A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents

Beni-Suef University Journal of Basic and Applied Sciences xxx (2017) xxx–xxx

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Review Article

A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents Mustapha C. Mandewale a,⇑, Udaysinha C. Patil a, Supriya V. Shedge c, Uttam R. Dappadwad a, Ramesh S. Yamgar b a b c

P.G. and Research Centre, Department of Chemistry, Government of Maharashtra, Ismail Yusuf College of Arts, Science and Commerce, Jogeshwari (East), Mumbai 400 060, India Department of Chemistry, Chikitsak Samuha’s Patkar-Varde College of Arts, Science and Commerce, Goregaon (West), Mumbai 400 062, India Deogiri College of Science, Aurangabad 431001, India

a r t i c l e

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Article history: Received 3 January 2017 Received in revised form 8 July 2017 Accepted 19 July 2017 Available online xxxx Keywords: Biological activity Quinoline Hydrazone Cancer Tuberculosis

a b s t r a c t Tuberculosis (TB) and Cancer remains a global public health problem in recent years. There is an urgent need for the screening of new bioactive molecules with new targets and with a different mechanism of action. Among heterocyclic compounds, compounds with Quinoline core gained much importance in medicinal chemistry. Quinoline hydrazone scaffold plays an important role in anti-tuberculosis and anticancer drug development as their derivatives have shown outstanding results. This broad spectrum of biological and biochemical activities has been further assisted by the synthetic flexibility of quinoline, which permits the invention of a large number of structurally varied hydrazone derivatives and their metal complexes. In order to pave the way for future advanced research, there is a need to collect and analyze the latest information available so far in this promising area. In this review, we have compiled and discussed the published reports specifically on anti-tuberculosis and anticancer potential of quinoline hydrazone derivatives. It is hoped that this review will be helpful for researchers in developing a new view in the search for rational designs of more active and less toxic quinoline-based anti-TB and anticancer drugs. Ó 2017 Beni-Suef University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quinoline: structural requirements for antituberculosis and anticancer activity. . . . . Biologically active scaffolds in relevance to quinoline hydrazones as anti-TB agents . Anticancer potential of bioactive quinoline hydrazones . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Tuberculosis (TB) is a sort of lung infection, which is mainly caused by Mycobacterium tuberculosis (MTB). Some other species of bacteria causing tuberculosis include M. africanum, M. pinnipedii, M. bovis, M. canettii, M. microti and M. caprae (Brooks et al., 2009;

⇑ Corresponding author. E-mail address: [email protected] (M.C. Mandewale).

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Grange, 2009). Along with the HIV infection, TB is nowadays one of the biggest risks to the human beings. It is believed to be one of the most infectious and fatal diseases and is a major threat to public health. There has been a continuous rise in new TB cases mostly in developing countries (Dye et al., 1999). The TB situation may become even worse with the appearance of multi-drug resistant (MDR-TB) and the extensively drug resistant (XDR-TB) strains. In 1882, Robert Koch achieved the isolation of the bacteria responsible for TB and received Noble Prize for this finding (Nobel Foundation, 1905). According to the WHO (World Health Organization) more than

http://dx.doi.org/10.1016/j.bjbas.2017.07.005 2314-8535/Ó 2017 Beni-Suef University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Mandewale, M.C., et al. A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ. J. Basic Appl. Sci. (2017), http://dx.doi.org/10.1016/j.bjbas.2017.07.005

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75% of tuberculosis patients belong to economically productive age, which brings about a tremendously affecting economic and social crisis (Okada and Kobayashi, 2007; Global tuberculosis report, 2012). Though the six to nine month multidrug protocol employed currently in the treatment of TB is extremely effective with drugsusceptible TB, the non-compliance of economically poor patients promote the growth of drug resistance (Ginsberg and Spigelman, 2007). Even though the existing method of treatment is highly effective against tuberculosis, the side effects, the long duration of treatment and the potential for drug-drug interactions are issues that highlight the requirement of new anti-TB drugs (Dye and Williams, 2010; Burman, 2010). Besides, MTB is resistant to some of the first and second line drugs (LoBue, 2009). Hence, some efficient new drugs and advanced strategies are necessary to treat tuberculosis (Zhang et al., 2006; Brown and Wright, 2005). Quinoline hydrazones bear polar and nonpolar properties together, this makes them suitable for permeation to the bacterial cell. This finding indicates that these type of compounds enhanced the amphiphilic properties and solubility and hence, the penetration of hydrazones into the cell wall of the M. tuberculosis, which translated into better activity. According to one more probable mechanism, quinolone hydrazones might be interacting with the

DNA gyrase enzyme, which is necessary for DNA multiplication step. The DNA gyrase is inhibited by metal complexes, which alters the multiplication of bacterial cells, eventually resulting in death of the bacteria. The cancer includes series of malignant diseases that may affect different parts of the body. These malignant diseases are distinguished by a fast and uncontrolled formation of abnormal cells, which may accumulate together to form a tumor or propagate throughout the body, beginning abnormal growth at other sites. If this process is not controlled, it may lead to the death of the patient. Anticancer agents can be classified with respect to their mechanism of action, such as DNA-interactive agents, hormones, antitubulin agents, monoclonal antibodies, antimetabolites, molecular targeting agents and other biological agents (Thurston, 2007). In recent years, many attempts have been made to the synthesis of potent anticancer drugs. However, a large number of chemical alternatives of known class of cancer chemotherapeutic agents has been synthesized but has not been successful due to more side effects. anti-cancer drugs kill cancer cells by stopping its growth or its multiplication at some point in their life cycles. Radiation therapy is also employed in the treatment of cancer. The ionizing radiations in radiation therapy are used to destroy cancerous cells or

Fig. 1. Clinically used drugs containing quinoline motif.

Please cite this article in press as: Mandewale, M.C., et al. A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ. J. Basic Appl. Sci. (2017), http://dx.doi.org/10.1016/j.bjbas.2017.07.005

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the genetic material which restrict the growth of these cells. A successful anticancer drug is expected to kill or inhibit the growth of cancer cells without affecting the normal cells. Since such an ideal condition is difficult to attain, synthesis or modifications of known drugs is continued and it is an important aspect of ongoing research. Now a days there is a sustained need for new prototype, new templates to develop and design novel structures as potential chemotherapeutic agents for the treatment of cancer. It is well known that heterocyclic compounds play an important role in developing a new class of structural entities for pharmaceutical applications. Among the heterocyclic compounds quinoline and its derivatives are pharmacologically important because of their wide spectrum of biological activities (Prescott et al., 2007). Recently, quinoline derivatives have attracted an enormous attention from chemists as well as biologists as it is an important key building component for many naturally occurring bioactive compounds; especially quinoline alkaloids which are found in many different plants including Rutaceae, Fumariaceae, Berberidaceae and Papavaraceae (Srivastava et al., 2005; Canel et al., 2000; Du, 2003; Byler et al., 2009). The quinoline derivatives belong to a significant class of bioactive molecules in the field of drugs and pharmaceuticals. They display significant activity against numerous viruses and bacterias including antimalarial (LaMontagne et al., 1982; Nasveld and Kitchener, 2005), antibiotic (Mahamoud et al., 2006; Eswaran et al., 2009; Mandewale et al., 2011), anticancer (Denny et al., 2006), anti-inflammatory (Leatham et al., 1983), antihypertensive (Muruganantham et al., 2004), tyrokinase PDGF-RTK inhibition (Maguire et al., 1994) and anti-HIV (Wilson et al., 1992; Strekowski et al., 1991) properties. One of the quinoline derivatives, Quinine (1) (Fig. 1), shows antimalarial, antipyretic, antiinflammatory and analgesic properties. Another important quinoline derivative Chloroquine (2) (Fig. 1) demonstrates antimalarial activity. Amodiaquine (3) (Fig. 1) is also a quinoline derivative used as anti-inflammatory and antimalarial agent. The Saquinavir (5) (Fig. 1) (anti-retroviral drug) and Camptothecin (4) (Fig. 1) (DNA

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enzyme topoisomerase I), are used in the pharmacological field. This broad spectrum of biological activities has been further facilitated by the synthetic flexibility of quinoline, which permits synthesis of a large number of structurally assorted derivatives. The quinoline ring has been believed as a pharmacophore for the design of new anti-TB agents. The Ciprofloxacin (6) (Fig. 1) and Moxifloxacin (7) (Fig. 2) are promising agents for the treatment of TB having quinoline moiety (Ginsburg et al., 2003). Quinolinebased compound Mefloquine (10) (Fig. 1) is known for potent anti-tubercular activity (Jayaprakash et al., 2006; Bermudez et al., 1999, 2003, 2004) and its analogs (8, 9) (Fig. 1) have exhibited moderate to submicromolar anti-TB activity (Mao et al., 2007; Andries et al., 2005). Tibotec Medicinal Compound TMC207 (11) (Fig. 1) has emerged as a lead molecule in the development of new anti-TB agent and currently this compound is approved by US-FDA on 28th December 2012. It is also known as Bedaquiline. It is first new drug for TB in more than forty years. It is on World health organization’s list of essential medicins. The mechanistic study revealed that oligomeric (F-ATPase) and proteolipid (VATPase) subunit of ATP synthase of MTB is the target of this compound. TMC207 is effective for resistant and non-resistant strains of MTB at MIC 0.03 mg/mL. The results of its clinical trials show that TMC207 may shorten the treatment of TB and be effective in its treatment (Koul et al., 2007; Rustomjee et al., 2008). Topotecan (12) (Fig. 1) is a chemotherapeutic agent that acts as a topoisomerase inhibitor. Topotecan has the same mechanism of action as irinotecan and is supposed to affect during the S phase of DNA synthesis. It is also used to treat a small cell lung cancer. Topotecan is also employed in the treatment of cancer of the cervix, which cannot be treated with surgery or radiation therapy. Irinotecan (13) (Fig. 1) is an antineoplastic enzyme inhibitor mainly used in the treatment of colorectal cancer because it is believed that it inhibits topoisomerase-I. It is used for the treatment of metastatic colorectal cancer as well as extensive small cell lung cancer. Irinotecan is currently under clinical trials for the treatment of metastatic

Fig. 2. Structural requirement around quinoline nucleus for an anti-TB and anticancer activity.

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or recurrent cervical cancer. Therefore, the syntheses of quinoline and its derivatives have received an increasing consideration by synthetic organic chemists and biologists. In this review, we have tried to highlight the most significant examples of quinoline hydrazone derivatives which exhibit antituberculosis and anticancer activity. It also draws attention to different approaches that will help the researchers in designing and synthesis of future generation prospective compounds for antituberculosis and anticancer activity.

2. Quinoline: structural requirements for antituberculosis and anticancer activity From the recent literature reports, it is observed that the quinoline ring substituted at all positions with different substituents has produced effective anti-TB and anticancer activity. However, the unsubstituted R4-position of the quinoline enhances the anti-TB activities. The nitrogen of quinoline ring may be unsubstituted or substituents may differ from alkyl and aryl groups. Similarly, the

Fig. 3. Quinoline hydrazones as anti-tuberculosis agents.

Please cite this article in press as: Mandewale, M.C., et al. A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ. J. Basic Appl. Sci. (2017), http://dx.doi.org/10.1016/j.bjbas.2017.07.005

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R1-position may be substituted with alkyl or bulky aromatic groups and demonstrates a good anti-TB activity. The substituents at R2 or R3-position of the Quinoline ranging from functional groups like halogens, alkene linker, hydrazones, and amide derivatives to heteroaryl groups are favorable for the activity. The R5 or R6-position of the quinoline may be unsubstituted or substituents may vary from functional groups like halogens, nitro, amino, 5nitrofuran, dialkylamino, 4-fluorophenoxy, dimethylamino groups and quinoline with at-CF3 at R7 position, shows good anti-TB activity (Fig. 2). The unsubstituted R4 and R5-position of the quinoline enhance the better anticancer activity. Similarly, the R1-position may be unsubstituted or substituted with heterocyclic aromatic groups and demonstrates a good activity. The R2 or R3-position of the quinoline may be unsubstituted or substituted with secondary amino, alkyl or hydrazone group. The R6 or R7-position of the quinoline may be unsubstituted or substituted with halogen like Br and quinoline ring unsubstituted at R7 position facilitates good anticancer activity (Fig. 2).

3. Biologically active scaffolds in relevance to quinoline hydrazones as anti-TB agents Several authors have reviewed a broad spectrum of pharmacological activities demonstrated by quinoline and its derivatives (Marella et al., 2013; Keri and Patil, 2014; Afzal et al., 2015). A series of biologically important quinolinyl hydrazone derivatives were synthesized by Andre et al. (Candea et al., 2009) and evaluated for their in vitro anti-tuberculosis activity. The test compounds (14– 17) (Fig. 3) were non-cytotoxic and displayed a significant Minimum Inhibitory Concentration (MIC) activity (2.50 lg/mL), which was compared with Ethambutol and Rifampicin with MIC 3.12 lg/mL and 2.00 lg/mL respectively.

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New series of fluorine-containing quinoline hydrazone derivatives were prepared. The newly synthesized compounds (18–23) (Fig. 3) were screened for their in vitro antituberculosis activity. Preliminary results indicated that the quinoline hydrazone derivatives demonstrated very good antituberculosis activities with MIC 6.25 lM against Mycobacterium tuberculosis H37Rv and MDR-TB (Eswaran et al., 2010a,b). The quinoline hydrazone derivatives (24–30) (Fig. 3) were synthesized and screened for their in vitro anti-TB activity against various strains of Mycobacterium. The occurrence of quinoline hydrazones moiety has tremendously enhanced the TB activity. The test compounds showed better anti-tuberculosis potency than rifampin and isoniazid (Eswaran et al., 2010a,b). Compounds (31– 33) (Fig. 4) showed significant activity against the MDR-TB strain at 6.25 lg/mL. The activities of these compounds could be attributed to the quinoline hydrazone motif (Thomas et al., 2011). New fluorine substituted hydrazones (34–37) (Fig. 4) were prepared and assessed for their anti-tuberculosis potency (Vavríkova et al., 2011). In addition to this, we have synthesized a new series of fluorine bearing quinoline hydrazone derivatives and their Zn (II) complexes. All the compounds were tested for anti-tubercular activities against M. tuberculosis H37 RV strain. The copper complexes of compounds (38, 39) (Fig. 4) displayed 100% inhibitory activity at a concentration of 6.25 lg/mL, against Mycobacterium tuberculosis. Similarly zinc complex of compound (40) (Fig. 4) shows MIC at 12.5 lg/mL (Mandewale et al., 2015a,b,c, 2016a,b). 4. Anticancer potential of bioactive quinoline hydrazones Several new Platinum (II) complexes of the novel quinoline hydrazone obtained from quinoline-4-carboxaldehyde (41) (Fig. 5) as carrier ligands, have been prepared and characterized (Chackal et al., 2004). These synthesized platinum complexes were assessed for their cytotoxicity on Human promyelocytic Leukemia

Fig. 4. Anti-tuberculosis agents containing quinoline hydrazones motif.

Please cite this article in press as: Mandewale, M.C., et al. A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ. J. Basic Appl. Sci. (2017), http://dx.doi.org/10.1016/j.bjbas.2017.07.005

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Fig. 5. Anti-cancer agents containing quinoline hydrazone moiety.

cells (HL-60). Preliminary results indicated that these complexes are comparatively more cytotoxic and performed like Cisplatin. Liu et al. (Liu et al., 2009) synthesized and spectroscopically characterized the novel quinoline hydrazones (42, 43) (Fig. 5) and their Cu (II) complexes. The advanced techniques like Fluorescence spectroscopy, viscosity measurement and electronic absorption spectroscopy were employed to explore the interaction of the two Cu (II) complexes with calf thymus DNA (CT-DNA). The experimental observations indicated that the Cu (II) complexes could powerfully bind to CT-DNA via an intercalation mechanism. Gligorijevic et al. synthesized and characterized some new complexes of Pt (II) and Pd (II) with 2-quinolinecarboxaldehyde selenosemicarbazone

(Gligorijevic et al., 2009). The cytotoxic activity of the new Zn (II), Pt (II) and Pd (II) compounds was evaluated against human cancer cell lines such as breast cancer cells (MDA-361), human melanoma cells (FemX) and human cervix carcinoma cells (HeLa). Complexes of ligand (44) (Fig. 5) possess a strong dose-dependent cytotoxic activity is comparable with Cisplatin. Szumilak et al. (Szumilak et al., 2010) depicted the preparation of new quinoline hydrazone derivatives. Their antituberculosis activity was evaluated against melanoma cell line A375. The quinoline diamides were more potent than cinnoline ones. The DNA interactions of the new complexes were examined by viscosity, emission and absorption studies. The new complexes show very good antioxidant activity against DPPH

Please cite this article in press as: Mandewale, M.C., et al. A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ. J. Basic Appl. Sci. (2017), http://dx.doi.org/10.1016/j.bjbas.2017.07.005

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radical. The cytotoxicity of the new Co (III) complexes was assessed. The complex of compound (45) (Fig. 5) was identified as strong cytotoxic agents against lung cancer cell line A549. Serda et al. prepared a series of novel quinoline hydrazones and screened as potent anti-cancer agents (Serda et al., 2012). The quinoline derivatives were screened for cancer and non-neoplastic cells, including the normal human dermal fibroblast (NHDF), HCT116 colon cancer cell lines and human SKNMC neuroepithelioma cells by standard methods to evaluate anti-proliferative activity. The antiproliferative activity and iron chelation efficacy of several of these agents, in particular, compound (46) (Fig. 5) indicates that further investigation of this class of compounds is definitely worthwhile. Ghorab et al. reported the synthesis of some novel quinoline derivatives bearing a quinoline hydrazone motif (Ghorab et al., 2009). These hydrazones act as CA inhibitors, which may play a role in their anticancer activity. They evaluated some quinoline hydrazone derivatives for their in vitro anti-cancer activity against MCF7 (breast cancer cell line. Preliminary results show that compounds (47) (Fig. 5) having tetrahydroquinoline moiety was more potent. Ghorab et al. described the synthesis fluorine substituted quinoline hydrazone derivatives (Ghorab et al., 2011). All the compounds were assessed for their in vitro anticancer activity against (MCF7) human breast cancer cell line. The compound (48) (Fig. 5) (IC50 67.3 mM) exhibited better potency than the reference drug Doxorubicin. Makawana et al. recently reported a compound (49) (Fig. 5), which showed efficient EGFR inhibitor activity (Makawana et al., 2014). Adsule et al. synthesized and characterized novel Cu (II) complexes of quinoline hydroxime derivatives (Adsule et al., 2006). All the complexes were screened for anticancer activity against various prostate cancer cell lines such as PC-3 and LNCaP. The quinoline thiosemicarbazone (50) (Fig. 5) was the most active against cancer cell line PC-3 and LNCaP cells, which was compared to clioquinol and pyrrolidine dithiocarbamate (IC50 of 10 and 20 mM). Chen et al. synthesized novel quinoline hydrazone derivatives and screened against the cancer cell lines (NCI 60) (Chen et al., 2005). The compound (51) (Fig. 5) showed potent inhibitory activities on cell lines UO-31, UACC-257, and UACC-62. The similar cytotoxicity activity was observed for compound (52) (Fig. 5). Chen et al. reported the synthesis of new quinoline hydrazone derivatives and screened against cell line SF-268, NCI-H460, and MCF7 (Chen et al., 2006). The quinoline hydrazone derivative (53–56) (Fig. 5) showed good anticancer activity. Creaven et al. prepared Cu (II) complexes of quinoline hydrazone derivatives and assessed for anticancer activity against Hep-G2 cell line (Creaven et al., 2010). The cytotoxicity of Cu (II) complex of Schiff base ligand (57) (Fig. 4) (IC50 17.90 ± 3.75 mM) was comparable to that of Cisplatin (IC50 15.00 ± 2.65 mM). Montenegro et al. reported 7chloroqunoline hydrazone (58) (Fig. 5) exhibiting an outstanding cytotoxic activity and was found to be potent against all cancer cell lines particularly against MDAMB-435 (melanoma cells) (Montenegro et al., 2012). Several quinoline hydrazone derivatives with different side chains at the 8th position of the quinoline ring were synthesized by Arafa et al. and screened for their anticancer activity against the cell line HT29 and MDA-MB (Arafa et al., 2013). The most active derivative in this study against both tested cell lines was the quinoline hydrazone (59) (Fig. 5) with IC50 of 4.7 and 4.6 mM against HT29 and MDA-MB 231, respectively. The new copper (II) complexes of quinoline hydrazone derivatives have been synthesized (Raja et al., 2012). The DNA binding properties of the free ligand and two Cu (II) complexes were studied. The Cu (II) complex of compound (60) (Fig. 5) shows considerable cytotoxic activity against cancer cell lines HeLa, HEp-2 and Hep G2. These findings are important for exploring the DNA and protein interaction, cytotoxic and antioxidative potency of the metal complexes containing quinoline hydrazone.

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5. Conclusion The present review is expected to highlight the potential of quinoline hydrazone derivatives as a template for the development of anti-TB and anticancer agents having a diverse mechanism of action. However, the biological activity of this class of compounds needs more investigation. Although the research on this subject is incipient, a number of reports disclosing the effects of the quinoline hydrazones on the pathogens of clinical interest have recently been increasing. It can be concluded that with proper designing and SAR studies of known quinoline hydrazone derivatives, prospective compounds can be designed for anti-tuberculosis and anticancer activity. Acknowledgments The authors thank Principal and Head Department of Chemistry, Government of Maharashtra, Ismail Yusuf of Arts, Science and Commerce for providing research and library facilities. The authors also thank Dr. Bapu Thorat, Mr. T. L. Dadmal, Dr. Sudhir Sawant, Dr. R. B. Kanhere, Dr. V. R. Shedge, Ram jadhav, Bhushan Nazirkar, Devidas Anuse, Vijay Desale, Vishal Udmale, and Bhagwat Jadhav for encouragement and guidance during the research work.

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Please cite this article in press as: Mandewale, M.C., et al. A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-Suef Univ. J. Basic Appl. Sci. (2017), http://dx.doi.org/10.1016/j.bjbas.2017.07.005