New potential drug leads against MDR-MTB: A short review

Bioorganic Chemistry 95 (2020) 103534

Contents lists available at ScienceDirect

Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg

New potential drug leads against MDR-MTB: A short review Srikanth Gatadi, Srinivas Nanduri

⁎

T

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India

ARTICLE INFO

ABSTRACT

Keywords: Drug resistance Multidrug resistant Mycobacterium tuberculosis (MDR-MTB) In vitro activity Structure Activity Relationship (SAR)

Multidrug resistant Mycobacterium tuberculosis (MDR-MTB) infections have created a critical health problem globally. The appalling rise in drug resistance to all the current therapeutics has triggered the need for identifying new antimycobacterial agents effective against multidrug-resistant Mycobacterium tuberculosis. Structurally unique chemical entities with new mode of action will be required to combat this pressing issue. This review gives an overview of the structures and outlines on various aspects of in vitro pharmacological activities of new antimycobacterial agents, mechanism of action and brief structure activity relationships in the perspective of drug discovery and development. This review also summarizes on recent reports of new antimycobacterial agents.

1. Introduction

2. Antimycobacterial agents

Mycobacterium tuberculosis, one of the ubiquitous infectious pathogen and main causative agent of dreadful multi drug resistant tuberculosis has become an alarming health menace causing high rate of morbidity and mortality globally [1–7]. Alarmingly, India is among the 30 high TB burden countries as estimated by WHO [8]. Rise in drug resistance to all the available therapeutics has spurred the need for identifying new antimycobacterial agents with new mode of action to combat this pressing issue [9–12]. Multidrug resistant Mycobacterium tuberculosis has emerged as the formidable bacterial strains for the current antimycobacterial chemotherapeutics which includes isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, pyriodoxine, cycloserine, rifabutine, levofloxacin, etc. [13–26]. Exploration of antimycobacterial agents of new heterocycles with new mechanism of action has recently gained enormous interest to evade drug resistance. In the quest for new antimycobacterial agents against multidrug resistant Mycobacterium tuberculosis, several medicinal chemists have developed various heterocyclic systems with appealing antimycobacterial properties. This review provides an overview on recent reports of new antimycobacterial agents and summarizes on different aspects of in vitro pharmacological activities of new antitubercular agents, mechanism of action and Structure Activity Relationships.

2.1. 4(3H)-Quinazolinone derivatives Quinazolinone is a privileged heterocycle having significant antimycobacterial properties. Currently, it gained interest in synthesis and research. Several researchers have reported the anti-Mycobacterial properties of quinazolinone derivatives. Trivedi et al. reported the in vitro antimycobacterial activity of thiazolidinone (1), hydrazide (2) and thiosemicarbazide derivatives (3), (Fig. 1) which was performed by serial two fold dilution method against Mycobacterium tuberculosis (H37Rv) using Löwenstein–Jensen medium. They inferred that the reduction of growth rate at 37 °C until six weeks. All the compounds tested were found to be active against M. tuberculosis with MIC value of 0.03 µg/mL and exhibited zone of inhibition < 20 mm [27]. Pattan et al. screened a series of new thiazolino quinazolin-4-(3H)-one derivatives (4) (Fig. 1) against M. tuberculosis at 10, 50 and 100 µg/mL concentration level and compared with drug streptomycin. The results suggested that incorporation of isoniazid, p-amino salicylic acid and pyrazinamide with quinazolinone nucleus resulted in increased activity. SAR studies indicated that the p-nitrophenyl, p-methylphenyl and pyrazine derivatives exhibited modest anti-tubercular activity whereas, pchlorophenyl, p-fluorophenyl and p-methoxyphenyl derivatives did not exhibit anti-tubercular activity [28]. Primary screening of 3-phenyl-6-

Abbreviations: ADMET, Absorption, Distribution, Metabolism, Excretion, Toxicity; BCG, Bacille Calmette Guerin; ctDNA, Circulating tumor DNA; CGM, Cyclohexylgriselimycin; ELT, Encoded Library Technology; INH, Isoniazid; LJ, Lowenstein-Jensen medium; MDR, multidrug-resistant; MIC, Minimum Inhibitory Concentration; MGIT, Mycobacterium Growth Indicator Tube; MBC, Minimum Bactericidal Concentration; PLG-NPs, poly(lactide-co-glycolide) nanoparticles; PLGA, poly(lactide-co-glycolide); RIF, Rifampicin; SAR, Structure−activity relationships; XDR, Extensively Drug-Resistant ⁎ Corresponding author. E-mail address: [email protected] (S. Nanduri). https://doi.org/10.1016/j.bioorg.2019.103534 Received 3 October 2019; Received in revised form 26 November 2019; Accepted 20 December 2019 Available online 23 December 2019 0045-2068/ © 2019 Elsevier Inc. All rights reserved.

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 1. Some new 4(3H)-quinazolinone derivatives possessing antimycobacterial activity.

methyl-4-(3H)-quinazolinone-2-yl-mercapto acetic acid arylidene hydrazide derivatives (5) (Fig. 1) using BACTEC radiometric sensitivity assay against M. tuberculosis H37Rv strain indicated that the none of tested compounds were found active at 6.5 µg/mL doses [29]. Shirodkar et al. reported the In vitro anti-tubercular studies of new 6-nitro quinazolinones derivatives (6) (Fig. 1) at concentration level 100, 50, 25, 12.5, 6.25, 3, 2 and 1 µg/mL against H37Rv strain and compared with isoniazid. The In vitro activity data revealed that the nitro group containing compounds exhibited better activity among the tested compounds with MIC value of 6.25 µg/mL [30]. Trivedi et al. introduced some new 4-thiazolidinone derivatives (7) (Fig. 1) and primarily examined against H37Rv strain of M. tuberculosis. The in vitro data revealed that none of the compounds were found to be active at 12.5 µg/mL concentration [31]. Nandy and co-workers reported the antimycobacterial activity of Mannich bases of 2-methyl quinazolin-4(3H)-one (8) derivatives (Fig. 1) and evaluated against M. tuberculosis H37Rv at concentrations 100, 10 and 1 µg/mL. The studies revealed that the 6-chloro benzothiazole derivatives exhibited absolute growth inhibition at all tested concentrations which is equivalent to standard streptomycin. SAR results concluded that in benzothiazole ring at position C-6 and C-7 and presence of electron acceptor group make the compound loss of antimycobacterial activity [32]. Recently, Gatadi et al. reported the antimycobacterial properties of new 4(3H)-quinazolinone derivatives. SAR studies revealed that the compounds possessing phenyl (9), 4-floro phenyl (10) group at position C-7 on quinazolinone heterocycle exhibited modest activity against M. tuberculosis H37Rv. Compounds possessing N-prop-2-yn-1-yl group (11) at C-7, and 3- or 4-chlorophenyl-1H-1,2,3-triazol-4-ylmethoxy moieties (12, 13) at C-6 also exhibited activity against M. tuberculosis H37Rv ranged from 4 to 16 µg/mL. Compounds 14 and 15 with 4-cyanostyryl moiety at C-2 exhibited inhibitory activity against M. tuberculosis H37Rv with MIC values of 8 and 2 µg/mL respectively (Fig. 2). However, compounds with substituted phenyl at C-6, prop-2-yn-1-ylamino group at C-7, phenyl at C-7, 4-phenyl-1H-1,2,3-triazole group at C-7, ((4-(4methoxyphenyl)-1H-1,2,3-triazole group at C-7)) with styryl moiety at C-2 on ring A of quinazolin-4(3H)-one did not exhibit activity against mycobacteria. Additionally, quinazolinone compounds with allyloxy

and nitrile group at meta position of the N-phenyl moiety, replacement of X = C with X = N at C8 position did not display activity against mycobacteria. Compounds with methyl acetate or benzyl group at N-3 with prop-2-yn-1-yloxy or phenyl-1H-1,2,3-triazol-4-ylmethoxy group at C-6 also did not exhibit antimycobacterial activity [33]. The brief Structure Activity Relationships are summarised in Fig. 3. In conclusion, the SAR studies indicated that the methyl acetate, 2carboxy-4-hydroxy phenyl, naphthalen-1-yl, benzyl, (trifluoromethyl) phenyl amino, (indol-3-yl)ethyl, pyridin-3-yl moieties at R1 did not exhibit activity against M. tuberculosis (Fig. 3). However, methylamine, benzohydrazide, thiazole moieties were well favoured. Un-substituted styryl moiety at R2 did not exhibit activity, whereas 4-cyano styryl moiety exhibited potent activity against M. tuberculosis H37Rv. Methyl, thiol and phenyl moieties at C-2 were also tolerated for anti-mycobacterial activity and benzyl group at N-3 was found to be detrimental for antimycobacterial activity (Fig. 3). Replacement of H with fluoro group at R3 was favoured and showed potent activity against Mycobacterium tuberculosis H37Rv. Substitutions at R4 was not tolerated against M. tuberculosis. Substitutions at R5 with phenyl, 4-fluoro phenyl, prop-2-yn-1-ylamino groups were tolerated against Mycobacterium tuberculosis. Replacement of X = C with X = N was not favourable against Mycobacterium tuberculosis H37Rv (Fig. 3). Taken together, these quinazolinones were found to be promising templates for further development as potent anti-mycobacterial leads. 2.2. Indole-2-carboxamide derivatives Stec et al. [34] identified a set of new indolecarboxamides as trehalose monomycolate transporter MmpL3. SAR analysis of these compounds, resulted in identification of a new active analogue, 4,6-difluoro-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1Hindole-2-carboxamide (16), (Fig. 4). which exhibited excellent activity against drug-sensitive, multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosis isolates. These compounds showed synergy with rifampin, superior ADMET properties and promising activity in the TB aerosol lung infection model. Onajole et al. discovered a new indole-2-carboxamide derivatives as a potent 2

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 2. Some new 2-methyl and 2-styryl quinazolinone derivatives possessing antimycobacterial activity.

antimycobacterial agent. The group efforts led to the identification of molecules having a potent activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis, with MIC values lower than the available anti-TB drugs. Compound 17 (Fig. 4) was found to be most active against the tested XDR-TB strains [35]. Kondreddi and co-workers identified indole-2-carboxamides as a promising class of antituberculosis agents by using phenotypic screening technique. Structure–activity relationship analysis revealed that attaching alkyl groups to the cyclohexyl ring enhanced anti-Mtb activity but reduced solubility. Chloro, fluoro, or cyano groups on the -positions 4- and 6 of the indole ring as well as methyl group on the cyclohexyl ring prominently improved metabolic stability. Compounds 18, 19 and 20 (Fig. 4) displayed improved in vitro activity compared to the current standard TB drugs. Due to favorable oral pharmacokinetic properties and excellent in vivo efficacy represent indole-2-carboxamides as a promising new class of antituberculosis agents [36]. The Structure Activity Relationships are summarised in Fig. 5. In conclusion, the SAR studies suggested that the Indole-2-carboxamide is a validated moiety for the antimycobacterial activity. Amide linker is essential for inhibitory activity. (1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane, methylcyclohexane, dimethylcyclohexane, cyclooctane moieties at position R1 exhibited potent activity against Mycobacterium tuberculosis H37Rv (Fig. 5). Chloro, fluoro, and methyl groups at R2 are found to be active against M. tuberculosis H37Rv.

Chloro, fluoro, and methyl groups at R3 are also favoured and found to be active against M. tuberculosis H37Rv (Fig. 4). All together, these Indole-2-carboxamide derivatives are found to be potential scaffolds for further development as potent antitubercular leads. 2.3. Benzofuran derivatives He et al. [37] described a medicinal chemistry oriented approach that transformed a benzofuran salicylic acid scaffold into a potent and selective mPTPB inhibitor (21) with IC50 = 38 nM. Importantly, the inhibitor was capable of restoring the macrophage’s IL-6 secretion and undergo apoptosis in response to interferon-γ stimulation. The study demonstrated that the bicyclic salicylic acid pharmacophores could be used to deliver PTP inhibitors with high selectivity, potency and cellular efficacy. Encinas et al. [38] introduced the series of new compounds that directly target InhA and without activation by mycobacterial catalase peroxidase KatG as promising drug templates for treating INH resistant infections. Making use of encoded library technology (ELT) for the direct InhA inhibitors, which produced compound 22 bestowed with good enzymatic activity but with low antimycobacterial potency. The results indicated that the lead (23) (Fig. 6) optimised by the selected strategy, the structure–activity relationships and the in vivo efficacy studies. Patpi et al. [39] designed new molecules with improved pharmacophoric properties by using molecular

Fig. 3. SAR of quinazolinone derivatives possessing antimycobacterial activity. 3

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 4. Some new indole-2-carboxamide derivatives possessing antimycobacterial activity.

hybridization approach. The group synthesized 1,2,3- triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural productbased tricyclic dibenzo[b,d]furan 24 (MIC = 6.25–25 µg/mL) and integrated in one molecular platform using click chemistry. In vitro activity, Structure − Activity Relationships against M. tuberculosis H37Rv of new derivatives revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. The Structure Activity Relationships are summarised in Fig. 7. In conclusion, the SAR studies suggested that the H and phenyl groups at R1 are well tolerated (Fig. 7). Benzene fused furan moiety is also favoured. phenylacetylene, 3-carbonyl-5-carbamoylpyrrolidin-3yl-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide moieties at R2 are well favoured and exhibited potent antimycobacterial activity. H and carboxy groups at R3 are found to be active against M. tuberculosis H37Rv (Fig. 7). H and hydroxy groups at R4 are also favoured and found to be active against Mycobacterium tuberculosis H37Rv (Fig. 7). Collectively, these Indole-2-carboxamide derivatives are found to be promising templates for further development as potential leads against Mycobacterium tuberculosis.

through phenotypic screening against replicating Mycobacterium tuberculosis. Ty38c was found to be bactericidal with MIC99 and MBC of 3.1 μM. Biochemical studies revealed that Rv3406 decarboxylates Ty38c into inactive keto metabolite. Genetic studies, biochemical validation, and X-ray crystallography unveiled Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. SAR studies produced a family of DprE1 inhibitors with a good range of IC50′s and bactericidal activity [42]. A series quinoxaline derivatives (31) were synthesized, and examined against M. tuberculosis (Mtb) and Mycobacterium avium (MAC) by Seitz et al. SAR revealed that 4-acetoxybenzyl ester of pyrazinoic acid and 4‘-acetoxybenzyl 2-quinoxalinecarboxylate exibited excellent activity against Mtb with MIC ranging from 1 − 6.25 μg/mL [43] (Fig. 8). The Structure Activity Relationships are summarised in Fig. 9. In conclusion, the SAR studies suggested that the methyl, acetoxy benzyl and carboxylate groups at position R1 are well favoured against M. tuberculosis (Fig. 9). Benzylamine, acetyl, methoxy carbonyl moieties at R2 are favoured and exhibited inhibitory activity against M. tuberculosis H37Rv. H, chloro, methyl, trifloromethyl, methoxy groups at R3 are found to be active against Mycobacterium tuberculosis H37Rv (Fig. 9). Quinoxaline and Quinoxaline 1,4-dioxide are found to be unique validated scaffolds for further development as potent narrow spectrum antimycobacterial leads.

2.4. Quinoxaline derivatives Jaso et al. synthesized and evaluated a series of new 6(7)-substituted quinoxaline-2-carboxylate 1,4-dioxide derivatives (25) (Fig. 8) against M. tuberculosis H37Rv. SAR data suggested that the presence of a chloro, methyl, or methoxy group at position 7 of the benzene moiety reduces the MIC and IC50 values. Antimycobacterial activity of the compounds having substituents in the carboxylate group, improved in the order: benzyl > ethyl > 2-methoxyethyl > allyl > tert-butyl. In vitro results showed that ethyl and benzyl 3-methylquinoxaline-2-carboxylate-1,4-dioxide derivatives with the chlorine group at position 7 of the benzene moiety and the unsubstituted derivatives possesed good antimycobacterial activity [40]. Jaso and co workers also reported a series of new 2-acetyl and 2-benzoyl-6(7)-substituted quinoxaline-1,4di-N-oxide derivatives 26 and examined for in vitro antimycobacterial activity. SAR results showed that 2-acetyl-3-methylquinoxaline 1,4-diN-oxide derivatives with chlorine (27), methyl (28) or methoxy (29) group (Fig. 8) in position 7 of the benzene moiety exhibited good antimycobacterial activity with EC90/MIC values between 0.80 and 4.29 [41]. Nares et al. identified a lead compound Ty38c (30) (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid)

2.5. Benzothiazole derivatives Mehra, et al. screened a library of twenty thousand compounds of commercially available ChemBridge database through combined approach of in silico similarity search and pharmacophore building. The group on In silico screening, identified 15 hits and evaluated in vitro for Mtb-SK (Shikimate kinase) enzyme inhibition. Two compounds 32 and 33 (Fig. 10) exhibited promising enzyme inhibition with IC50 values of 10.69 ± 0.9 µM and 46.22 ± 1.2 µM respectively. The docking studies were conducted in order to find the mode of binding of the hit in presence of substrates and the products. Furthermore, Molecular dynamics (MD) simulations revealed the probability of inhibitor binding at the allosteric site in presence of the ADP and shikimate-3-phosphate (S-3-P). They identified the crucial residues ARG43, ILE45 and PHE57 which involved in interactions with the best hit [44]. Huang et al. [45] reported on the synthesis and antimycobacterial activity of a new series of potent 5-(2-methylbenzothiazol-5-yloxymethyl)isoxazole-3-carboxamide derivatives against replicating Mycobacterium tuberculosis (Mtb)

Fig. 5. Brief SAR of Indole-2-carboxamide derivatives possessing antimycobacterial activity. 4

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 6. Some new benzofuran derivatives possessing antimycobacterial activity.

Fig. 7. SAR of benzofuran derivatives possessing antimycobacterial activity.

H37Rv. The most potent compounds 34 and 35 (Fig. 10) were found to be non toxic and active with MIC values of 1.4 and 1.9 μM, respectively. A new series of substituted 2-(2-(4-aryloxybenzylidene)hydrazinyl) benzothiazole derivatives incorporated with 2-hydrazinyl benzothiazole and 4-(aryloxy)benzaldehyde were designed and synthesized by Telvekar et al. using molecular hybridization strategy. All the compounds tested, exhibited promising activity against Mycobacterium tuberculosis H37Rv strains with MIC value of 1.5–29.00 μg/mL [46]. Netalkar et al. prepared and characterized a set of new air and moisture stable coordination compounds Co(II), Ni(II), Cu(II) and Zn(II) with a new ligand, 2-(2-benzo[d]thiazol-2-yl)hydrazono)propan-1-ol (LH) (36) by using various spectro-analytical techniques. Single-crystal X-ray

diffraction method revealed that the [Ni(LH)2]Cl2·3H2O complex was stabilized by intermolecular CH⋯π stacking interactions between the methyl hydrogen and the C-18 atom of the phenyl ring resulted in 1D zig-zag chain structure. The biological results showed that the ligand could bind to CT-DNA via partial intercalation, whereas the complexes bind electrostatically. Furthermore, all the compounds were examined for anti-mycobacterial activity with an MIC value of 0.8 μg/mL, which is almost 8 times active than Streptomycin [47] (Fig. 10). In conclusion, the SAR studies revealed that the methyl, benzamide, (E)-1-benzylidene-hydrazine groups are well favoured and exhibited activity against M. tuberculosis (Fig. 11). H, chloro, methyl groups at R2 are well tolerated. Oxymethyl-furan-3-carboxamide, oxymethyl-

Fig. 8. Some new quinoxaline derivatives possessing antimycobacterial activity. 5

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 9. Brief SAR of quinoxaline derivatives possessing antimycobacterial activity.

isoxazole-3-carboxamide moieties are well favoured and exhibited potent activity against M. tuberculosis (Fig. 11). Finally, these benzothiazole derivatives are found to be promising candidates for further development as potential antitubercular agents.

Bottari et al. [51] also synthesized various new complexes and conducted diffractometric analysis, which displayed a binuclear structure with two octahedral nickel(II) ions bridged by two helicoidal dap (bishydrazonates) in a spheroidal structure of C2V symmetry. Among the compounds tested, compound 45 (Fig. 13) displayed significant activity 10-fold higher than rifampin and equivalent to isoniazid. 2,6diacetylpyridine bishydrazone derivatives act with respect to nickel(II) as pentadentate ligands which could be easily deprotonated leading to enolate complexes. Compound 45 is also has the property of reducing HIV-induced cytopathogenic effects in human T4 lymphocytes. Pavan et al. [52] described the synthesis and characterization of a new ruthenium complexes and evaluated against Mycobacterium tuberculosis. All the synthesized complexes showed excellent MIC against M. tuberculosis, low toxicity and a selectivity index higher than 10. Compound 46 showed a better activity than rifampin and SQ109. SAR revealed that the substitution of the two Cl atoms by Hpic in the cis[RuCl2(dppb)(bipy)] resulted in [Ru(pic)(dppb)(-bipy)]PF6 enhanced the anti-TB activity five folds. It was noticed that the interaction with DNA is the basis of the cytostatic effect of ruthenium compounds and modulated by the nature of the ligands present in the complexes. The meclofenamic acid metal complexes were prepared and characterized by Demertzi et al. using X-ray crystallography, vibrational, 1H and 13C NMR spectroscopies. X-ray studies revealed a penta-coordinated structure containing Ph3Sn coordinated to the chelated carboxylato group with polar imino hydrogen atom involves in intra-molecular hydrogen bonding. Meclofenamic acid complex [Ph3Sn(Meclo)] were tested for anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv and found to be a promising anti-mycobacterial lead [53]. Hunoor et al. reported the synthesis of various Ni(II) (47), Cu(II) (48), Co(II) (49) and Zn(II) (50) complexes (Fig. 13). The research group found that the Schiff base acts as a monobasic tridentate ligand coordinating in the imidol form with 1:1 metal to ligand stoichiometry. The compounds

2.6. Metal complexes Yu et al. identified and reported a new class of compounds with antimycobacterial activity and efficacy against clinically relevant M. tuberculosis. In primary screening, compounds were tested against Mycobacterium bovis BCG and Mycobacterium avium, the latter an selective activity against M. tuberculosis which displayed a generalized pattern of resistance to available antibiotics. The most active compounds were 1,8-naphthalimide derivatives possessing two pendant groups. Many of these leads 39, 40 and 41 (Fig. 12) contain a metal ion (Cu(II) or Zn(II)) coordinated to the macrocycle. Significantly, studies on cyclam have suggested rapid Zn(II) binding under physiological conditions. The group inferred that mono-pendant derivative exhibited low bioactivity, where as free cyclam and the pendant groups alone did not display activity, indicating the composite structure and modification of side chains is required for the promising antimycobacterial effect [48]. Hadda et al. reported a series of new polypyridyl-ruthenium (II) complexes and tested against Mycobacterium tuberculosis. The complex (42) exhibited significant activity against M. tuberculosis as compared to other complexes. The aquo ligand of complex 42, active than chloro and acetonitrile derivatives, appeared to play a key role in the antimycobacterial potency of this new class of metal-based compounds [49]. Bottari et al. obtained isonicotinoylhydrazones by the primary antimycobacterial agent isoniazid. The group used monoanionic ligands (L) to prepare copper(II) (43) and nickel(II) (44) octahedral complexes (Fig. 12) and examined antimycobacterial in vitro activity against Mycobacterium tuberculosis H37Rv compared with the ligands [50].

Fig. 10. Some new benzothiazole derivatives possessing antimycobacterial activity. 6

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 11. SAR of benzothiazole derivatives possessing antimycobacterial activity.

were examined for anti-tubercular activity using serial broth dilution method. Antimycobacterial activity of the ligand has enhanced on complexation with metals Co(II) and Ni(II) ions due to chelation. Since all complexes have not exhibited increased activity as compared to parent ligand which explain the fact that, steric and pharmacokinetic parameters also play a crucial role for potency of an antimycobacterial agent [54].

thiouridyl derivatives [56]. Shirude et al. identified quinolinyl pyrimidines (54, 55) (Fig. 14) a new structural class of inhibitors for NDH2. SAR studies revealed that, quinolinyl pyrimidine with two primary amines is a key pharmacophore used for critical hydrogen-bonding interactions with NDH-2 target protein. To reduce the hydrophobic requirement of the scaffold, they introduced a number of different substituents at various positions of the scaffold 54. On the pyrimidine nucleus, a monosubstituted phenyl ring (R2) was found to be better than hetero aryl groups like pyridine or pyrazole and simple aliphatic groups like ethyl or isopropyl group. On the quinoline ring, a phenyl ring (R1) with a 4-fluoro or 2-methoxy substituent exhibited better anti-TB activity than the unsubstituted one [57]. Pieroni et al. reported the SAR studies of new 5-[(E)-2-arylethenyl]3-isoxazolecarboxylic acid alkyl ester derivatives 56 (Fig. 15). The study revealed that halogens, small alkyl groups, methoxy groups bulkier aromatic and heteroaromatic rings were found to be suitable substituents for promising anti-TB properties. Hydroxyl, amino, and Nmethylpiperazine showed a detrimental effect on the activity. Active trans- alkene showed 4–8-fold greater potency than less active cis-isomers. Moreover, the reduction of the trans alkene led to a marked decrease of potency. The n-butyl ester derivatives were found to have good anti-TB potency than bulkier alkyl esters. Finally, hydrolysis of the ester group or the removal of the carboxylic moiety led to a complete loss of activity [58]. De et al. [59] synthesized new cinnamic acid-based molecules by using simple, clean, and efficient synthetic protocols. The importance of the double bond and alkyl groups were also probed.

2.7. Miscellaneous Yempalla et al. [55] identified nitrofuranyl methylpiperazine derivatives as potent anti-TB agents. These compounds exhibited potent MIC in the range of 0.17–0.0072 μM against H37Rv Mycobacterium tuberculosis (MTB), nonreplicating and resistant strains. Among the compounds tested, two analogues 51 and 52 (Fig. 14) were found to have comparatively better solubility and good pharmacokinetic properties. Yempalla and co-workers also designed and synthesized a series of novel polar functionalities (sulfonyl, uridyl, and thiouridyl) containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) derivatives and examined against Mycobacterium tuberculosis (MTB) H37Rv. Among the compounds tested, compound 53 exhibited high microsomal stability, solubility and favorable oral in vivo pharmacokinetics. SAR data revealed that polar functionalities and hydrophobic groups/atoms at the terminal ring (ringD/E) are essential for activity. Moreover, sulfonyl group in between C & D rings and D & E rings are favorable. The group inferred that uridyl derivatives found to be more preferable than

Fig. 12. Some new metal complexes with antimycobacterial activity. 7

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 13. Some new metal complexes possessing antimycobacterial activity.

Lilienkampf et al. also identified a new class of quinoline-isoxazole hybrids with good antitubercular activity against both the replicating and nonreplicating forms of Mtb. Among the compounds tested, compounds 60 and 61 (Fig. 15), exhibited submicromolar activity with MIC values of 0.77 and 0.95 µM, respectively. SAR analysis suggested that C2, C8- or C2, C7-disubstitution and C2, C5, C7-trisubstition on quinoline core would be preferred. Trifluomethyl and isoxazole moieties played a significant role in the antimycobacterial activity. Replacement of the oxymethylene linker at the C4 position of the lead, with a aryl ether linker was found to be promising. Notably, the two potent compounds, 60 and 61, possessed similar activity against the RMP, INH, and SM resistant strains [61]. Guo et al. reported a novel class of tetrahydroindazole based compounds as potent inhibitors of MTB. Compounds 62, 63 exhibited activity in the low micromolar range against replicating Mycobacterium tuberculosis with MIC values of 1.7, 1.9 μM, respectively. The research group also performed in vitro metabolic stability of 62 and 63 (Fig. 15) in mouse liver microsomes and in vivo pharmacokinetic profiles in plasma levels. SAR data suggested that reduction of the N-oxide moiety and benzoxadiazole derivative led to a complete loss of activity. Presence of a para substituent on the N-aryl group, rather than ortho or meta improved antimycobacterial potency. Furthermore, replacement of the p-trifluoromethyl group by the p-trifluoromethoxy group did not affect the activity and cytotoxicity profile [62]. Chiaradia et al. [63] reported a new series of naphthylchalcones and developed Structure − activity relationships (SAR) which led to the discovery of new potent Protein Tyrosine Phosphatase (Ptp) inhibitors with IC50 values in the low-micromolar range. The best inhibitory effect of Mtb PtpA was achieved by compound 64 obtained from benzylated vanillin structure, with methoxyl groups at positions 2 and 4 at the ring A. SAR suggested that the 2- naphthyl group as B-ring seemed to be favorable. Hydrophobicity of the ring B as well as the presence of hydrogen bond donor/acceptor substituents in the ring A found to be important for inhibitory activity. The most active compounds represented hydrophobic B-rings and polar-substituted A-rings. Compound 65, which bears the 2-naphthyl and the 4-carboxy-phenyl

Fig. 14. Some new compounds possessing antimycobacterial activity.

Compounds 57, 58 (Fig. 15) were found to possess good anti-TB activity. Compound 57 was found to inhibit the biosynthesis of mycolic acids whereas compound 58 did not inhibit mycolic acid biosynthesis but was highly active against two INH-resistant strains. Lilienkampf et al. reported the benzyloxy, benzylamino and phenoxy derivatives of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters (59) as potent anti-TB agents possessing nanomolar potency against R-TB and compared to current first-line anti-TB drugs. SAR studies revealed that mono-, di-, and tri- substitutions on the benzyloxy moiety yielded good anti-TB agents. The preferred monosubstitution was found in the order, para ≥ meta > ortho, Moreover, di- and tri- substituted derivatives, mainly fluorinated compounds, resulted in good anti-TB activity. The original oxymethylene linker at the meta position could be replaced with an oxy, aminomethylene, or amide linker. Incorporation of the aminomethylene linker to the para position is advantageous for the activity [60] (Fig. 15). 8

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 15. New compounds possessing antimycobacterial activity.

groups was found to be most potent with IC50 = 12 μM. The presence of bulky or electron withdrawing groups in the phenyl group (B-ring) was favored against M. tuberculosis. Additionally, the bioisosteric replacement of the phenyl moiety with a pyrrole or 3-chlorotiophene were well tolerated (Fig. 15). Azzali et al. [64] reported two new compounds, namely N-phenyl-5(2-(p-tolylamino)thiazol-4-yl)isoxazole-3-carboxamide 66 and N-(pyridin-2-yl)-5-(2-(ptolylamino)thiazol-4-yl)isoxazole-3-carboxamide 67 (Fig. 17), which exhibited high inhibitory activity toward sensitive M. tuberculosis strains, with an MIC90 of 0.125–0.25 µg/mL and 0.06–0.125 µg/mL respectively. SAR studies revealed that the unsubstituted amide nitrogen, mono– or disubstituted with moieties had significant effect on activity and stability. A primary amide and smallsized aliphatic substituents at the amide nitrogen are not suitable for antimycobacterial activity. Compounds 66 and 67 possessing an aromatic or heteroaromatic ring attached at the amide nitrogen were found to be active toward the replicating Mtb with MIC90 = 0.125–0.250 µg/ mL and MIC90 = 0.06–0.125 µg/mL respectively. Pitta et al. [65] synthesized and evaluated, a new series of quinoline derivatives 68 against Mycobacterium tuberculosis (H37Rv). The compounds synthesized exhibited MIC values in the low micromolar range but with low blood stability and high hERG affinity. Compound 69 which contains a benzoxazole ring in lieu of the amide group was found to be with good blood stability and no hERG affinity. Many compounds exhibited potent antimycobacterial activities with MICs in the low micromolar range and excellent intracellular IC90 values ranging from 0.20 to 2.51 μM, with the best compound 70 exhibiting a MIC value of 0.6 μM and no cytotoxicity (Fig. 17). Karabanovich et al. reported the 5-substituted 2-[(3,5-dinitrobenzyl) sulfanyl]-1,3,4-oxadiazoles (71) and 1,3,4-thiadiazoles (72) (Fig. 16) with excellent activity against drug-susceptible and multidrug-resistant M.tb. The MIC values of the active compounds against M. tuberculosis were found to be 0.03 μM. SAR studies indicated that 3,5-dinitro substitution has a vital role in antimycobacterial activity. Any modifications to the positions or numbers of nitro groups led to a significant diminish in anti-mycobacterial activity. The 2,4-dinitrobenzylsulfanyl derivatives possessed 10–100 times lower antimycobacterial effects, and the 4-nitrobenzylsulfanyl derivatives lost antimycobacterial activity. Due to high variability of substituent R1 on the oxadiazole/ thiadiazole moieties did not negatively affect their antimycobacterial activities. Excitingly, the replacement of one nitro group with a trifluoromethyl moiety resulted in compounds with diminished antimycobacterial activity. 5-Substituted-2-[(3,5-dinitrobenzyl)sulfanyl]1,3,4-oxadiazoles and 1,3,4-thiadiazoles proved to be promising antimycobacterial agents [66]. Ren et al. designed and synthesized a series of novel (E)-4-oxo-2-crotonamide derivatives 73. All the compounds were screened for their in vitro activity against Mycobacterium

tuberculosis H37Rv. SAR results revealed that 4-phenyl moiety at part A and methyl group at part C were found to be tolerable. Most of the compounds tested exhibited promising activity with MIC ranged from 0.125 − 4 µg/mL. Especially, compound 74 (Fig. 16) was found to possess the best activity with MIC in the range of 0.05–0.48 µg/mL against drug-resistant clinical MTB isolates. SAR studies further unveils that substituents at the meta-position of the benzene ring led to diminished activity. In the N,N-diethyl series, compounds with electronwithdrawing groups (F, Cl, NO2) showed good activity (MIC = 0.24 μg/ mL), than that with electron-donating groups (methoxyl, ethyoxyl, phenyl, benzodiazepyl). Antimycobacterial activity of the para-substitued groups is in the order: phenyl > bromo > methoxyl ≈ chloro > fluoro ≈ ethyoxyl > nitro. Generally, the antimycobacterial activity of the derivatives against Mycobacterium tuberculosis is in the order: methyl ester > ethyl ester > isopropyl ester > amide > Boc aminoethyl ester [67]. Wang and co-workers [68] reported a series of less lipophilic IPA derivatives containing alkaline fused ring moieties. Most of the compounds exhibited acceptable potency against MTB H37Rv with MIC < 0.25 μM. Most potent compound 75 displayed acceptable safety, greater absorption in plasma and aqueous solubility than standard. Bhagat et al. reported the screening of anti-TB activity of the synthesized compounds 76 against Mycobacterium tuberculosis H37Rv. Most of the compounds, exhibited MIC values ranged from 1.56 μg/mL − 3.125 μg/mL. The most active compounds were found non-cytotoxic to RAW 264.7 (mouse leukemic monocyte macrophage) cell lines [69]. Gising et al. reported the synthetic strategy in which a 2amino group was introduced into the 4-pyridyl ring resulted in potent inhibitor 77 (Fig. 16) with IC50 = 0.049 μM on MtGS and an MIC = 2 μg/mL against M. tuberculosis. The X-ray crystallographic studies revealed that the 2-amino group formed an additional interaction with the hydroxyl oxygen of Ser280 in its primary binding mode [70]. 2.8. Anti-mycobacterial nanoparticles Nanoparticles offers various advantages over conventional chemotherapy such as long shelf life (high stability), high drug carrier capacity, feasibility of introducing both hydrophilic and hydrophobic substances and feasibility in administration, enables sustained drug release from the matrix and improves patient compliance [71–74]. Sharma et al. [75] conducted a series of studies to explore lectin-functionalized poly(lactide-co-glycolide) nanoparticles (PLG-NPs) as bio adhesive anti-TB drug carriers, for the purpose to minimize the drug dosage frequency and to improve patient compliance in TB chemotherapy. In this study, they mainly observed that, upon administration of uncoated PLG-NPs (oral/aerosolized) rifampicin was detectable in plasma for 4–6 days, while, isoniazid and pyrazinamide were 9

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 16. Novel compounds possessing antimycobacterial activity.

detectable for 8–9 days. Finally, they inferred that WGA-functionalized PLG-NPs could be promising drug carriers for antitubercular drugs. Johnson et al. exaamined the efficacy of nanoparticle-encapsulated antimycobacterial drugs administered every 10 days versus that of daily non encapsulated drugs against Mycobacterium tuberculosis aerosol infection in guinea pigs. In couple of cases the treatments prominently reduced the bacterial count [76]. D'Addio et al. prepared and evaluated the drug efficacy in vitro in M. tuberculosis-infected macrophages. Rifampicin (RIF) was conjugated by bio-degradable ester bonds to form hydrophobic prodrugs. NCs encapsulated different ratios of non-conjugated RIF and the prodrugs exhibited the potential ability to rapidly deliver and knockdown intracellular M. tuberculosis by non-conjugated RIF. NCs of the new antibiotic SQ641 and a combination NC with cyclosporine A, were formed by Flash NanoPrecipitation. A nanocarrier formulation with a triple combination of SQ641, cyclosporine A, and vitamin E inhibited intracellular replication of M. tuberculosis significantly better than SQ641 alone or drug isoniazid [77]. Rajan et al. [78] made an effort to encapsulate anti-tuberculosis drug, Rifampicin (RIF) by using designed carrier Chitosan (CS) and polyethylene glycol 600 (PEG) nanoparticles which were produced by Ionic gelation technology. PEG binded CS-RIF had a significant prolonged retention compared to non-coated CS-RIF. Several factors such as encapsulation efficiency, loading capacity, SEM, FTIR and in vitro release were utilized for characterization of nanoparticles. All results indicated that CS and CS-PEG nanoparticles are promising carriers for delivering RIF in treatment of MDR-tuberculosis. Furthermore, the results indicated that the RIF-conjugated with CS and CS-PEG polymers could be potential systems for drug loading and long-acting antimycobacterial drugs. Fenaroli et al. introduced animal studies on transparent zebrafish embryo system for noninvasive, simultaneous imaging of fluorescent Nanoparticles (NP) and Mycobacterium marinum. The study was conducted by using transgenic lines of macrophages, neutrophils, and endothelial

cells expressing fluorescent markers. The study also unveiled that injection of NPs induced rapid uptake by both infected and uninfected macrophages and recruited them to the site of infection, thereby offering an efficient targeting into granulomas. Quantitative fluorescence analysis indicated that Rifampicin loaded NPs profoundly improved embryo survival and lowered bacterial load [79]. Ali et al. developed a drug delivery system, in which gold nanorods (AuNRs) were conjugated to rifampicin (RF), which was released after macrophages uptake. In this delivery system, the nanoparticles were actively internalized into macrophages and released RF. AuNRs without RF conjugation showed an obvious antimycobacterial activity, suggesting that the AuNRs could be an effective delivery vehicle for the antimycobacterial drug Rifampicin [80]. Horváti et al. designed a novel lipopeptide carrier based on the sequence of tuftsin, which was reported as a macrophage-targeting agent. The conjugate exhibited promising in vitro activity on Mtb H37Rv culture with low cell toxicity and hemolytic activity. Inorder to improve bioavailability, the conjugate was encapsulated into poly(lactide-co-glycolide) (PLGA) nanoparticles and examined in vivo in a guinea pig infection model.The data revealed that the new conjugate directly killed intracellular Mtb and exhibited much greater efficacy than INH alone [81]. 2.9. Natural products Ganihigama et. al. examined different natural products and their derivatives against reference strains and clinically relevant isolates of Mycobacterium tuberculosis. Among the compounds tested, Vermelhotin (78) (Fig. 17) was found to be the most active compound with an MIC value of 3.1 µg/mL against H37Ra strain of Mtb. The tetramic acid moiety was found to be responsible for antimycobacterial activity of vermelhotin. In addition to vermelhotin, 3-nitropropionic acid was found to display modest antitubercular activities with MIC values of 10

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 17. Some natural products possessing antimycobacterial activity.

12.5 and 50.0 µg/mL against H37Rv and H37Ra strains, respectively [82]. Murali et al. examined the antimycobacterial activity of denigrins, obtained from the marine sponge Dendrillanigra. 3,4-diaryl pyrrole alkaloid class, denigrins A, B and C were found to exhibit potent antimycobacterial activity. Among all, Denigrin C (79) (Fig. 17) was found to exhibit potent activity with an MIC of 4 µg/mL, when examined against Mycobacterium tuberculosis H37Rv. The protein kinase inhibitory activity of 3,4-diarylpyrrole alkaloids probably the reason for antimycobacterial activity of denigrins [83]. Zheng et al. synthesized a series of new pyranocoumarin based calanolide derivatives, seperated from a tropical plant Calophyllumlanigerum. (+)-Calanolide A (80) displayed potent inhibitory activity against M. tuberculosis with an MIC value of 3.1 μg/mL. A 2- nitrofurano moiety was introduced at ring-D of Calanolide derivatives to improve the cytotoxicity profile and to increase the invitro activity. Compound (81) showed MIC of 0.3 μg/mL and 0.6 μg/mL against R-Mtb and NR-Mtb respectively, with a SI of 8. An alkoxyl substitution like 2-morpholinoethoxy introduced at Ring C, resulted in compound (82) with improved potency (MIC values of 0.08 μg/mL and 0.2 μg/mL against R-Mtb and NR-Mtb, respectively) with a SI of 128. Among the calanolide derivatives, compound 83 was found to be the most potent compound with MIC values of < 0.1 μg/mL and 0.2 μg/ mL against R-Mtb and NR-Mtb, respectively with SI value > 510 suggesting the positive effect of fluoro group at the C-3 position of ring B [84]. To evade genotoxicity, a series of new compounds with furan-2nitro mimics were synthesized by Liu et al. The ammonia vinyl form of nitro group of Ring-D, was the basis of designing lead compounds. Introducing carboxyl group and acyl hydrazine group improved the solubility of the compounds. Compounds 84 and 85 (Fig. 18) found to be active against (R)Mtb with MIC values of 50 and 25 µg/mL, respectively. SAR studies suggested that among all the compounds, calanolides incorporated with furan-2-hydrazides were found to be active against R Mtb [85]. Dong et al. designed and synthesized a series of new pleuromutilin derivatives, that showed increased affinity for the ribosome. New pleuromutilin derivatives having N-benzylamine substitution at C-14 acyloxy group were synthesized and their anti-TB activity was examined against virulent strain of Mycobacterium tuberculosis (H37Rv). Among these compounds, Four of the compounds 86, 87, 88 and 89, (Fig. 19) possessing electron-donating groups substituted at the position-4 of benzene, showed good inhibitiory activity against M. tuberculosis at 20 µM. Replacement the ethyl group on the N atom with either a benzyl or cyclohexyl group retained the potent activity. Piperidine as the linker reduced the activity, due to its rigidity. SAR studies revealed that changes in the para position of phenyl ring retained the activity, while rigidifying the linker resulted in a decrease in

Fig. 18. New natural products possessing antimycobacterial activity.

the activity [86]. Mutai et al. synthesized a series of new isoflavone based Formononetin derivatives with modifications on Ring A and B. The parent compound, formononetin exhibited 88% inhibition of the strain of Mycobacterium tuberculosis (H37Rv) at a concentration of 10 µM. Any variations on ring A was not tolerated. On ring B, only tertbutyl substituent (90) showed increased activity with 95% inhibition. Mechanism studies suggested that formononetin inhibited the P-gp efflux pump, that played vital role for drug resistance in Mycobacterium tuberculosis. Pharmacophore modeling studies on formononetin derivatives revealed that the presence of a hydroxyl group in formononetin was found to be essential for high potency [87]. Pore et al. reported a series of new bile acid derivatives and were examined for inhibitory activity against Mycobacterium tuberculosis H37Ra at 3, 10 and 30 µg/mL levels. The group synthesized a series of new 11α-triazoyl bile acid derivatives and another series of N-alkyl and N-acyl derivatives of C-11 amino bile acid esters. The 1,2,3-triazole moiety was introduced to enhance metabolic stability, binding affinity to biomolecular targets and solubility by their hydrogen bond forming ability. Four compounds were found to be active against both dormant and active stage MTB and exhibited dose dependant effect. The compounds were found to be active under both in vitro as well as within THP1 host macrophages. The mechanism studies suggested that the antitubercular activity of 1,2,3triazole compounds was attributed to the inhibition of decaprenylphosphoryl-b-D-ribose-20-epimerase (DprE1) enzyme, which was involved in the biosynthesis of decaprenylphosphoryl-D-arabinose. Cytotoxicity studies revealed that the compound 91 was found to be a promising candidate with no cytotoxicity upto 100 µg/mL and an IC90 value of approximately 3 µg/mL [88] (Fig. 19). Kling et al. examined the antimycobacterial activity of griselimycin derivatives, a cyclic peptide derived from Streptomyces spp. Cyclohexylgriselimycin (CGM) (92) (Fig. 20) was identified to be the most active compound with MIC value of 0.06 µg/mL against Mtb H37Rv. The antimycobacterial activity of compounds was attributed to 11

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 19. Some natural products possessing antimycobacterial activity.

inhibition of DnaN, which encodes for DNA polymerase sliding clamp [89]. Baldwin et al. evaluated a series of new monocarbonyl analogues of curcumin, a phenolic compound isolated from the plant Curcuma longa. The compounds were examined against M. tuberculosis (Mtb) and Mycobacterium marinum (Mm) including rifampicin resistant isolates by using disk diffusion and liquid culture assays. Poor bioavailability was the major drawback of curcumin, which could be overcomed by monocarbonyl derivatives of curcumin. The bioavailability of the compound (EF-24) falls at 35% and 60% after i.p. and oral administration, respectively. The i.p. and p.o. pharmacokinetics parameters for 93 were found to be similar to EF-24 indicated a comparable bioavailability. SAR studies indicated that the presence of Michael acceptors was a key feature for antitubercular activity. The zone of inhibition for compound with no double bonds was not clear. Whereas, the compound with one double bond had a zone of inhibition of 4.6 mm compared to compound 93 (5.7 mm). The compound 93 exhibited IC50 values

of ~ 10 µM for Mtb H37Rv and 20 µM for Beijing F2 strain. Further studies revealed the effect of 93 on the rifampicin-resistant Mtb (H37Rv RifR) which showed an IC50 value of ~ 7 µM [90]. The antimycobacterial activity of meridianins was first reported by Yadav et al. A new series of sulphonamide derivatives along with acyl, alkyl and Cring modified derivatives of meridianins were synthesized and examined against Mtb H37Rv, These compounds displayed promising results with MIC values in the range of 5–64 µg/mL. Meridianin C and meridianin G showed MIC values of 32 and 64 µg/mL, respectively. Compounds 94 and 95, with a variation in the C-ring, showed potent antimycobacterial activity with an MIC value of 2 µg/mL and 8 µg/mL, respectively. The replacement of 2-aminopyrimidine ring with quinazolinone moiety in (94) and (95) (Fig. 20) resulted in improved antimycobacterial activity. Furthermore, these derivatives were examined against two clinical isolates of MDR (multidrug resistant) and M. tuberculosis INHR (isoniazid resistant) and one laboratory generated

Fig. 20. Natural products possessing antimycobacterial activity. 12

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 21. Some natural products having antimycobacterial activity.

mutant strain RifR(rifampicin resistant), which exhibited promising activity against resistant isolates with MIC values ranged from 2 − 64 µg/mL. The bromo substituted meridianin derivative 94 was found to possess modest activity against the resistant strains RifR, INHR and MDR with MICs of 16, 16 and 64 µg/mL, respectively. The iodosubstituted analog 95 exhibited potent activity against RifR strain with an MIC of 8 µg/mL, and also showed MIC values of 4 µg/mL and 8 µg/mL for INHR and MDR, respectively [91]. Arai et al. examined the anti-mycobacterial activity of nybomycin and analysed the target molecule of nybomycin. This work was an extension of work done by Strelitz et al. Aria et al. rediscovered nybomycin (96) (Fig. 21) from marine isolated Streptomyces species and screened the anti-dormant activity against Mycobacterium smegmatis, M. bovis and M. tuberculosis. The MIC values of isoniazid, under aerobic conditions, were 2.5 µg/mL and 0.05 µg/mL against M. smegmatis and M. bovis BCG, respectively. Whereas, in hypoxic conditions, the MIC values were found to be > 25 µg/mL. Nybomycin (96) showed a potent antimycobacterial activity with an MIC of 1.0 µg/mL against both M. smegmatis and M. bovis in both aerobic and hypoxic conditions. Furthermore, nybomycin (96) also displayed potent activity against pathogenic isolates of M. tuberculosis with MIC values in the range of 4.2–6.3 µg/mL. For mechanistic analysis, a probe was fixed to nybomycin (96) and a dummy probe was used as such. This affirmed the binding of nybomycin 96 to mycobacterial genome, which resulted in the inhibition of DNA replication and transcription [92]. Balaji et al. reported a series of new hispolon derivatives, initially seperated from Inonotushispidus and then noticed in a number of mushrooms, like Phellinus linteus and Phellinus igniarius. The anti-tubercular activity was examined by MABA method. Among the compounds synthesized, the dihydrohispolon derivatives 97, 98, 99 and 100 (Fig. 21) were found to be active with MIC values of 1.6, 6.25, 12.5, 3.125 µg/mL respectively. Docking simulation studies unveiled the possibility of interaction of the compounds with the β-keto acyl synthase enzyme (mtbFabH). These compounds also showed significant synergism with drugs like rifampicin and ciprofloxacin, but did not exhibit synergism with mycolic acid targeting drugs (isoniazid and ethambutol). SAR studies suggested that the presence of hydroxyl group at para position was quite essential for activity and substitution adjacent to 4-hydroxyl group or protection of hydroxyl group as alkoxy or acetate was not favoured. Among the lead molecules, (97) was found to be the most potent molecule with an MIC value of 1.6 µg/mL. The cytotoxicity profile of compound showed that the compound was benign to normal human cells upto concentrations of 100 µg/mL [93]. Nam et al. purified and reported the antimycobacterial activity of (−)-deoxypergularinine (101), derived from the roots of Cynanchumatratum Bunge (Asclepiadaceae). The active compound, (−)-Deoxypergularinine (101) (Fig. 21) showed its antimycobacterial effects on both M. tuberculosis and MDR/XDR strains and also exhibited synergy with first line anti-TB drugs, which were evaluated through resazurin, MGIT and checkerboard assays. The

compound 101 displayed an MIC of about 12.5 µg/mL against six strains of M. tuberculosis (MDR-TB, XDR-TB, INH-resistant-TB, H37RaTB, H37Rv-TB and pyrazinamide-resistant-TB) and an MIC value of 6.25 µg/mL against rifampicin-resistant TB [94]. Börger et al. tested a series of new oxygenated tricyclic carbazole alkaloids for antimycobacterial activity, Among all, four compounds were found to be potent with MIC values in the range of 1.5–3.7 µM. Carbalexin-C (102), (Fig. 22) a 2,6-dioxygenated carbazole, was found to be the most potent with an MIC90 value 1.5 µM. The other compounds murryaline-C (103) (2,7-dioxygenated carbazoles), synthetic derivative of pityriazole (104) (2-oxygenated carbazoles) and clauszoline-M (105) (2,8-dioxygenated carbazoles) exhibited activity with MIC90 values of 2.8, 2.9 and 3.7 µM, repectively. These compounds are nontoxic to mammalian cells with SI of 13 to 33. SAR studies revealed that the inhibitory activity of carbazole derivatives was mainly due to oxidation state of carbon substituents, oxygenation pattern and the position of additional functional groups. It further affirmed that the presence of lipophilic groups, like prenyl or geranyl, only had a minimal effect on the antitubercular activity [95]. Oladosu et al. isolated and reported the antitubercular activity of 3-β-hydroxylupanetype isoprenoids isolated from S. guineense stem bark, belonging to the family Myrtaceae. Two bioactive isoprenoids were extracted, namely, betulinic acid methylenediol ester (106) andbetulinic acid (107) (Fig. 22). The antituberculosis assay was conducted through Mycobacterium Growth Indicator Tube (MGIT) method. Compound 106 had a better MIC value of 0.15 µg/mL than the compound 107 (MIC = 0.60 µg/mL), due to the enhanced lipophilicity of compound 106, which could have improved its penetration through mycolic acid bilayers [96]. Asfaw et al. synthesized and evaluated the anti-TB activity of a series of new wollamide derivatives, obtained from Australian soil derived Streptomyces spp. Wollamide A showed MIC value of 1.1 µM against Mtb H37Rv. Despite, Wollamide B having drug like properties, it had poor membrane permeability. Among the compounds tested, Wollamide B derivatives exhibited potent antitubercular activity with IC50 values in the range of 0.2–1.26 µM against Mtb H37Rv infected human macrophages. The cytotoxicity data of the these compounds revealed the IC50 values as 50.1 µM against human Hep2G cells. Among the compounds tested, the most potent compound was found to be 108 (Fig. 23) with IC50 value of 0.2 µM, which was supported by its good extracellular potency with MIC value of 0.6 µM. However, these derivatives failed to exhibit promising in vivo results at 5 mg/kg, probably due to its poor membrane permeability [97].The antitubercular activity of Dinactin was evaluated by Hussain et al. Dinactin 109, a macrotetrolide obtained from Streptomyces puniceus AS13. Although, possessing potent antitubercular activity with an MIC value of 1 µg/mL against H37Rv of Mtb, it also exhibited good cytotoxicity profile with an IC50 value of approximately 80 µM against normal HEK-293 cells. Dinactin 109 exhibited synergy with first line and second line standard 13

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

Fig. 22. Natural products possessing antimycobacterial activity.

antitubercular drugs reflecting its suitability for use in multidrug regimen [98]. Baldin et al. evaluated the antimycobacterial activity of Tetradenia riparia essential oil (TrEO), obtained from the leaves of T. riparia (Lamiaceae) and the compound 6,7-dehydroroyleanone (110), one of the fractions obtained from essential oil TrEO. TrEO and 6,7dehydroroyleanone (110) exhibited MIC values of 62.5 μg/mL and 31.2 μg/mL, respectively, when examined against M. tuberculosis H37Rv. Resazurin Microtiter Assay Plate (REMA) was used to assess the in vitro activities and the cytotoxicity studies were screened by Alamar Blue assay in murine peritoneal macrophages. TrEO and compound 110 exhibited SI of 1.9 and 7.9 and CC50 values of 122 and 247 μg/mL, respectively [99] (Fig. 23). Safwat et al. screened the antimycobacterial activity of wild Egyptian Sahara plants against three strains of Mycobacterium. Jasonia candicans and Moltkiopsis ciliate showed good antimycobacterial activity against M. smegmatis and M. tuberculosis H37Rv. Quercetin 3-O-β-D-glucoside (Q3G) (111), (Fig. 23) obtained from the Euphorbia paralias, was

found to possess potent antimycobacterial activity with zone of inhibitons of 28.5 mm, 25 mm and 27 mm against M. phlei, M. smegmatis and M. tuberculosis, respectively. The antimycobacterial activity of Q3G 111 was due to the inhibition of glutamine synthetase enzyme (IC50 = 0.048 µM) [100]. Fernandez et al. characterized and evaluated the antimycobacterial activity of the crude extract of roots of Piper corcovadensis (Brazil). Four pyrrolidine alkaloids were obtained from the crude extract, viz., piperlonguminine, isopiperlonguminine, piperovatine and chingchengenamide A. The fraction of 90% piperlonguminine and 10% isopiperlonguminine was also screened for antimycobacterial activity. Piperovatine (112) displayed MIC values in the range of 0.48–1.95 μg/mL for clinical isolates [101]. Jiang et al.[102] evaluated the mycobacterial biofilm inhibitory activity of compounds isolated from Arisaemasinii. Bioassay guided isolation resulted in active compound 113, (E)-2-(methyl(phenyl)amino)ethyl2-(2-hydroxyundecanamido)7,11-dimethyl-3-oxotetradec-4-enoate. Compound 113 inhibited the biofilm formation and disrupted the biofilms at MIC

Fig. 23. New natural products possessing antimycobacterial activity. 14

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

values of 4 μg/mL and 32 μg/mL, respectively (Fig. 23). Wide range of biological properties displayed by natural products remain an attractive area for exploration. Notwithstanding, some of the natural products with reactive groups called PAINS (Pan Assay Interference Compounds) show nonspecific interference properties. The concept of PAINS holds to low micromolar potency natural products with weak biological activities, which pose a major problem for clinical progression. On the other hand, a low-micromolar activity natural product hit in a target-based screen may result into an acceptable starting point for drug optimization where structural alerts that encode for promiscuity are absent.

to further systematic development with a new mode of action to tackle the drug resistance. In the near future a number of these potential derivatives would surely be emerge as potent antimycobacterial agents. Acknowledgements G. S. conveys cordial thanks to DoP, Ministry of Chemicals & Fertilizers, Govt. of India, for the award of NIPER fellowship. This study was supported by the DST grant from Department of Science and Technology, Govt. of India to S.N. (EMR/2017/000220). Declaration of Competing Interest

2.10. Mechanism of action of antimycobacterial agents

The authors declared that there is no conflict of interest.

The currently available antimycobacterial therapeutics effectively act on various targets such as Catalase/peroxidase; enoyl reductase (Isoniazid), RNA polymerase (Rifampicin), Pyrazinamidase; ribosomal protein 1(Pyrazinamide), Arabinosyl transferase (Ethambutol), S12 ribosomal protein, 16A rRNA, 7-methylguanosine methyltransferase (Streptomycin), DNA gyrase(Quinolones), 16S rRNA, rRNA methyltransferase (Capreomycin), 16S rRNA (Kanamycin/Amikacin), EnoylACP reductase (Ethionamide), Thymidylate synthase A (Para-aminosalicylic acid). However, drug resistance to all the available therapeutics has been on rise. Hence, discovery and development of new antimycobacterial agents to overcome the resistance mechanisms is a crucial step to address the multidrug resistance. Some new antimycobacterial agents which target various enzymes or its homologs includes, a series of new 2-mercapto-quinazolinones which target the ndh encoded NDH-2 protein with nanomolar potencies against Mycobacterium tuberculosis [103]. These quinazolinone derivatives are also show effective interaction with LfrA amino acid residues that are also present in efflux pump in M. tuberculosis i.e., Rv2330c and Rv2846c [104]. Indolecarboxamides, were identified to target mainly on the trehalose monomycolate transporter MmpL3 present in M. tuberculosis [34]. Benzofuran class of molecules selectively inhibit the mycobacterial DNA gyrase enzyme with promising attributes of synthetic accessibility and antitubercular activity [105]. Quinoxalines, act by similar mechanism of action that of the class of Benzofurans and fluoroquinolones (FQs). Benzothiazoles exert their antimycobacterial activity against Mycobacterium tuberculosis (Mtb) via potent inhibition of decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1), the crucial enzyme involved in arabinogalactan biosynthesis [106]. Integration of metal ions into the drug structure offers structural diversity, access to numerous oxidation states of the metal and enhancing the efficacy of a drug through its coordination to the metal [107]. Similarly, nanoparticles enhance the antimycobacterial activity of isoniazid- (INH) and rifampicin (RIF) [108]. Natural products mechanism studies suggested that the antitubercular activity of some compounds were due to the inhibition of decaprenylphosphoryl-b-D-ribose-20-epimerase (DprE1) enzyme, which was involved in the biosynthesis of decaprenylphosphoryl-D-arabinose, inhibition of DnaN, which encodes for DNA polymerase sliding clamp, inhibition of DNA replication and transcription etc [109].

References [1] (a) Global tuberculosis report 2019 (WHO/CDS/TB/2019.15). Geneva: World Health Organization; 2019. (https://apps.who.int/iris/bitstream/handle/10665/ 329368/9789241565714-eng.pdf?ua=1). (b) A. Matteelli, et al., Tuberculosis elimination and the challenge of latent tuberculosis, Presse Med. 46 (2017) e13–e21 [2] (a) P. Nahid, et al., Official american thoracic society/centers for disease control and prevention/infectious diseases society of america clinical practice guidelines: treatment of drug-susceptible tuberculosis, Clin. Infect. Dis. 63 (2016) e147–e195; (b) The Global Plan to End TB, 2016–2020. Geneva: Stop TB Partnership, 2015. http://www.stoptb.org/global/plan/ (accessed 28 June 2019). [3] Y. Zhang, W.W. Yew, M.R. Barer, Targeting persisters for tuberculosis control, Antimicrob. Agents Chemother. 56 (2012) 2223–2230. [4] World Health Organization, Stop TB Dept. Treatment of Tuberculosis: Guidelines, fourth ed., World Health Organization, 2010. [5] E. Toner, A. Adalja, G.K. Gronvall, A. Cicero, T.V. Inglesby, Antimicrobial resistance is a global health emergency, Health Secur. 13 (2015) 153–155. [6] M. Bassetti, M. Merelli, C. Temperoni, A. Astilean, New antibiotics for bad bugs: where are we? Ann. Clin. Microbiol. Antimicrob. 12 (2013) 22. [7] R. Sugden, R. Kelly, S. Davies, Combating antimicrobial resistance globally, Nat. Microbiol. 1 (2016) 16187. [8] (a) Global tuberculosis report 2018. Geneva: World Health Organization, 2018. https://apps.who.int/iris/ handle/10665/274453. (b) C.L. Ventola, The antibiotic resistance crisis: part 2: management strategies and new agents, Pharm.Ther. 40 (2015) 344–352 [9] E.C. Rivers, R.L. Mancera, New anti-tuberculosis drugs in clinical trials with novel mechanisms of action, Drug Discov Today. 13 (2008) 1090–1098. [10] S.K. Fridkin, C.D. Steward, J.R. Edwards, E.R. Pryor, J.E. McGowan Jr, L.K. Archibald, R.P. Gaynes, F.C. Tenover, P.I.C.A.R.E. Hospitals, Surveillance of antimicrobial use and antimicrobial resistance in United States hospitals: project ICARE phase 2, Clin. Infect. Dis. 29 (1999) 245–252. [11] S.R. Malwal, D. Sriram, P. Yogeeswari, V.B. Konkimalla, H. Chakrapani, Design, synthesis, and evaluation of thiol-activated sources of sulfur dioxide (SO2) as antimycobacterial agents, J. Med. Chem. 55 (2012) 553–557. [12] 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) 4946–4952. [13] (a) A. Bahuguna, D.S. Rawat, An overview of new antitubercular drugs, drug candidates, and their targets, Med. Res. Rev. 1–30 (2019); (b) Y.Q. Hu, S. Zhang, F. Zhao, C. Gao, L.S. Feng, Z. Sheng Lv, Z. Xu, X. Wu, Isoniazid derivatives and their anti-tubercular activity, Eur. J. Med. Chem. 133 (2017) 255–267. [14] Y. Zhang, B. Heym, B. Allen, D. Young, S. Cole, The catalase—peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis, Nature. 358 (1992) 591–593. [15] A. Telenti, P. Imboden, F. Marchesi, L. Matter, K. Schopfer, T. Bodmer, D. Lowrie, M.J. Colston, S. Cole, Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis, Lancet 341 (1993) 647–651. [16] S. Sreevatsan, K.E. Stockbauer, X. Pan, B.N. Kreiswirth, S.L. Moghazeh, W.R. Jacobs Jr, A. Telenti, J.M. Musser, Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations, Antimicrob. Agents Chemother. 41 (1997) 1677–1681. [17] A. Somoskovi, L.M. Parsons, M. Salfinger, The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium tuberculosis, Respir. Res. 2 (2001) 164. [18] P. Juréen, J. Werngren, J.C. Toro, S. Hoffner, Pyrazinamide resistance and pncA gene mutations in Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 52 (2008) 1852–1854. [19] N. Honoré, S.T. Cole, Streptomycin resistance in mycobacteria, Antimicrob. Agents Chemother. 38 (1994) 238–242. [20] M.E. Visser, C.T. Swiegelaar, G. Maartens, The short-term effects of anti-tuberculosis therapy on plasma pyridoxine levels in patients with pulmonary tuberculosis, Int. J. Tuberc. Lung Dis. 8 (2004) 260–262. [21] C.A. Desjardins, K.A. Cohen, V. Munsamy, T. Abeel, K. Maharaj, B.J. Walker,

3. Conclusion Emergence of multidrug resistant Mycobacterium tuberculosis infections has created a health threat universally. Thus, unique chemical entities with new mode of action are greatly sought, and exploration for the antimycobacterial agents has been conducted to combat this burgeoning issue. In the current review, we have demonstrated various new multidrug resistant Mycobacterium tuberculosis active agents such as natural products, quinazolinones, Indole-2-carboxamides, benzofurans, quinoxalines, benzothiazoles, metal complexes, nanoparticles and miscellaneous derivatives which exhibited significant in vitro and in vivo activity. Various new heterocyclic derivatives with SAR may lead 15

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

[22] [23]

[24] [25] [26] [27] [28] [29] [30] [31] [32] [33]

[34]

[35]

[36]

[37]

[38]

[39]

[40] [41] [42]

[43] [44]

T.P. Shea, D.V. Almeida, et al., Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance, Nat. Genet. 48 (2016) 544–551. M. Heep, U. Rieger, D. Beck, N. Lehn, Mutations in the beginning of the rpoBGene can induce resistance to rifamycins in both Helicobacter pylori and Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 44 (2000) 1075–1077. R.M. Anthony, A.R.J. Schuitema, I.L. Bergval, T.J. Brown, L. Oskam, P.R. Klatser, Acquisition of rifabutin resistance by a rifampicin resistant mutant of Mycobacterium tuberculosisinvolves an unusual spectrum of mutations and elevated frequency, Ann. Clin. Microbiol. Antimicrob. 4 (2005) 9. X. Yin, Z. Yu, Mutation characterization of gyrA and gyrBgenes in levofloxacinresistant Mycobacterium tuberculosis clinical isolates from Guangdong Province in China, J. Infect. 61 (2010) 150–154. A. Rabha, A. Singh, S. Grover, A. Kumari, B. Pandey, A. Grover, Structural basis for isoniazid resistance in KatG double mutants of Mycobacterium tuberculosis, Microb. Pathog. 129 (2019) 152–160. E. Martinez, D. Hennessy, P. Jelfs, T. Crighton, S.C.A. Chen, V. Sintchenko, Mutations associated with in vitro resistance to bedaquiline in Mycobacterium tuberculosis isolates in Australia, Tuberculosis (Edinb). 111 (2018) 31–34. P.B. Trivedi, N.K. Undavia, A.M. Dave, Synthesis and anti-microbial activity of some heterocyclic compounds, Indian J. Chem. 32B (1993) 497–500. S.R. Pattan, V.V. Krishna Reddy, F.V. Manvi, B.G. Desai, A.R. Bhat, Synthesis of N3[4(4-chlorophenyl thiazol-2-yl)2-aminomethyl]quinazolin-4(3H)-one and their derivatives for anti-tubercular activity, Indian J. Chem. 45B (2006) 1778–1781. A. Gursoy, B. Unal, N. Karali, G. Otuk, Synthesis, characterization and primary anti-microbial activity evaluation of 3-phenyl-6-methyl-4(3H)-quinazolinone-2-ylmercaptoacetic acid arylidenehydrazides, Turk. J. Chem. 29 (2005) 233–245. P.Y. Shirodkar, M.V. Meghana, Synthesis and pharmacological activities of 6bromo-3-N-arylaminomethyl-1,2,3,4-tetrahydro-4-oxo-2-thio-quinazolines, Indian Drugs 35 (1998) 597–599. V.P. Trivedi, N.K. Undavia, P.B. Trivedi, Synthesis and biological activity of some new 4-thiazolidinone derivatives, J. Indian Chem. Soc. 81 (2004) 506–508. P. Nandy, M.T. Vishalakshi, A.R. Bhat, Synthesis and anti-tubercular activity of Mannich bases of 2-methyl-3H-quinazolin-4-ones, Indian J. Heterocycl. Chem. 15 (2006) 293–294. S. Gatadi, J. Gour, M. Shukla, G. Kaul, A. Dasgupta, Y.V. Madhavi, S. Chopra, S. Nanduri, Synthesis and evaluation of new quinazolin-4(3H)-one derivatives as potent antibacterial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis, Eur. J. Med. Chem. 175 (2019) 287–308. J. Stec, O.K. Onajole, S. Lun, H. Guo, B. Merenbloom, G. Vistoli, W.R. Bishai, A.P. Kozikowski, Indole-2-carboxamide-based MmpL3 inhibitors show exceptional antitubercular activity in an animal model of tuberculosis infection, J. Med. Chem. 59 (2016) 6232–6247. O.K. Onajole, M. Pieroni, S.K. Tipparaju, S. Lun, J. Stec, G. Chen, H. Gunosewoyo, H. Guo, N.C. Ammerman, W.R. Bishai, A.P. Kozikowski, Preliminary structureactivity relationships and biological evaluation of novel antitubercular indolecarboxamide derivatives against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains, J. Med. Chem. 56 (2013) 4093–4103. R.R. Kondreddi, J. Jiricek, S.P.S. Rao, S.B. Lakshminarayana, L.R. Camacho, R. Rao, M. Herve, P. Bifani, N.L. Ma, K. Kuhen, A. Goh, A.K. Chatterjee, T. Dick, T.T. Diagana, U.H. Manjunatha, P.W. Smith, Design, Synthesis, and biological evaluation of indole-2-carboxamides: a promising class of antituberculosis agents, J. Med. Chem. 56 (2013) 8849–8859. Y. He, J. Xu, Z.H. Yu, A.M. Gunawan, L. Wu, L. Wang, Z.Y. Zhang, Discovery and evaluation of novel inhibitors of mycobacterium protein tyrosine phosphatase B from the 6–hydroxy-benzofuran-5-carboxylic acid scaffold, J. Med. Chem. 56 (2013) 832–842. L. Encinas, H. O’Keefe, M. Neu, M.J. Remuiñán, A.M. Patel, A. Guardia, C.P. Davie, N. Pérez-Macías, H. Yang, M.A. Convery, J.A. Messer, et al., Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA, J. Med. Chem. 57 (2014) 1276–1288. (a) S.R. Patpi, L. Pulipati, P. Yogeeswari, D. Sriram, N. Jain, B. Sridhar, R. Murthy, A. Devi T, S.V. Kalivendi, S. Kantevari, Design, synthesis, and structureactivity correlations of novel dibenzo[b, d]furan, dibenzo[b, d]thiophene, and Nmethylcarbazole clubbed 1,2,3-triazoles as potent inhibitors of mycobacterium tuberculosis, J. Med. Chem. 55 (2012) 3911–3922; (b) Z. Xu, S. Zhao, Z. Lv, L. Feng, Y. Wang, F. Zhang, L. Bai, J. Deng, Benzofuran derivatives and their anti-tubercular, anti-bacterialactivities, J. Med. Chem. 162 (2019) 266–276. A. Jaso, B. Zarranz, I. Aldana, A. Monge, Synthesis of new quinoxaline-2-carboxylate 1,4-dioxide derivatives as anti-Mycobacterium tuberculosis agents, J. Med. Chem. 48 (2005) 2019–2025. A. Jaso, B. Zarranz, I. Aldana, A. Monge, Synthesis of new 2-acetyl and 2-benzoyl quinoxaline 1,4-di-N-oxide derivatives as anti-Mycobacterium tuberculosis agents, Eur. J. Med. Chem. 38 (2003) 791–800. J. Neres, R.C. Hartkoorn, L.R. Chiarelli, R. Gadupudi, M.R. Pasca, G. Mori, A. Venturelli, S. Savina, V. Makarov, G.S. Kolly, E. Molteni, C. Binda, et al., 2Carboxyquinoxalines kill Mycobacterium tuberculosis through noncovalent inhibition of DprE1, ACS Chem. Biol.. 10 (2015) 705–714. L.E. Seitz, W.J. Suling, R.C. Reynolds, Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives, J. Med. Chem. 45 (2002) 5604–5606. R. Mehra, V.S. Rajput, M. Gupta, R. Chib, A. Kumar, P. Wazir, I.A. Khan, A. Nargotra, Benzothiazole derivative as a novel Mycobacterium tuberculosis shikimate kinase inhibitor: identification and elucidation of its allosteric mode of inhibition, J. Chem. Inf. Model. 56 (2016) 930–940.

[45] Q. Huang, J. Mao, B. Wan, Y. Wang, R. Brun, S.G. Franzblau, A.P. Kozikowski, Searching for new cures for tuberculosis: design, synthesis, and biological evaluation of 2-methylbenzothiazoles, J. Med. Chem. 52 (2009) 6757–6767. [46] V.N. Telvekar, V.K. Bairwa, K. Satardekar, A. Bellubi, Novel 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives as anti-tubercular agents, Bioorg. Med. Chem. Lett. 22 (2012) 649–652. [47] P.P. Netalkar, S.P. Netalkar, S. Budagumpi, V.K. Revankar, Synthesis, crystal structures and characterization of late first row transition metal complexes derived from benzothiazole core: anti-tuberculosis activity and special emphasis on DNA binding and cleavage property, Eur. J. Med. Chem. 79 (2014) 47–56. [48] M. Yu, G. Nagalingam, S. Ellis, E. Martinez, V. Sintchenko, M. Spain, P.J. Rutledge, Matthew H. Todd, J.A. Triccas, Non-toxic metal-cyclam complexes, a new class of compounds with potency against drug-resistant Mycobacterium tuberculosis, J. Med. Chem. 59 (2016) 5917–5921. [49] T.B. Hadda, M. Akkurt, M.F. Baba, M. Daoudi, B. Bennani, A. Kerbal, Z.H. Chohan, Anti-tubercular activity of ruthenium (II) complexes with polypyridines, J. Enzyme Inhib. Med. Chem. 24 (2009) 457–463. [50] B. Bottari, R. Maccari, F. Monforte, R. Ottana, E. Rotondo, M.G. Vigorita, Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in vitro activity, Bioorg. Med. Chem. Lett. 10 (2000) 657–660. [51] B. Bottari, R. Maccari, F. Monforte, R. Ottana, M.G. Vigorita, G. Bruno, F. Nicolo, A. Rotondob, E. Rotondo, Nickel(II) 2,6-diacetylpyridine bis(isonicotinoylhydrazonate) and Bis(benzoylhydrazonate) complexes: structure and antimycobacterial evaluation. Part XI, Bioorg. Med. Chem. 9 (2001) 2203–2211. [52] F.R. Pavan, G.V. Poelhsitz, M.I.F. Barbosa, S.R.A. Leite, A.A. Batista, J. Ellena, L.S. Sato, S.G. Franzblau, V. Moreno, D. Gambino, C.Q.F. Leite, Ruthenium(II) phosphine/diimine/picolinate complexes: inorganic compounds as agents against tuberculosis, Eur. J. Med. Chem. 46 (2011) 5099–5107. [53] D.K. Demertzi, V. Dokorou, A. Primikiri, R. Vargas, C. Silvestru, U. Russo, M.A. Demertzis, Organotin meclofenamic complexes: synthesis, crystal structures and antiproliferative activity of the first complexes of meclofenamic acid – Novel anti-tuberculosis agents, J. Inorg. Biochem. 103 (2009) 738–744. [54] R.S. Hunoor, B.R. Patil, D.S. Badiger, R.S. Vadavi, K.B. Gudasi, V.M. Chandrashekhar, I.S. Muchchandi, Spectroscopic, magnetic and thermal studies of Co(II), Ni(II), Cu(II) and Zn(II) complexes of 3-acetylcoumarin–isonicotinoylhydrazone and their antimicrobial and anti-tubercular activity evaluation, Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 77 (2010) 838–844. [55] K.R. Yempalla, G. Munagala, S. Singh, A. Magotra, S. Kumar, V.S. Rajput, S.S. Bharate, M. Tikoo, G.D. Singh, I.A. Khan, R.A. Vishwakarma, P.P. Singh, Nitrofuranyl methyl piperazines as new anti-TB agents: identification, validation, medicinal chemistry, and PK studies, ACS Med. Chem. Lett. 6 (2015) 1041–1046. [56] K.R. Yempalla, G. Munagala, S. Singh, G. Kour, S. Sharma, R. Chib, S. Kumar, P. Wazir, G.D. Singh, S. Raina, S.S. Bharate, I.A. Khan, R.A. Vishwakarma, P.P. Singh, Synthesis and biological evaluation of polar functionalities containing nitrodihydroimidazooxazoles as anti-TB agents, ACS Med. Chem. Lett. 6 (2015) 1059–1064. [57] P.S. Shirude, B. Paul, N.R. Choudhury, C. Kedari, B. Bandodkar, B.G. Ugarkar, Quinolinyl pyrimidines: potent inhibitors of NDH-2 as a novel class of anti-TB agents, ACS Med. Chem. Lett. 3 (2012) 736–740. [58] M. Pieroni, A. Lilienkampf, B. Wan, Y. Wang, S.G. Franzblau, A.P. Kozikowski, Synthesis, biological evaluation, and structure−activity relationships for 5-[(E)-2Arylethenyl]-3-isoxazolecarboxylic acid alkyl ester derivatives as valuable antitubercular chemotypes, J. Med. Chem. 52 (2009) 6287–6296. [59] P. De, G.K. Yoya, P. Constant, F.B. Belval, H. Duran, N. Saffon, M. Daff, M. Baltas, Design, synthesis, and biological evaluation of new cinnamic derivatives as antituberculosis agents, ACS J. Med. Chem. 54 (2011) 1449–1461. [60] A. Lilienkampf, M. Pieroni, B. Wan, Y. Wang, S.G. Franzblau, A.P. Kozikowski, Rational design of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters as growth inhibitors of mycobacterium tuberculosis. A potent and selective series for further drug development, ACS J. Med. Chem. 53 (2010) 678–688. [61] A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S.G. Franzblau, A.P. Kozikowski, Structure-activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating mycobacterium tuberculosis, J. Med. Chem. 52 (2009) 2109–2118. [62] S. Guo, Y. Song, Q. Huang, H. Yuan, B. Wan, Y. Wang, R. He, M.G. Beconi, S.G. Franzblau, A.P. Kozikowski, Identification, synthesis, and pharmacological evaluation of tetrahydroindazole based ligands as novel antituberculosis agents, J. Med. Chem. 53 (2010) 649–659. [63] L.D. Chiaradia, P.G.A. Martins, M.N.S. Cordeiro, R.V.C. Guido, G. Ecco, A.D. Andricopulo, R.A. Yunes, J. Vernal, R. JoséNunes, H. Terenzi, Synthesis, biological evaluation, and molecular modeling of chalcone derivatives as potent inhibitors of mycobacterium tuberculosis protein tyrosine phosphatases (PtpA and PtpB), J. Med. Chem. 55 (2012) 390–402. [64] E. Azzali, D. Machado, A. Kaushik, F. Vacondio, S. Flisi, C.S. Cabassi, G. Lamichhane, M. Viveiros, G. Costantino, M. Pieroni, Substituted N-phenyl-5-(2(phenylamino)thiazol-4-yl)isoxazole-3-carboxamides are valuable antitubercular candidates that evade innate efflux machinery, J. Med. Chem. 60 (2017) 7108–7122. [65] E. Pitta, M.K. Rogacki, O. Balabon, S. Huss, F. Cunningham, E.M. Lopez-Roman, J. Joossens, K. Augustyns, L. Ballell, R.H. Bates, P.V. Veken, Searching for new leads for tuberculosis: design, synthesis, and biological evaluation of novel 2–quinolin-4-yloxyacetamides, J. Med. Chem. 59 (2016) 6709–6728. [66] G. Karabanovich, J. Zemanova, T. Smutný, R. Szekely, M. Šarkan, I. Centarova, ̌ A. Vocat, Ivona Pavkova, P.Č. onka, J. Nemecek, J.S. íkova, M. Vejsova, K. Vavrova, V. Klimesova, A. Hrabalek, P. Pavek, S.T. Cole, K. Mikusova, J. Roh, Development of 3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles and thiadiazoles as

16

Bioorganic Chemistry 95 (2020) 103534

S. Gatadi and S. Nanduri

[67]

[68]

[69]

[70]

[71] [72] [73] [74] [75] [76]

[77] [78] [79]

[80]

[81]

[82]

[83] [84] [85] [86] [87] [88]

selective antitubercular agents active against replicating and nonreplicating Mycobacterium tuberculosis, J. Med. Chem. 59 (2016) 2362–2380. J. Ren, J. Xu, G. Zhang, C. Xu, L. Zhao, X. You, Y. Wang, Y. Lu, L. Yu, J. Wang, Design, synthesis, and bioevaluation of a novel class of (E)-4-oxo-crotonamide derivatives as potent antituberculosis agents, Eur. J. Med. Chem. 29 (2019) 539–543. A. Wang, H. Wang, Y. Geng, L. Fu, J. Gu, B. Wang, K. Lv, M. Liu, Z. Tao, C. Ma, Y. Lu, Design, synthesis and antimycobacterial activity of less lipophilic Q203 derivatives containing alkaline fused ring moieties, Bioorg. Med. Chem. 27 (2019) 813–821. S. Bhagat, M. Supriya, S. Pathak, D. Sriram, A.K. Chakraborti, αSulfonamidophosphonates as new anti-mycobacterial chemotypes: design, development of synthetic methodology, and biological evaluation, Bioorg. Med. Chem. 82 (2019) 246–252. J. Gising, M.T. Nilsson, L.R. Odell, S. Yahiaoui, M. Lindh, H. Iyer, A.M. Sinha, B.R. Srinivasa, M. Larhed, S.L. Mowbray, A. Karlen, Trisubstituted imidazoles as Mycobacterium tuberculosis glutamine synthetase inhibitors, J. Med. Chem. 55 (2012) 2894–2898. S. Gelperina, K. Kisich, D. Michael, Iseman, H. Leonid, The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis, Am. J. Respir. Crit. Care Med. 172 (2005) 1487. C. Schmidt, R. Bodmeier, Incorporation of polymeric nanoparticles into solid dosage forms, J. Control. Release 57 (1999) 115–125. O. Kayser, C. Olbrich, S.L. Croft, A.F. Kiderlen, Formulation and biopharmaceutical issues in the development of drug delivery systems for antiparasitic drugs, Parasitol. Res. 90 (2003) S63–S70. G.K. Khuller, Subcutaneous nanoparticle-based antitubercular chemotherapy in an experimental model, J. Antimicrob. Chemother. 54 (2004) 266–268. S. Sharma, G.K. Khuller, Lectin-functionalized poly (lactide-co-glycolide) nanoparticles as oral/aerosolized antitubercular drug carriers for treatment of tuberculosis, J. Antimicrob. Chemother. 54 (2004) 761–766. C.M. Johnson, R. Pandey, S. Sharma, G.K. Khuller, R.J. Basaraba, I.M. Orme, A.J. Lenaerts, Oral therapy using nanoparticle-encapsulated antituberculosis drugs in guinea pigs infected with mycobacterium tuberculosis, Antimicrob. Chemother. 49 (2005) 4335. S.M. D'Addio, V.M. Reddy, Y. Liu, P.J. Sinko, L. Einck, R.K. Prud'homme, Antitubercular nanocarrier combination therapy: formulation strategies and in vitro efficacy for rifampicin and SQ641, Mol. Pharm. 12 (2015) 1554–1563. M. Rajan, V. Raj, Encapsulation, characterisation and in-vitro release of anti-tuberculosis drug using chitosan – poly ethylene glycol nanoparticles, Int. J. Pharm. Pharm. Sci. 4 (2012) 255–259. F. Fenaroli, D. Westmoreland, J. Benjaminsen, T. Kolstad, F.M. Skjeldal, A.H. Meijer, M. Vaart, L. Ulanova, N. Roos, B. Nystro, J. Hildahl, G. Griffiths, Nanoparticles as drug delivery system against tuberculosis in zebrafish embryos: direct visualization and treatment, ACS Nano 8 (2014) 7014–7026. H.R. Ali, Moustafa R.K. Ali, Y. Wu, S.A. Selim, H.F.M. Abdelaal, E.A. Nasr, M.A. ElSayed, Gold nanorods as drug delivery vehicles for rifampicin greatly improve the efficacy of combating mycobacterium tuberculosis with good biocompatibility with the host cells, Bioconjug. Chem. 27 (2016) 2486–2492. K. Horváti, B. Bacsa, E. Kiss, G. Gyulai, K. Fodor, G. Balka, M. Rusvai, E. Szabó, F. Hudecz, S.E. Bosze, Nanoparticle encapsulated lipopeptide conjugate of antitubercular drug isoniazid: in vitro intracellular activity and in vivo efficacy in a guinea pig model of tuberculosis, Bioconjug. Chem. 25 (2014) 2260–2268. D. Ganihigama, S. Sureram, S. Sangher, P. Hongmanee, T. Aree, C. Mahidol, Antimycobacterial activity of natural products and synthetic agents: pyrrolodiquinolines and vermelhotin as anti-tubercular leads against clinical multidrug resistant isolates of Mycobacterium tuberculosis, Eur. J. Med. Chem. 89 (2015) 1–12. M. Murali Krishna Kumar, J. Devilal Naik, K. Satyavathi, H. Ramana, P. Raghuveer Varma, K. PurnaNagasree, Denigrins A–C: new antitubercular 3,4-diarylpyrrole alkaloids from Dendrillanigra, Nat. Prod. Res. 28 (2014) 888–894. P. Zheng, S. Somersan-Karakaya, S. Lu, J. Roberts, M. Pingle, T. Warrier, Synthetic calanolides with bactericidal activity against replicating and nonreplicating mycobacterium tuberculosis, J. Med. Chem. 57 (2014) 3755–3772. Z. Liu, X. Guo, G. Liu, Modified calanolides incorporated with furan-2-nitro mimics against Mycobacterium tuberculosis, Bioorg. Med. Chem. Lett. 25 (2015) 1297–1300. Y. Dong, Z. Meng, Y. Mi, C. Zhang, Z. Cui, P. Wang, Synthesis of novel pleuromutilin derivatives. Part 1: Preliminary studies of antituberculosis activity, Bioorg. Med. Chem. Lett. 25 (2015) 1799–1803. P. Mutai, E. Pavadai, I. Wiid, A. Ngwane, B. Baker, K. Chibale, Synthesis, antimycobacterial evaluation and pharmacophore modeling of analogues of the natural product formononetin, Bioorg. Med. Chem. Lett. 25 (2015) 2510–2513. V. Pore, J. Divse, C. Charolkar, L. Nawale, V. Khedkar, D. Sarkar, Design and

[89] [90]

[91] [92] [93] [94] [95]

[96] [97] [98] [99]

[100]

[101]

[102] [103]

[104] [105]

[106]

[107]

[108] [109]

17

synthesis of 11α-substituted bile acid derivatives as potential anti-tuberculosis agents, Bioorg. Med. Chem. Lett. 25 (2015) 4185–4190. A. Kling, P. Lukat, D. Almeida, A. Bauer, E. Fontaine, S. Sordello, Targeting DnaN for tuberculosis therapy using novel griselimycins, Science 348 (2015) 1106–1112. P. Baldwin, A. Reeves, K. Powell, R. Napier, A. Swimm, A. Sun, Monocarbonylanalogs of curcumin inhibit growth of antibiotic sensitive and resistant strains of Mycobacterium tuberculosis, Eur. J. Med. Chem. 92 (2015) 693–699. R. Yadav, S. Khan, S. Singh, I. Khan, R. Vishwakarma, S. Bharate, Synthesis, antimalarial and antitubercular activities of meridianin derivatives, Eur. J. Med. Chem. 98 (2015) 160–169. M. Arai, K. Kamiya, P. Pruksakorn, Y. Sumii, N. Kotoku, J. Joubert, Anti-dormant mycobacterial activity and target analysis of nybomycin produced by a marinederived Streptomyces sp, Bioorg. Med. Chem. 23 (2015) 3534–3541. N. Balaji, B. Hari Babu, G. Subbaraju, K. PurnaNagasree, M. Murali Krishna Kumar, Synthesis screening and docking analysis of hispolonanalogs as potential antitubercular agents, Bioorg. Med. Chem. Lett. 27 (2017) 11–15. K. Nam, W. Jang, M. Jyoti, S. Kim, B. Lee, H. Song, In vitro activity of (-)-deoxypergularinine, on its own and in combination with anti-tubercular drugs, against resistant strains of Mycobacterium tuberculosis, Phytomedicine 23 (2016) 578–582. C. Börger, C. Brütting, K. Julich-Gruner, R. Hesse, V. Kumar, S. Kutz, Anti-tuberculosis activity and structure–activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives, Bioorg. Med. Chem. 25 (2017) 6167–6174. I. Oladosu, L. Lawson, O. Aiyelaagbe, N. Emenyonu, O. Afieroho, Anti-tuberculosis lupane-type isoprenoids from syzygiumguineense wild DC. (Myrtaceae) stem bark, Future J. Pharmaceutical Sci. 3 (2017) 148–152. H. Asfaw, T. Wetzlar, M. Martinez-Martinez, P. Imming, An efficient synthetic route for preparation of antimycobacterialwollamides and evaluation of their in vitro and in vivo efficacy, Bioorg. Med. Chem. Lett. 28 (2018) 2899–2905. A. Hussain, M. Rather, Z. Bhat, A. Majeed, M. Maqbool, A. Shah, In vitro evaluation of dinactin, a potent microbial metabolite against Mycobacterium tuberculosis, Int. J. Antimicrob. Agents 53 (2019) 49–53. V. Baldin, R. Scodro, M. Lopes-Ortiz, A. de Almeida, Z. Gazim, L. Ferarrese, AntiMycobacterium tuberculosis activity of essential oil and 6,7-dehydroroyleanone isolated from leaves of Tetradeniariparia (Hochst.) Codd (Lamiaceae), Phytomedicine 47 (2018) 34–39. N. Safwat, M. Kashef, R. Aziz, K. Amer, M. Ramadan, Quercetin 3-O-glucoside recovered from the wild Egyptian Sahara plant, Euphorbia paralias L., inhibits glutamine synthetase and has antimycobacterial activity, Tuberculosis 108 (2018) 106–113. C. Fernandez, V. Baldin, A. Ieque, K. Bernuci, R. Almeida, L. Valone, AntiMycobacterium tuberculosis activity of dichloromethane extract of Piper corcovadensis (Miq.) C. DC. roots and isolated compounds, Ind. Crops Prod. 131 (2019) 341–347. C. Jiang, M. Gan, T. An, Z. Yang, Bioassay-guided isolation of a Mycobacterium tuberculosis bioflim inhibitor from Arisaemasinii Krause, Microb. Pathog. 126 (2019) 351–356. D. Murugesan, P.C. Ray, T. Bayliss, G.A. Prosser, et al., 2-Mercapto-quinazolinones as inhibitors of NDH-2 and Mycobacterium tuberculosis: structure-activity relationships, mechanism of action and ADME characterization, ACS Infect. Dis. 4 (2018) 954–969. T. Sen, K. Neog, S. Sarma, P. Manna, H.P.D. Boruah, P. Gogoi, A.K. Singh, Efflux pump inhibition by 11H-pyrido[2,1-b]quinazolin-11-one analogues in mycobacteria, Bioorg. Med. Chem. 26 (2018) 4942–4951. K.I. Reddy, K. Srihari, J. Renuka, K.S. Sree, et al., An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition, Bioorg. Med. Chem. 22 (2014) 6552–6563. S. Landge, A.B. Mullick, K. Nagalapur, J. Neres, et al., Discovery of benzothiazoles as antimycobacterial agents: synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-b-D-ribose 20 -oxidase, Bioorg. Med. Chem. 23 (2015) 7694–7710. P. McCarron, M. McCann, M. Devereux, K. Kavanagh, C. Skerry, et al., Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs, Front. Microbiol. 9 (2018) 1432. K. Kumarasingam, M. Vincent, S.R. Mane, R. Shunmugam, S. Sivakumar, K.R. Uma Devi, Enhancing antimycobacterial activity of isoniazid and rifampicin incorporated norbornene nanoparticles, Int. J. Microbiol. 7 (2018) 84–88. Sandra M. Newton, Clara Lau, Colin W. Wright, A review of antimycobacterial natural products, Phytother. Res. 14 (2000) 303–322.