole, Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis, Science 8 (2009) 801e804. Y. Zhang, K. Post-Martens, S. Denkin, New drug candidates and therapeutic targets for tuberculosis therapy, Drug Discov. Today 11 (2006) 21e27. U.H. Manjunatha, P.W. Smith, Perspective, Challenges and opportunities in TB drug discovery from phenotypic screening, Bioorg. Med. Chem. 23 (2015) 5087e5097. H.I. Boshoff, T.G. Myers, B.R. Copp, M.R. McNeil, M.A. Wilson, C.E. Barry 3rd, The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism, novel insights into drug mechanisms of action, J. Biol. Chem. 279 (2004) 40174e40184. M. Wilson, J. De Risi, H.H. Kristensen, P. Imboden, S. Rane, P.O. Brown, et al., Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 12833e12838. M.P. Finken, A. Kirchner, A. Meier, A. Wrede, E.C. Bottger, Molecular basis of streptomycin resistance in Mycobacterium tuberculosis, Alteration of the ribosomal protein S12 gene and point mutation within a functional 16S ribosomal RNA pseudoknot, Mol. Microbiol. 9 (1993) 1239e1246. E.M. Brown, D.S. Reeves, Quinolones, in: F. O'Grady, H.P. Lambert, R.G. Finch, D. Greenwood (Eds.), Antibiotic and Chemotherapy, Anti-infective Agents and Their Use in Therapy, Churchill Livingstone, Edinburgh, 1997, pp. p.419e452. R.G. Ducati, A. Ruffino-Netto, L.A. Basso, D.S. Santos, The resumption of consumption-A review on tuberculosis, Mem. Inst. Oswaldo Cruz 101 (2006) 697e714. R. Loddenkemper, D. Sagebiel, A. Brendel, Strategies against multidrugresistant tuberculosis, Eur. Respir. J. 20 (2000) 66e77. G.D. Perri, S. Bonora, Which agents should we use for the treatment of multidrug resistant Mycobacterium tuberculosis? J. Antimicrob. Chemother. 54 (2004) 593e602. W.R. Bishai, R.E. Chaisson, Short-course chemoprophylaxis for tuberculosis, Clin. Chest. Med. 18 (1997) 115e122. P.G. Smith, A.R. Moss, Epidemiology of Tuberculosis, in: Barry Bloom (Ed.), Tuberculosis, Pathogenesis, Protection, and Control, ASM Press, Washington D.C., 1994, pp. p.47e59. P.C. Hopewell, Overview of clinical tuberculosis, in: Barry Bloom (Ed.), Tuberculosis, Pathogenesis, Protection, and Control, ASM Press, Washington D.C, 1994, pp. 25e46. D.E. Snider Jr., M. Raviglione, A. Kochi, Global burden of tuberculosis, in: Barry Bloom (Ed.), Tuberculosis, Pathogenesis, Protection, and Control, ASM Press, Washington D.C, 1994, pp. 3e11. C.E. Barry, R.A. Slayden, A.E. Sampson, R.E. Lee, Use of genomics and combinatorial chemistry in the development of new antimycobacterial drug, Biochem. Pharmacol. 59 (2000) 221e231. S. Khasnobis, V.E. Escuyer, D. Chatterjee, Emerging therapeutic targets in tuberculosis, post-genomic era, Exp. Opin. Ther. Targ. 6 (2002) 21e40. P.J. Brennan, D.C. Crick, The cell-wall core of Mycobacterium tuberculosis in the context of drug discovery, Curr. Top. Med. Chem. 7 (2007) 475e488. S. Sarkar, M.R. Suresh, An overview of tuberculosis chemotherapy-a literature review, J. Pharm. S. C. 14 (2001) 148e161. Y. Wu, D.C. Xiong, S.C. Chen, Y.S. Wang, X.S. Ye, Total synthesis of mycobacterial arabinogalactan containing 92 monosaccharide units, Nat. Commun. 8 (2017) 1e7. S. Mishra, K. Upadhayay, K.B. Mishra, A.K. Shukla, R.P. Tripathi, V.K. Tiwari, Carbohydrate based potential chemotherapeutic agents, Stud. Nat. Prod. Chem. 49 (2016) 307e361. R.P. Tripathi, R. Tripathi, V.K. Tiwari, L. Bala, S. Sinha, A. Srivastava, R. Srivastava, B.S. Srivastava, Synthesis of glycosylated beta-amino acids as new class of antitubercular agents, Eur. J. Med. Chem. 37 (2002) 773e781. D. Katiyar, V.K. Tiwar, N. Tiwari, S.S. Verma, S. Sinha, A. Giakwad, A. Srivastava, V. Chaturvedi, R. Srivastava, B.S. Srivastava, R.P. Tripathi, Synthesis and antimycobacterial activity of glycosylated b-amino alcohols and amines, Eur. J. Med. Chem. 40 (2005) 351e360. V.K. Tiwari, N. Tewari, R.P. Tripathi, K. Arora, S. Gupta, A.K. Srivastava, M.A. Khan, P.K. Murthy, R.D. Walter, Synthesis and Antifilarial Evaluation of N1, Nn- Diglycosylated Diaminoalkanes, Bioorg. Med. Chem. 11 (2003) 1789e1800. R.P. Tripathi, V.K. Tiwari, N. Tiwari, A. Giakwad, S. Sinha, S. Srivastava, V. Chaturvedi, B.S. Srivastava, Synthesis and antitubercular activities of bisglycosylated diamino alcohols, Bioorg. Med. Chem. 13 (2005) 5668e5679. N. Tewari, N. Dwivedi, V.K. Tiwari, V. Chaturvedi, Y.K. Manju, A. Srivastava, A. Giakwad, S. Sinha, R.P. Tripathi, An efficient synthesis of aryloxyphenyl cyclopropyl methanones, A new class of anti-mycobacterial agents, Bioorg. Med. Chem. Lett. 15 (2005) 4526e4530. N. Tewari, V.K. Tiwari, R.P. Tripathi, A. Gaikwad, S. Sinha, A.K. Chaturvedi, P.K. Shukla, R. Srivastava, B.S. Srivastava, Synthesis of Galactopyranosyl Amino Alcohols as a new class of Antitubercular and antifungal agents, Bioorg. Med. Chem. Lett. 14 (2004) 329e332. K. Bloch, Control mechanisms for fatty acid synthesis in Mycobacterium smegmatis, Adv. Enz. Rel. Areas Mol. Biol. 45 (1977) 1e84.

[184] G. Gago, D. Kurth, L. Diacivich, S.C. Tsai, H. Gramajo, Biochemical and structural characterization of an essential acyl coenzyme a carboxylase from Mycobacterium tuberculosis, J. Bacteriol. 188 (2006) 477e486.
elle, M. Daffe
, Mycolic Acids: Structures, Biosyn[185] H. Marrakchi, M.A. Lane thesis, and Beyond, Chem. Biol. 21 (2014) 67e85. [186] F.G. Winder, P.B. Collins, D. Whelan, Effects of ethionamide and isoxyl on mycolic acid synthesis in Mycobacterium tuberculosis BCG, J. Gen. Microbiol. 66 (1997) 379e380. [187] B. Phetsuksiri, A.R. Baulard, A.M. Cooper, D.E. Minnikin, J.D. Douglas, G.S. Besra, P.J. Brennan, Anti-mycobacterial activities of isoxyl and new derivatives through the inhibition of mycolic acid synthesis, Antimicrob. Agents Chemother. 43 (1999) 1042e1051. [188] E. Dubnau, P. Fontan, R. Manganelli, S. Soares-Appel, I. Smith, Mycobacterium tuberculosis genes induced during infection of human macrophages, Infect. Immun. 70 (2002) 2787e2795. [189] J.E. Graham, C. Curtiss, Identification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS), Proc. Natl. Acad. Sci. 96 (1999) 11554e11559. [190] L.G. Wayne, K.Y. Liu, Glyoxalate metabolism and adaptation of Mycobacterium tuberculosis to survival under anaerobic conditions, Infect. Immun. 37 (1982) 1042e1049. [191] L.E. Alksne, S.J. Projan, Bacterial virulence as a target for antimicrobial chemotherapy, Curr. Opin. Biotechnol. 11 (2000) 625e636. [192] T.A. Gould, H. van de Langemheen, E.J. Munoz-Elia, J.D. McKinney, J.C. Sacchettini, Dual role of isocitrate lyase-1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis, Mol. Microbiol. 61 (2006) 940e947. [193] E.J. Munoz-Elias, J.D. McKinney, Mycobacterium tuberculosis isocitrate lyase-1 and 2 are jointly required for in vitro growth and virulence, Nat. Med. 11 (2005) 638e644. [194] K. Andries, P. Verhasselt, J. Guillemont, H.W. Gohlmann, J.M. Neefs, H. Winkler, J. Van Gestel, P. Timmerman, M. Zhu, E. Lee, P. Williams, D. de Chaffoy, E. Huitric, S. Hoffner, E. Cambau, C. Truffot-Pernot, N. Lounis, V. Jarlier, A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis, Science 307 (2005) 223e227. [195] N. Tewari, R.C. Mishra, V.K. Tiwari, R.P. Tripathi, DBU/TBAB/4A0 catalysed cyclatic amidation reactions, A highly efficient & convenient synthesis of CNucleosides, Synlett 11 (2002) 1779e1782. [196] N. Tewari, V.K. Tiwari, R.C. Mishra, R.P. Tripathi, A.K. Srivastava, R. Ahmad, R. Srivastava, B.S. Srivastava, Synthesis and bioevaluation of glycosyl ureas as a-glucosidase inhibitors and their effect on Mycobacterium, Bioorg. Med. Chem. 11 (2003) 2911e2922. [197] N. Tewari, D. Katiyar, V.K. Tiwari, R.P. Tripathi, Amberlite IR -120 catalysed efficient synthesis of glycosyl enaminones and their application, Tetrahedron Lett. 44 (2003) 6639e6642. [198] J. Pandey, A. Sharma, V.K. Tiwari, D. Dube, R. Ramachandran, V. Chaturvedi, S. Sinha, N. Mishra, P.K. Shulka, R.P. Tripathi, Synthesis, molecular modeling and antitubercular activities of glycopeptide analogs with both furanose and pyranose ring structures, J. Comb. Chem. 11 (2009) 422e427. [199] S.K. Srivastava, R.P. Tripathi, R. Ramachandran, NADþ-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors, J. Biol. Chem. 280 (2005) 30273e30281. [200] S.K. Srivastava, D. Dube, N. Tewari, N. Dwivedi, R.P. Tripathi, Mycobacterium tuberculosis NADþ-dependent DNA ligase is selectively inhibited by glycosylamines compared with human DNA ligase-I, Nucl. Acid. Res. 33 (2005) 7090e7101. [201] E.L. Nuermberger, T. Yoshimatsu, S. Tyagi, R.J. O'Brien, A.N. Vernon, R.E. Chaisson, W.R. Bishai, K.H. Grosset, Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis, Am. J. Respir. Crit. Care. Med. 169 (2004) 421e426. [202] H. Saita, H. Tomioka, K. Sato, T. Yamne, K. Yamashita, K. Hosol, Antimicrob. Agents Chemother. 35 (1991) 542. [203] L. Collins, S. Franzblau, Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium, Antimicrob. Agents Chemother. 41 (1997) 1004e1009. [204] C.N. Lee, L.B. Heifets, Determination of minimal inhibitory concentrations of antituberculosis drugs by radiometric and conventional methods, Am. Rev. Respir. Dis. 136 (1967) 349e352. [205] M. Czajkowska, E. Augustynowicz-Kopec, Z. Zwolska, I. Bestry, M. Martusewicz-Boros, M. Marzinek, E. Radzikowska, P. Remiszewski, B. Roszkowska-Sliz, J. Szopinski, J. Zaleska, J. Zych, E. Rowinska-Zakrzewska, Pulmonary mycobacterioses frequency of occurrence, clinical spectrum and predisposing factors, Pnemonol Alergol. Pol. 70 (2002) 550e560. [206] C.A. Sanders, R.R. Nieda, E.P. Desmond, Validation of the use of Middlebrook 7H10 agar, BACTEC MGIT 960, and BACTEC 460 12B media for testing the susceptibility of Mycobacterium tuberculosis to levofloxacin, J. Clin. Microbiol. 42 (2004) 5225e5228. [207] M.S. Diaz-Infantes, M.J. Ruiz-Serrano, L. Martinez-Sanchez, A. Ortega, E. Bouza, Evaluation of the MB/BacT mycobacterium detection system for susceptibility testing of Mycobacterium tuberculosis, J. Clin. Microbiol. 38 (2000) 1988e1999. [208] S.G. Franzblau, R.S. Witzig, J.C. McLaughlin, P. Torres, G. Madico,

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

[209] [210]

[211]

[212] [213] [214]

[215]

[216]

[217]

[218] [219] [220] [221]

[222] [223]

[224]

[225]

[226] [227]

[228]

[229] [230] [231] [232] [233] [234]

[235]

[236] [237] [238]

A. Hernandez, M.T. Degnan, M.B. Cook, V.K. Quenzer, R.M. Ferguson, R.H. Gilman, Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate alamar blue assay, J. Clin. Microbio 36 (1998) 362e366. N.D. Connell, H. Nikaido, in: B.R. Bloom (Ed.), Tuberculosis, Pathogenesis, Protection and Control, ASM Press, Washington D.C., 1994, pp. 333e352. C. Changsen, S.G. Franzblau, P. Palittapongarnpim, Improved green fluorescent protein reporter gene-based microplate screening for antituberculosis compounds by utilizing an acetamidase promoter, Antimicrob. Agents Chemother. 47 (2003) 3682e3687. L.A. Collins, M.N. Torrero, S.G. Franzblau, Green fluorescent protein reporter microplate assay for high-throughput screening of compounds against Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 42 (1998) 344e347. S.H. Cho, C.L. Chang, S.G. Franzblau, Interscience Conference on Antimicrob Agents Chemother, 42nd Am. Soc. Micro, San Diego, 2002. T.K. Kent, G.P. Kubica, Public Health Mycobacteriology, a Guide for Level III Laboratories, Centers for Disease Control, Atlanta, 1985. K.A. Angeby, S.E. Hoffner, Rapid and inexpensive drug susceptibility testing of Mycobacterium tuberculosis with a nitrate reductase assay, J. Clin. Microbiol. 40 (2002) 553e555. L.A. Solis, S.S. Shin, L.L. Han, F.L. lanos, M. Stowell, A. Sloutsky, Validation of a rapid method for detection of M. tuberculosis resistance to isoniazid and rifampin in Lima, Peru. Int. J. Tuberc. Lung Dis. 9 (2005) 760e764. H.R. Musa, M. Ambroggi, A. Souto, K.A. Angeby, Drug susceptibility testing of Mycobacterium tuberculosis by a nitrate reductase assay applied directly on microscopy positive sputum samples, J. Clin. Microbiol. 43 (2005) 3159e3161. J.C. Palomino, A. Martin, F. Portaels, Rapid drug resistance detection in Mycobacterium tuberculosis, a review of colourimetric methods, Clin. Microbiol. Infect. 13 (2007) 754e762. H.I. Boshoff, C.E. Barry, Tuberculosis metabolism and respiration in the absence of growth, Nat. Rev. Microbiol. 3 (2005) 70e80. T. Dick, Dormant tubercle bacilli, the key to more effective TB chemotherapy, J. Antimicrob. Chemother. 47 (2001) 117e118. L.G. Wayne, C.D. Sohaskey, Non-replicating persistence of M. tuberculosis, Ann. Rev. Microbiol. 55 (2001) 139e163. A. Khan, D. Sakhar, A simple whole cell based high throughput screening protocol using M. bovis BCG for inhibitors against dormant and active tubercle bacilli, J. Microbiol. Methods 73 (2008) 62e68. Z. Sun, Y. Zhang, Antituberculosis activity of certain antifungal and antihelmintic drugs, Tuberc. Lung. Dis. 79 (1999) 319e320. Y. Li, S.G. Franzblau, Microplate Assay for Testing Bactericidal Activity of Compounds against Non-growing Mycobacterium tuberculosis, Inter-Sci Conf Antimicrob. Agents Chemother. 39th, Abstract, 1999, p. 863. P814. L.G. Wayne, L.G. Hayes, An in vitro model for sequential study of shift down of M. tuberculosis through two stages of non-replicating persistence, Infect. Immun. 64 (1996) 2062e2069. K. Falzari, Z. Zhu, D. Pan, H. Liu, P. Hongmanee, S.G. Franzblau, In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 49 (2005) 1447e1454. I. Orme, Search for new drugs for treatment of tuberculosis, Antimicrob. Agents Chemother. 45 (2001) 1943e1946. D.S. Boyle, R. McNerney, L.H. Teng, B.T. Leader, A.C. Perez-Osorio, J.C. Meyer, D.M. O'Sullivan, D.G. Brooks, O. Piepenburg, M.S. Forrest, Rapid detection of Mycobacterium tuberculosis by recombinase polymerase amplification, PLoS One 9 (2014) e103091. I. Abubakar, M. Zignol, D. Falzon, M. Raviglione, L. Ditiu, S. Masham, I. Adetifa, N. Ford, H. Cox, S.D. Lawn, B.J. Marais, T.D. McHugh, P. Mwaba, M. Bates, M. Lipman, L. Zijenah, S. Logan, R. McNerney, A. Zumla, K. Sarda, P. Nahid, M. Hoelscher, M. Pletschette, Z.A. Memish, P. Kim, R. Hafner, S. Cole, G.B. Migliori, M. Maeurer, M. Schito, A. Zumla, Drug-resistant tuberculosis, time for visionary political leadership, Lancet Infect. Dis. 13 (2013) 529e539. J. McNerney, P. Cunningham, A. Hepple, Zumla, New tuberculosis diagnostics and roll out, Int. J. Infect. Dis. 32 (2015) 81e86. B.B. Mishra, V.K. Tiwari, Natural products, an evolving role in future drug discovery, Eur. J. Med. Chem. 46 (2011) 4769e4807. A. Zumla, P. Nahid, S.T. Cole, Advances in the development of new tuberculosis drugs and treatment regimens, Nat. Rev. 12 (2015) 388e404. G.F. Pauli, R.J. Case, T. Inui, Y. Wang, S. Cho, N.H. Fischer, New perspectives on natural products in TB drug research, Life Sci. 78 (2005) 485e494. P.P. Mitra, Drug discovery in tuberculosis, a molecular approach, Ind. J. Tuberc. 59 (2012) 194e206. J.D. Guzman, A. Gupta, F. Bucar, Antimycobacterials from natural sources, ancient times, antibiotic era and novel scaffolds, Front. Biosci. 17 (2012) 1861e1881. M. Iwatsuki, R. Uchida, Y. Takakusagi, A. Matsumoto, C.L. Jiang, Y. Takahashi, M. Arai, S. Kobayashi, M. Matsumoto, J. Inokoshi, H. Tomoda, S. Omura, Lariatins, novel antimycobacterial peptides with a lasso structure, produced by Rhodococcus jostii K01eB0171, J. Antibiot. 60 (2007) 357e363. C.E. Salomon, L.E. Schmidt, Natural products as leads for tuberculosis drug development, Curr. Top. Med. Chem. 12 (2012) 735e765. H.A. Kirst, Developing new antibacterials through natural product research, Expert. Opin. Drug. Discov. 8 (2013) 479e493. S.B. Singh, K. Young, L. Miesel, Screening strategies for discovery of

541

antibacterial natural products, Exp. Rev. Anti Infect. Ther. 9 (2011) 589e613. [239] K. Mdluli, T. Kaneko, A. Upton, Tuberculosis drug discovery and emerging targets, Ann. N. Y. Acad. Sci. 1323 (2014) 56e75. [240] J.M. Nguta, R. Appiah-Opong, A.K. Nyarko, D. Yeboah-Manu, G.A. Addo, Medicinal plants used to treat TB in Ghana, Int. J. Mycobacteriol 4 (2015) 116e123. [241] A. Garcia, V. Bocanegra-Garcı
a, S.J.P. Palma-Nicola, G. Rivera, Recent advances in antitubercular natural products, Eur. J. Med. Chem. 49 (2012) 1e23. [242] S.S. Ramachandran, S. Balasubramanian, Plants: A Source for new antimycobacterial drugs, Planta Med. 80 (2014) 9e21. [243] O. Potterat, M. Hamburger, Natural products in drug discovery e concepts and approaches for tracking bioactivity, Curr. Org. Chem. 10 (2006) 899e920. [244] L.N. Rogoza, N.F. Salakhutdinov, G.A. Tolstikov, Antituberculosis activity of natural and synthetic compounds, Chem. Sust. Dev. 18 (2010) 343e375. [245] D.S. Seigler, Plant Secondary Metabolism, Springer, 2001, p. 628. [246] A. Krunic, S. Mo, G. Chlipala, J. Orjala, Antimicrobial ambiguine isonitriles from the cyanobacterium Fischerella ambigua, J. Nat. Prod. 72 (2009) 894e899. [247] A. Krunic, S. Mo, B.D. Santarsiero, S.G. Franzblau, J. Orjala, Hapalindole related alkaloids from the cultured cyanobacterium Fischerella ambigua, Phytochemistry 71 (2010) 2116e2123. [248] A.P.G. Macabeo, K. Krohn, D. Gehle, R.W. Read, J.J. Brophy, G.A. Cordell, S.G. Franzblau, A.M. Aguinaldo, Indole alkaloids from the leaves of Philippine Alstonia scholaris, Phytochemistry 66 (2005) 1158e1162. [249] C.A. Pallant, A.D. Cromarty, V. Steenkamp, Effect of an alkaloidal fraction of Tabernaemontana elegans (Stapf.) on selected micro-organisms, J. Ethnopharmacol. 140 (2012) 398e404. [250] S. Kanokmedhakul, K. Kanokmedhakul, N. Phonkerd, K. Soytong, P. Kongsaeree, A. Suksamrarn, Antimycobacterial anthraquinonechromanone compound and diketopiperazine alkaloid from the fungus Chaetomium globosum KMITL-N0802, Planta Med. 68 (2002) 834e836. [251] A.P.G. Macabeo, W.S. Vida, X. Chen, M. Decker, J. Heilmann, B. Wan, G.A. Cordell, Mycobacterium tuberculosis and cholinesterase inhibitors from Voacanga globosa, Eur. J. Med. Chem. 46 (2011) 3118e3123. [252] G. Cihan-Üstündag, G. Capan, Synthesis and evaluation of functionalized indoles as antimycobacterial and anticancer agents, Mol. Divers 16 (2012) 525e539. [253] H.M.E. Tehrani, S. Sardari, V. Mashayekhi, Z.M. Esfahani, P. Azerang, F. Kobarfard, One pot synthesis and biological activity evaluation of novel Schiff bases derived from 2-hydrazinyl- 1,3,4-thiadiazole, Chem. Pharm. Bull. 61 (2013) 160e166. [254] E. Yamuna, R.A. Kumar, M. Zeller, P.K.J. Rajendra, Synthesis, antimicrobial, antimycobacterial and structureeactivity relationship of substituted pyrazolo-, isoxazolo, pyrimido- and mercaptopyrimidocyclohepta[b]indoles, Eur. J. Med. Chem. 47 (2012) 228e238. [255] T.A. VanBeek, A.M. Deelder, R. Verpoorte, A.B. Svendsen, Antimicrobial, antiamoebic and antiviral screening of some Tabernaemontana species, Planta Med. 50 (1984) 180e185. ne, P. Bourgeois, A. Ahond, C. Poupat, P. Potier, Contri[256] J. Abaul, E. Philoge
es VI Alkaloids Taberbution to the study of American Tabernaemontane naemontana citrifolia leaves, J. Nat. Prod. 52 (1989) 1279e1283. [257] J. Vicente, B. Vera, A.D. Rodríguez, I. Rodríguez-Escudero, R.G. Raptis, Euryjanicin A, a new cycloheptapeptide from the Caribbean marine sponge Prosuberites laughlini, Tetrahedron Lett. 50 (2009) 4571e4574. [258] A. Domagala, T. Jarosz, M. Lapkowski, Living on pyrrolic foundations - Advances in natural and artificial bioactive pyrrole derivatives, Eur. J. Med. Chem. 50 (2015) 176e187. [259] A. Pansanit, E.J. Park, T.P. Kondratyuk, J.M. Pezzuto, K. Lirdprapamongkol, P. Kittakoop, Vermelhotin, an anti-inflammatory agent, suppresses nitric oxide production in RAW 264.7 cells via p38 inhibition, J. Nat. Prod. 76 (2013) 1824e1827. [260] K.A. El Sayed, M.T. Hamann, H.A. Abd El-Rahman, A.M. Zaghloul, New pyrrole alkaloids from Solanum sodomaeum, J. Nat. Prod. 61 (1998) 848e850. [261] D.R. Santo, R. Costi, M. Artico, S. Massa, G. Lampis, D. Deidda, R. Pompei, Pyrrolnitrin and related pyrroles endowed with antibacterial activities against Mycobacterium tuberculosis, Bioorg. Med. Chem. Lett. 8 (1998) 2931e2936. [262] J. Pandey, V.K. Tiwari, S.S. Verma, V. Chaturvedi, S.S. Bhatnagar, S. Sinha, R.P. Tripathi, Synthesis and antitubercular screening of imidazole based molecules, Eur. J. Med. Chem. 44 (2009) 3350e3355. [263] V.K. Tiwari, R.P. Tripathi, Unexpected Isomerisation of Double bond with DBU: A Convenient Synthesis of Tetrasubstituted a-alkylidene tetrahydrofuranoses, Ind. J. Chem. 41 (2002) 1681e1685. [264] C. Pullen, P. Schmitz, K. Meurer, D.D.V. Bamberg, S. Lohmann, S. de Castro € llmann, F. Gollmick, U. Gr€ França, I. Groth, B. Schlege, U. Mo afe, E. Leistner, New and bioactive compounds from Streptomyces strains residing in the wood of Celastraceae, Planta 216 (2002) 162e167. [265] J.M. Grange, N.J.C. Snell, Activity of bromhexine and ambroxol, semisynthetic derivatives of vasicine from the Indian shrub Adhatoda vasica, against Mycobacterium tuberculosis in vitro, J. Ethnopharma 50 (1996) 49e53. [266] M.M.K. Kumar, J.D. Naik, K. Satyavathi, H. Ramana, P.R. Varma, K.P. Nagasree, D. Smitha, D.V. Rao, Denigrins A-C, new antitubercular 3,4-diarylpyrrole alkaloids from Dendrilla nigra, Nat. Prod. Res. 28 (2014) 888e894.

542

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

[267] M. Biava, G.C. Porretta, G. Poce, L.A. De, M. Saddi, R. Meleddu, F. Manetti, R.E. De, M. Botta, 1,5-Diphenylpyrrole derivatives as antimycobacterial agents. Probing the influence on antimycobacterial activity of lipophilic substituents at the phenyl rings, J. Med. Chem. 51 (2008) 3644e3648. [268] M. Biava, G. Porretta, G. Poce, D. Deidda, R. Pompei, A. Tafic, F. Manetti, Antimycobacterial compounds. Optimization of the BM 212 structure, the lead compound for a new pyrrole derivative class, Bioorg. Med. Chem. 13 (2005) 1221e1230. [269] M. Biava, G.C. Porretta, G. Poce, S. Supino, D. Deidda, R. Pompei, P. Molicotti, F. Manetti, M. Botta, Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity, J. Med. Chem. 49 (2006) 4946e4952. [270] M. Biava, G.C. Porretta, G. Poce, L.A. De, R. Meleddu, R.E. De, F. Manetti, M. Botta, 1,5-Diaryl-2-ethyl pyrrole derivatives as antimycobacterial agents, design, synthesis, and microbiological evaluation, Eur. J. Med. Chem. 44 (2009) 4734e4738. [271] E.M.K. Wijeratne, H. He, S.G. Franzblau, A.M. Hoffman, A.A.L. Gunatilaka, Phomapyrrolidones A-C, antitubercular alkaloids from the endophytic fungus Phoma sp. NRRL 46751, J. Nat. Prod. 76 (2013) 1860e1865. [272] M. Isaka, W. Prathumpai, P. Wongsa, M. Tanticharoen, Hirsutellone F, a dimer of antitubercular alkaloids from the seed fungus Trichoderma sp. BCC 7579, Org. Lett. 8 (2006) 2815e2817. €lker, Occurrence, Biogenesis, and Synthesis [273] A.W. Schmidt, K.R. Reddy, H.J. Kno of Biologically Active Carbazole Alkaloids, Chem. Rev. 112 (2012) 3193e3328. [274] T. Thongthoom, U. Songsiang, C. Phaosiri, C. Yenjai, Biological activity of chemical constituents from Clausena harmandiana, Arch. Pharm. Res. 33 (2010) 675e680. [275] C. Auranwiwat, S. Laphookhieo, K. Trisuwan, S. Pyne, T. Ritthiwigrom, Carbazole alkaloids and coumarins from the roots of Clausena guillauminii, Phytochem. Lett. 9 (2014) 113e116. [276] A. Sunthitikawinsakul, N. Kongkathip, B. Kongkathip, S. Phonnakhu, S. Phonnakhu, J.W. Daly, T.F. Spande, Y. Nimit, S. Rochanaruangrai, Coumarins and carbazoles from Clausena excavata exhibited antimycobacterial and antifungal activities, Planta Med. 69 (2003) 155e157. [277] C. Ma, R.J. Case, Y. Wang, H.J. Zhang, G.T. Tan, N.V. Hung, Antituberculosis constituents from the stem bark of Micromelum hirsutum, Planta Med. 71 (2005) 261e267. [278] S. Gibbons, F. Fallah, C.W. Wright, Cryptolepine hydrochloride, a potent antimycobacterial alkaloid derived from Cryptolepis sanguinolenta, Phytother. Res. 17 (2003) 434e436. [279] K. Cimanga, T. de Bruyne, L. Pieters, J. Totte, L. Tona, K. Kambu, D.V. Berghe, A.J. Vlietinck, Antibacterial and antifungal activities of neocryptolepine, biscryptolepine and cryptoquindoline, alkaloids isolated from Cryptolepis sanguinolenta, Phytomedicine 5 (1998) 209e214. [280] G. O'Donnell, S. Gibbons, Antibacterial activity of two canthin-6-one alkaloids from Allium neapolitanum, Phytother. Res. 2l (2007) 653e657. [281] K.A. El Sayed, A.A. Khalil, M. Yousaf, G. Labadie, G.M. Kumar, S.G. Franzblau, A.M.S. Mayer, M.A. Avery, M.T. Hamann, Semisynthetic studies on the manzamine alkaloids, J. Nat. Prod. 71 (2008) 300e308. [282] J. Peng, K. Walsh, V. Weedman, J.D. Bergthold, J. Lynch, K.I. Lieu, I.A. Braude, M. Kelly, M.T. Hamann, The new bioactive diterpenes cyanthiwigins E-AA from the Jamaican sponge Myrmekioderma styx, Tetrahedron 58 (2002) 7809e7819. [283] NIAID's Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF), July 4, 2003. http//www.taacf.org/about-TB-background.htm. [284] S. Chandrasekhar, G.S.K. Babu, D.K. Mohapatra, Practical syntheses of (2S)R207910 and (2R)-R207910, Eur. J. Org. Chem. (2011) 2057e2061. [285] C.J. Qiao, X.K. Wang, F. Xie, W. Zhong, S. Li, Asymmetric synthesis and absolute configuration assignment of a new type of bedaquiline analogue, Molecules 20 (2015) 22272e22285. [286] A. Aguinaldo, V.M. Dalangin-Mallari, A.P. Macabeo, L. Byrne, F. Abe, T. Yamauchi, F.G. Franzblau, Quinoline alkaloids from Lunasia amara inhibit Mycobacterium tuberculosis H37Rv in vitro, Int. J. Antimicrob. Agents 29 (2007) 744e774. [287] H.Y. Huang, T. Ishikawa, C.F. Peng, I.L. Tsai, I.S. Chen, Constituents of the root wood of Zanthoxylum wutaiense with antitubercular activity, J. Nat. Prod. 71 (2008) 1146e1151. [288] N.S. Rao, A.B. Shaik, S.R. Routhu, S.M.A. Hussaini, S. Sunkari, A.V.S. Rao, A.M. Reddy, A. Alarifi, A. Kamal, New Quinoline Linked Chalcone and Pyrazoline Conjugates: Molecular Properties Prediction, Antimicrobial and Antitubercular Activities, Chem. Sel. (2017), http://dx.doi.org/10.1002/ slct.201602022. [289] R.S. Upadhayaya, J.K. Vandavasi, N.R. Vasireddy, V. Sharma, S.S. Dixit, J. Chattopadhyaya, Design, synthesis, biological evaluation and molecular modelling studies of novel quinoline derivatives against Mycobacterium tuberculosis, Bioorg. Med. Chem. 17 (2009) 2830e2841. [290] M.V.N.D. Souza, K.C. Pais, C.R. Kaiser, M.A. Peralta, M.D.L. Ferreira, M.C.S. Lourenco, Synthesis and in vitro antitubercular activity of a series of quinoline derivatives, Bioorg. Med. Chem. 17 (2009) 1474e1480. [291] S. Eswaran, A.V. Adhikari, I.H. Chowdhury, N.K. Pal, K.D. Thomas, New quinoline derivatives: synthesis and investigation of antibacterial and antituberculosis properties, Eur. J. Med. Chem. 45 (2010) 3374e3383. [292] A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S.G. Franzblau, A.P. Kozikowski, Structure activity relationships for a series of quinoline-based compounds

[293]

[294]

[295]

[296]

[297]

[298] [299]

[300]

[301] [302]

[303]

[304] [305]

[306]

[307]

[308]

[309]

[310]

[311] [312] [313]

[314]

[315]

[316]

[317] [318] [319]

active against replicating and nonreplicating mycobacterium tuberculosis, J. Med. Chem. 52 (2009) 2109e2118. P.J. Houghton, T.Z. Woldemariam, Y. Watanabe, M. Yates, Activity against Mycobacterium tuberculosis of alkaloid constituents of Angostura bark, Galipea officinalis, Planta Med. 65 (1999) 250e254. M. Adams, A.A. Wube, F. Bucar, R. Bauer, O. Kunert, E. Haslinger, Quinolone alkaloids from Evodia rutaecarpa, a potent new group of antimycobacterial compounds, Int. J. Antimicrob. Agents 26 (2005) 262e264. L.H. Rasoanaivo, A. Wadouachi, T.T. Andriamampianina, S.G. Andriamalala, E.J.B. Razafindrakoto, A. Raharisololalao, F. Randimbivololona, Triterpenes and steroids from the stem bark of Gambeya boiviniana Pierre, J. Pharma. Phytochem. 3 (2014) 68e72. M.Z. Ahmad, M. Ali, S.R. Mir, Anti-diabetic activity of Ficus carica L. stems barks and isolation of two new flavonol esters from the plant by using spectroscopical techniques, Asian J. Biomed. Pharm. Sci. 3 (2013) 23e28. A. Kamboj, A.K. Saluja, Isolation of Stigmasterol and b-sitosterol from petroleum ether extract of aerial parts of Ageratum conyzoides (Asteraceae), Int. J. Pharm. Pharm. Sci. 3 (2011) 94e96. L. Wirasathien, C. Boonarkart, T. Pengsuparp, R. Suttisri, Biological activities of alkaloids from Pseuduvaria setose, Pharm. Biol. 44 (2006) 274e278. S. Sureram, S.P.D. Senadeera, P. Hongmanee, C. Mahidol, S. Ruchirawat, P. Kittakoop, Antimycobacterial activity of bisbenzylisoquinoline alkaloids from Tiliacora triandra against multidrug-resistant isolates of Mycobacterium tuberculosis, Bioorg. Med. Chem. Lett. 22 (2012) 2902e2905. Z.J. Zhang Yan, K. Xu, Z. Ji, L. Li, Tetrandrine reverses drug resistance in isoniazid and ethambutol dual drug-resistant Mycobacterium tuberculosis clinical isolates, BMC Infect. Dis. 15 (2015) 153. N. Bhagya, K.R. Chandrashekar, Tetrandrine- A molecule of wide bioactivity, Phytochemistry 125 (2016) 5e13. A.E. Wright, D.A. Forleo, G.P. Gunawardana, S.P. Gunasekera, F.E. Koehn, O.J. McConnell, Antitumor tetrahydroisoquinoline alkaloids from the colonial ascidian Ecteinascidia turbinate, J. Org. Chem. 55 (1990) 4508e4512. K.L. Rinehart, T.G. Holt, N.L. Fregeau, J.G. Stroh, P.A. Keifer, F. Sun, L.H. Li, D.G. Martin, Ecteinascidins 729, 743, 745, 759A, 759B, and 770, potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinate, J. Org. Chem. 55 (1990) 4512e4515. K.L. Rinehart, T.G. Holt, WO8707610, 1992, US 5089273. K. Suwanborirux, K. Charupant, S. Amnuoypol, S. Pummangura, A. Kubo, N. Saito, Ecteinascidins 770 and 786 from the Thai tunicate Ecteinascidia thurstoni, J. Nat. Prod. 65 (2002) 935e937. J.D. Guzman, A. Gupta, D. Evangelopoulos, C. Basavannacharya, L.C. Pabon, E.A. Plazas, D.R. Munoz, W.A. Delgado, L.E. Cuca, W. Ribon, S. Gibbons, S. Bhakta, Antitubercular screening of natural products from Colombian plants, 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis, J. Antimicrob. Chemother. 65 (2010) 2101e2107. M.R. Camacho, G.C. Kirby, D.C. Warhurst, S.L. Croft, J.D. Phillipson, Oxoaporphine alkaloids and quinones from Stephania dinklagei and evaluation of their antiprotozoal activities, Planta Med. 66 (2000) 478e480. M.R. Camacho-Corona, J.M.J. Favela-Hernandez, O. Gonzalez-Santiago, E. Garza-Gonzalez, G.M. Molina-Salinas, S. Said-Fernandez, G. Delgado, J. Luna-Herrera, Evaluation of some plant-derived secondary metabolites against sensitive and multidrug-resistant Mycobacterium tuberculosis, J. Mex. Chem. Soc. 53 (2009) 71e75. R.S. Lekphrom, K. Kanokmedhakul, Bioactive styryllactones and alkaloid from flowers of Goniothalamus laoticus, J. Ethnopharmacol. 125 (2009) 47e50. X. Luo, D. Pires, J.A. Ainsa, B. Gracia, N. Duarte, S. Mulhovo, E. Anes, M.J.U. Ferreira, Zanthoxylum capense constituents with antimycobacterial activity against Mycobacterium tuberculosis in vitro and ex vivo within human macrophages, J. Ethnopharmacol. 146 (2013) 417e422. T. Ishikawa, Benzo[c]phenanthridine bases and their antituberculosis activity, Med. Res. Rev. 21 (2001) 61e72. L.A. Mitscher, W.R. Baker, A search for novel chemotherapy against tuberculosis amongst natural products, Pure Appl. Chem. 70 (1998) 365e371. A.L. Okunade, C.D. Hufford, M.D. Richardson, J.R. Peterson, A.M. Clark, Antimicrobial properties of alkaloids from Xanthorhiza simplicissima, J. Pharm. Sci. 83 (1994) 404e406. E.J. Gentry, H.B. Jampani, A. Keshavarz-Shokri, M.D. Morton, D. Velde, H. Telikepalli, Antitubercular natural products, berberine from the roots of commercial Hydrastis canadensis powder. Isolation of inactive 8oxotetrahydrothalifendine, canadine, beta-hydrastine, and two new quinic acid esters, hycandinic acid esters-1 and -2, J. Nat. Prod. 61 (1998) 1187e1193. A. Mahapatra, V. Maheswari, N.P. Kalia, V.S. Rajput, I.A. Khan, Synthesis and antitubercular activity of berberine derivatives, Chem. Nat. Comp. 50 (2014) 321e325. S.M. Newton, C. Lau, S.S. Gurcha, G.S. Besra, C.W. Wright, The evaluation of forty-three plant species for in vitro antimycobacterial activities, isolation of active constituents from Psoralea corylifolia and Sanguinaria Canadensis, J. Ethnopharmacol. 79 (2002) 5e67. Y. Fu, B. Hu, Q. Tang, Q. Fu, J. Xiang, Hypoglycemic activity of jatrorrhizine, J. Huazhong Univ. Sci. Tech. Med. Sci. 25 (2005) 491e493. A. Villar, M. Mares, J.L. Rıos, E. Canton, M. Gobernado, Antimicrobial activity of benzylisoquinoline alkaloids, Pharmazie 42 (1987) 248e250. Y. Tian, C. Zhang, M. Guo, Comparative analysis of amaryllidaceae alkaloids

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 from three Lycoris species, Molecules 20 (2015) 21854e21869. [320] S.D. Shanmugakumaran, G.S. Kumar, V. Layambhica, K. Natraj, Pharmacolognostical, Phytochemical & Antimycobacterial Perspectives of the Leaf Extracts of Samanea Saman, IJPT 3, 2011, pp. 3202e3217. [321] S.D. Shanmugakumar, G. Satheesh Kumar, Isolation of pithecolobine from the leaf extracts of Samanea saman (Jacq.) Merr and its in vitro antitubercular screening and related infections, IJIPSR 2 (2014) 1098e1109. [322] S. Ignacimuthu, N. Shanmugam, Antimycobacterial activity of two natural alkaloids, vasicine acetate and 2-acetyl benzylamine, isolated from Indian shrub Adhatoda vasica Ness. leaves, J. Biosci. 35 (2010) 565e570. [323] D.K. Jha, L. Panda, P. Lavanya, S. Ramaiah, A. Anbarasu, Detection and confirmation of alkaloids in leaves of Justicia adhatoda and bioinformatics approach to elicit its anti-tuberculosis activity, Appl. Biochem. Biotechnol. 168 (2012) 980e990. [324] W.R. Baker, L.A. Mitscher, B. Feng, S. Cai, M. Clark, T. Leung, J.A. Towell, I. Darwish, K. Stover Kereiswirth, S. Moghazeh, T. Hennquez, A. Resconi and T. Arain, 35th ICAAC, (San Francisco), 1995, Abst F17, 116. € ck, [325] J.H.H.L. de Oliveira, M.H.R. Seleghim, C. Timm, A. Grube, M. Ko G.C.F. Nascimento, A.C.T. Martins, E.G.O. Silva, A.O. de Souza, P.R.R. Minarini, F.C.S. Galetti, C.L. Silva, E. Hadju, R.G.S. Berlinck, Antimicrobial and antimycobacterial activity of cyclostellettamine alkaloids from sponge Pachychalina sp. Mar. Drugs 4 (2006) 1e8. [326] D.R. Appleton, A.N. Pearce, B.R. Copp, Anti-tuberculosis natural products, synthesis and biological evaluation of pyridoacridone alkaloids related to ascididemin, Tetrahedron 66 (2010) 4977e4986. [327] A.R. Carroll, P.J. Scheuer, Kuanoniamines A, B, C, and D, pentacyclic alkaloids from a tunicate and its prosobranch mollusk predator Chelynotus semperi, J. Org. Chem. 55 (1990) 4426e4431. [328] F.J. Schmitz, F.S. De Guzman, M.B. Hossain, D. Van der Helm, Cytotoxic aromatic alkaloids from the ascidian Amphicarpa meridiana and Leptoclinides sp., meridine and 11-hydroxyascididemin, J. Org. Chem. 56 (1991) 804e808. [329] B.R. Copp, R.P. Hansen, D.R. Appleton, B.S. Lindsay, C.J. Squire, G.R. Clark, C.E. Rickard, A Convenient New Route to 4-Substituted Benzo[de][3,6]Phenanthrolin-6(6H)-Ones, Important Intermediates in the Synthesis of Ring-A Analogues of the Cytotoxic Marine Alkaloid Ascididemin F, Synth. Commun. 29 (1999) 2665e2676. [330] N. Saxena, S.S. Verma, V.K. Tiwari, V. Chaturvedi, Y.K. Manju, A.K. Srivastva, A. Gaikwad, S. Sinha, R.P. Tripathi, Synthesis and antitubercular activities of substituted benzyl- and heteroaryl amines, Bioorg. Med. Chem. 14 (2006) 8186e8196. [331] J.R. Peterson, J.K. Zjawiony, S. Liu, C.D. Hufford, A.M. Clark, R.D. Rogers, Copyrine alkaloids, synthesis, spectroscopic characterization, and antimycotic/antimycobacterial activity of A- and B-ring functionalized sampangines, J. Med. Chem. 35 (1992) 4069e4077. [332] P.G. Waterman, I. Muhammad, Sesquiterpenes and alkaloids from Cleistopholis patens, Phytochemistry 24 (1985) 523e527. [333] P. Claes, D. Cappoen, B.M. Mbala, J. Jacobs, B. Mertens, V. Mathys Verschaeve, L.K. Huygen, N.D. Kimpe, Synthesis and antimycobacterial activity of analogues of the bioactive natural products sampangine and cleistopholine, Eur. J. Med. Chem. 67 (2013) 98e110. [334] A.L. Okunade, A.M. Clark, C.D. Hufford, B.O. Oguntimein, Azaanthraquinone, an antimicrobial alkaloid from Mitracarpus scaber, Planta Med. 65 (1999) 447e448. [335] P. Tuntiwachwuttikul, P. Phansa, Y. Pootaengon, W. Charles, Chemical constituents of the roots of Piper sarmentosum, Chem. Pharm. Bull. 54 (2006) 149e151. [336] L.A. Shaala, D.T.A. Youssef, K.L. McPhail, M. Elbandy, Malyngamide 4, a new lipopeptide from the Red Sea marine cyanobacterium Moorea producens (formerly Lyngbya majuscula), Phytochem. Lett. 6 (2013) 183e188. [337] M. Isaka, N. Rugseree, P. Maithip, P. Kongsaeree, S.P.Y. Thebtaranonth, Hirsutellones AeE, antimycobacterial alkaloids from the insect pathogenic fungus Hirsutella nivea BCC 2594, Tetrahedron 61 (2005) 5577e5583. [338] P. Aqueveque, T. Anke, O. Sterner, The himanimides, new bioactive compounds from Serpula himantoides (Fr.) Karst Z, Naturforsch C 57 (2002) 257e262. [339] H.V. Kemani Wangun, C. Hertweck, Epicoccarines A, B and epipyridone, tetramic acids and pyridine alkaloids from an Epicoccum sp. associated with the tree fungus Pholiota squarrosa, Org. Biomol. Chem. 5 (2000) 1702e1705. [340] B. Waters, G. Saxena, Y. Wanggui, D. Kau, S. Wrigley, R. Stokes, J. Davies, Identifying protein kinase inhibitors using an assay based on inhibition of aerial hyphae formation in Streptomyces, J. Antibiot. 55 (2002) 407e416. [341] S.J. Trew, S.K. Wrigley, L. Pairet, J. Sohal, P. Shanu-Wilson, M.A. Hayes, S.M. Martin, R.N. Manohar, M.I. Chicarelli-Robinson, D.A. Kau, C.V. Byrne, E.M.H. Wellington, J.M. Moloney, J. Howard, D. Hupe, E.R. Olson, Novel streptopyrroles from Streptomyces rimosus with bacterial protein histidine kinase inhibitory and antimicrobial activities, J. Antibiot. 53 (2000) 1e11. [342] J. Jin, J. Zhang, N. Guo, H. Feng, L. Li, J. Liang, K. Sun, X. Wu, X. Wang, M. Liu, X. Deng, L. Yu, The plant alkaloid piperine as a potential inhibitor of ethidium bromide efflux in Mycobacterium smegmatis, J. Med. Microbiol. 60 (2011) 223e229. [343] T. Rukachaisirikul, S. Prabpai, P. Champung, A. Suksamram, Chabamide, a novel piperine dimer from stems of Piper chaba, Planta Med. 68 (2002) 853e855. [344] X. Wei, K. Nieves, A.D. Rodríguez, Neopetrosiamine A, biologically active bispiperidine alkaloid from the Caribbean Sea sponge Neopetrosia proxima,

543

Bioorg. Med. Chem. Lett. 20 (2010) 5905e5908. [345] M. Arai, M. Sobou, C. Vilcheze, A. Baughn, H. Hashizume, P. Pruksakorn, S. Ishida, M. Matsumoto, W.R. Jacobs, M. Kobayashi, Halicyclamine A, a marine spongean alkaloid as a lead for antituberculosis agent, Bioorg. Med. Chem. 16 (2008) 6732e6736. [346] M. Arai, S. Ishida, A. Setiawan, M. Kobayashi, Haliclonacyclamines, Tetracyclic Alkylpiperidine Alkaloids, as Anti-dormant Mycobacterial Substances from a Marine Sponge of Haliclona sp. Chem. Pharm. Bull. 57 (2009) 1136e1138. [347] R.D. Charan, M.J. Garson, I.M. Brereton, A.C. Willis, J.N.A. Hooper, Haliclonacyclamines A and B, Cytotoxic Alkaloids from the Tropical Marine Sponge Haliclona sp. Tetrahedron 52 (1996) 9111e9120. [348] P. Panseeta, K. Lomchoey, S. Prabpai, P. Kongsaeree, A. Suksamrarn, S. Ruchirawat, S. Suksamrarn, Antiplasmodial and antimycobacterial cyclopeptide alkaloids from the root of Ziziphus mauritiana, Phytochemistry 72 (2011) 905e915. [349] H. Wu, H. Nakamura, J. Kobayashi, Y. Ohizumi, Y. Hirata, Agelasine-E and F, novel monocyclic diterpenoids with 9-methyladeninium unit possessing inhibitory effects on Naþ,Kþ-ATPase isolated from the Okinawan sea sponge Agelas nakamurai Hoshino, Tetrahedron Lett. 25 (1984) 3719e3722. [350] A.K. Bakkestuen, L.L. Gundersen, D. Petersen, B.T. Utenova, A. Vik, Synthesis and antimycobacterial activity of agelasine E and analogs, Org. Biomol. Chem. 3 (2005) 1025e1033. [351] R.J. Capon, D.J. Faulkner, Antimicrobial metabolites from a Pacific sponge, Agelas sp, J. Am. Chem. Soc. 106 (1984) 1819e1822. [352] G.C. Mangalindan, M.T. Talaue, L.J. Cruz, S.G. Franzblau, L.B. Adams, A.D. Richardson, Agelasine F from a Philippine Agelas sp. sponge exhibits in vitro antituberculosis activity, Planta Med. 66 (2000) 364e365. [353] A. Proszenyak, C. Charnock, E. Hedner, R. Lars, L. Bohlin, Synthesis, antimicrobial and antineoplastic activities for agelasine and agelasimine analogs with a b-cyclocitral derived substituents, Arch. Pharm. Chem. Life Sci. 340 (2007) 625e634. [354] A. Vik, E. Hedner, C. Charnock, O. Samuelsen, Z.R. Larsson, L.L. Gundersen, L. Bohlin, (þ)-agelasine D, Improved synthesis and evaluation of antibacterial and cytotoxic activities, J. Nat. Prod. 69 (2006) 381e386. [355] H.M. Hua, J. Peng, D.C. Dunbar, R.F. Schinazi, A.G. de Castro Andrews, C. Guevas, L.F. Garcia Fernandez, M. Kelly, M.T. Hamann, Batzelladine alkaloids from the Caribbeean sponge Monanchora unguifera and the significant activities against HIV-I and AIDS opportunistic infectious pathogens, Tetrahedron 63 (2007) 11179e11188.
uez, C. Ramý
rez, Serrulatane diterpenes with antimycobacterial [356] A.D. Rodrýg activity isolated from the West Indian sea whip Pseudopterogorgia elisabethae, J. Nat. Prod. 64 (2001) 100e102.
uez, A.D. Rodrýg
uez, Homopseudopteroxazole, a new anti[357] I.I. Rodrýg mycobacterial diterpene alkaloid from Pseudopterogorgia elisabethae, J. Nat. Prod. 66 (2003) 855e857. [358] A.D. Rodríguez, C. Ramírez, I.I. Rodríguez, E. Gonz
alez, Novel antimycobacterial benzoxazole alkaloids, from the west Indian Sea whip Pseudopterogorgia elisabethae, Org. Lett. 1 (1999) 527e530. [359] H. Sasaki, Y. Haraguchi, M. Itotani, H. Kuroda, H. Hashizume, T. Tomishige, M. Kawasaki, M. Matsumoto, M. Komatsu, H. Tsubouchi, Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3dihydroimidazo[2,1-b]oxazoles, J. Med. Chem. 49 (2006) 7854e7860. ne, P. Bourgeois, Anti[360] N. Rastogi, J. Abaul, K.S. Goh, A. Devallois, E. Philoge mycobacterial activity of chemically defined natural substances from the Caribbean flora in Guadeloupe, FEMS Immunol. Med. Microbiol. 20 (1998) 267e273. [361] A. Mukai, T. Fukai, Y. Matsumoto, J. Ishikawa, Y. Hoshino, K. Yazawa, K. Harada, Y. Mikami, Transvalencin Z, a new antimicrobial compound with salicylic acid residue from Nocardia transvalensis M 10065, J. Antibiot. 59 (2006) 366e369.
s, A.D. Rodríguez, Monamphilectine A, a potent antimalarial-lactam [362] E. Avile from marine sponge Hymenia cidon sp, isolation, structure, semisynthesis, and bioactivity, Org. Lett. 12 (2010) 5290e5293. [363] P. Kagthara, T. Upadhyay, R. Doshi, H.H. Parekh, Synthesis of some 2azetidinones as potential antitubercular agents, Ind. J. Hetrocyclic. Chem. 10 (2000) 9e12. [364] K. Ilango, S. Arunkumar, Synthesis, Antimicrobial and Antitubercular Activities of Some Novel Trihydroxy Benzamido Azetidin-2-one Derivatives, Trop. J. Pharm. Res. 10 (2011) 219e229. [365] G. O'Donnell, R. Poeschl, O. Zimhony, M. Gunaratnam, J.B.C. Moreira, S. Neidle, D. Evangelopoulos, S. Bhakta, J.P. Malkinson, A. Lenaerts, S. Gibbons, Bioactive pyridine-N-oxide disulfides from Allium stipitatum, J. Nat. Prod. 72 (2009) 360e365. [366] J. Boruwa, B. Kalita, N.C. Barua, J.H. Borah, S. Mazumder, D. Thakur, Synthesis, absolute stereochemistry and molecular design of the new antifungal and antibacterial antibiotic produced by Streptomyces sp.201, Bioorg. Med. Chem. Lett. 14 (2004) 3571e3574. [367] C.C. Cain, D. Lee, R.H. Waldo III, A.T. Henry, E.J. Casida, M.C. Wani, M.E. Wall, N.H. Oberlies, J.O. Falkinham 3rd., Synergistic antimicrobial activity of metabolites produced by a non-obligate bacterial predator, Antimicrob. Agents Chemother. 47 (2003) 2113e2117. [368] K.Y. Orabi, K.A. El Sayed, M.T. Hamann, D.C. Dunbar, M.S. Al-Said, T. Higa, M. Kelly, Araguspongines K and L, new bioactive bis-1-oxaquinolizidine Noxide alkaloids from Red Sea specimens of Xestospongia exigua, J. Nat. Prod.

544

S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

65 (2002) 1782e1785. [369] M.F. De Oliveira, J. de Oliveira, F.C.S. Galetti, A.O. De Souza, C.L. Silva, E. Hajdu, S. Peixinho, R.G.S. Berlinck, Antimycobacterial brominated metabolites from two species of marine sponges, Planta Med. 72 (2006) 437e441. [370] K.W. Nam, W.S. Jang, M.A. Jyoti, S. Kim, B.E. Lee, H.Y. Song, In vitro activity of (-)-deoxypergularinine, on its own and in combination with anti-tubercular drugs, against resistant strains of Mycobacterium tuberculosis, Phytomed 23 (2016) 578e582. [371] S. Lebrun, A. Couture, E. Deniau, P. Granddaudon, Total Syntheses of (þ)-Cryptopleurine, (þ)-Antofine and (þ)-Deoxypergnlarinine, Tetrahedron 55 (1999) 2659e2670. [372] M. Chinwornangsee, P. Kittakoop, J. Saenboonrueng, P. Kongsaeree, Y. Thebtaranonth, Bioactive compounds from the seed fungus Menisporopsis theobromae BCC 3975, J. Nat. Prod. 69 (2006) 1404e1410. ^a, L.V. Pozzi, A.E. Graminha, H.S. Selistre-de-Araújo, [373] E.R. dos Santos, R.S. Corre F.R. Pavan, A.A. Batista, Antitumor and anti-Mycobacterium tuberculosis agents based on cationic ruthenium complexes with amino acids, Inorg. Chim. Act. 463 (2017) 1e6. http://doi.org/10.1016/j.ica.2017.04.012.

[374] M.T. Hamann, The Manzamines as an Example of the Unique Structural Classes Available for the Discovery and Optimization of Infectious Disease Controls Based on Marine Natural Products, Curr. Pharm. Des. 13 (2007) 653e660. [375] P.H. França, D.P. Barbosa, D.L. Silva, E.A, A.E. Ribeiro, B.V. Santana, J.M. Santos, J.S. Barbosa-Filho, R.S. Quintans, L.J. Barreto, Quintans-Júnior, J.X. de AraújoJúnior, Indole alkaloids from marine sources as potential leads against infectious diseases, Biomed. Res. Int. 375423 (2014) 1e12. [376] W.M. Bennett, Organic reactions on solid-support-an overview, In Combinatorial Chemistry (ed. H. Fenniri), Oxford Univ. Press, pp. 139e262. [377] D. Kumar, D. Kushwaha, B.B. Mishra, V.K. Tiwari, Impact of Solid-supported Cyclization-Elimination Strategies towards the Natural Product Inspired Molecules in Drug Research, in: G. Brahmachari (Ed.), Bioactive Natural Products, CRC Press, Taylor & Francis Group, USA, 2012, pp. 9e30. [378] R.A. Fecik, K.E. Frank, E.J. Gentry, L.A. Mitscher, M. Shibata, Use of combinatorial and multiple parallel synthesis methodologies for the development of anti-infective natural products, Pure Appl. Chem. 71 (1999) 559e564.