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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification

Author(s): Katharigatta N. Venugopala*, Sandeep Chandrashekharappa, Melendhran Pillay, Subhrajyoti Bhandary, Mahmoud Kandeel, Fawzi M. Mahomoodally, Mohamed A. Morsy, Deepak Chopra, Bandar E. Aldhubiab, Mahesh Attimarad, Osama I. Alwassil, Sree Harsha, Koleka Mlisana and Bharti Odhav

Volume 15, Issue 3, 2019

Page: [311 - 326] Pages: 16

DOI: 10.2174/1573406414666180703121815

Price: $65


Background: Benzothiazole derivatives are known for anti-TB properties. Based on the known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1–7 and BNTZ 8–13).

Objective: The study aims to carry out the development of benzothiazole based anti-TB compounds.

Methods: Title compounds are synthesized by microwave method and purified by column chromatography. Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS and elemental analysis. Screening of test compounds for anti-TB activity is achieved by Resazurin Microplate Assay (REMA) Plate method.

Results: It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited remarkable anti-tubercular activity at 8 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis. On the other hand, the BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6 µg/mL and 11 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of M. tuberculosis, respectively. One of the selected BNTZ derivatives BNTZ 13 was used for single crystal X-ray studies.

Conclusion: To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-ɛ-aminotransferase and decaprenyl-phosphoryl-β-D-ribose 2'-oxidase. The interaction is derived by forming favorable hydrogen bonds and stacking interactions. This new class of BNTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs.

Keywords: Benzothiazole derivatives, characterization, whole cell anti-TB screening, in-silico screening for targets, single crystal X-ray studies, one-pot synthesis, microwave method, multidrug resistant tuberculosis.

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WHO, WHO Global Tuberculosis Report. visited on December 25, 2017, 1-249
Marcos, A.E. The global situation of MDR-TB. Tuberc, 2003, 83, 44-51.
Caminero, J.A.; Sotgiu, G.; Zumla, A.; Migliori, G.B. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet. Infect. Dis., 2010, 10(9), 621-629.
Hu, Y.; Xu, L.; He, Y.L.; Pang, Y.; Lu, N.; Liu, J.; Shen, J.; Zhu, D.M.; Feng, X.; Wang, Y.W.; Yang, C. Prevalence and molecular characterization of second-line drugs resistance among multidrug-resistant Mycobacterium tuberculosis isolates in southwest of China. BioMed Res. Int., 2017, 2017, 4563826.
Parida, S.K.; Axelsson-Robertson, R.; Rao, M.V.; Singh, N.; Master, I.; Lutckii, A.; Keshavjee, S.; Andersson, J.; Zumla, A.; Maeurer, M. Totally drug-resistant tuberculosis and adjunct therapies. J. Intern. Med., 2015, 277(4), 388-405.
Cox, E.; Laessig, K. FDA approval of bedaquiline - the benefit–risk balance for drug-resistant Tuberculosis. N. Engl. J. Med., 2014, 371(8), 689-691.
Barry Iii, C.E. Timing is everything for compassionate use of delamanid. Nat. Med., 2015, 21(3), 211.
Venugopala, K.N.; Krishnappa, M.; Nayak, S.K.; Subrahmanya, B.K.; Vaderapura, J.P.; Chalannavar, R.K.; Gleiser, R.M.; Odhav, B. Synthesis and antimosquito properties of 2,6-substituted benzo[d]thiazole and 2,4-substituted benzo[d]thiazole analogues against Anopheles arabiensis. Eur. J. Med. Chem., 2013, 65, 295-303.
Rida, S.M.; Youssef, A.M.; Badr, M.H.; Malki, A.; Sherif, Z.A.; Sultan, A.S. Design, synthesis and evaluation of novel benzimidazoles, benzothiazoles and benzofurans incorporating pyrazole moiety as antiangiogenic agents. Arzneim, 2012, 62(2), 63-74.
Shaikh, F.M.; Patel, N.B.; Sanna, G.; Busonera, B.; Colla, P.; Rajani, D.P. Synthesis of some new 2-amino-6-thiocyanato benzothiazole derivatives bearing 2,4-thiazolidinediones and screening of their in vitro antimicrobial, antitubercular and antiviral activities. Med. Chem. Res., 2015, 24(8), 3129-3142.
Singh, M.; Gangwar, M.; Nath, G.; Singh, S.K. Synthesis, DNA cleavage and antimicrobial activity of 4-thiazolidinones-benzothiazole conjugates. Ind. J. Exp. Biol., 2014, 52(11), 1062-1070.
Abuzar, S.; Sharma, S. Synthesis of 6-N-aryl and heteroaryl benzthiazoles as potential anthelmintics. Z. Naturforsch., 1981, 36B(1), 108-111.
Puranik, N.V.; Puntambekar, H.M.; Srivastava, P. Antidiabetic potential and enzyme kinetics of benzothiazole derivatives and their non-bonded interactions with α-glucosidase and α-amylase. Med. Chem. Res., 2016, 25(4), 805-816.
Nagoshi, N.; Nakashima, H.; Fehlings, M.G. Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside. Molecules, 2015, 20(5), 7775-7789.
Shah, F.; Wu, Y.; Gut, J.; Pedduri, Y.; Legac, J.; Rosenthal, P.J.; Avery, M.A. Design, synthesis and biological evaluation of novel benzothiazole and triazole analogs as falcipain inhibitors. MedChemComm, 2011, 2(12), 1201-1207.
Valcke, A.R.A.; Van Der Flaas, M.A.J. Synergistic compositions containing metconazole and another triazole. In Google Patents:, 1998.
Reshma, R.S.; Jeankumar, V.U.; Kapoor, N.; Saxena, S.; Bobesh, K.A.; Vachaspathy, A.R.; Kolattukudy, P.E.; Sriram, D. Mycobacterium tuberculosis lysine-varepsilon-aminotransferase a potential target in dormancy: Benzothiazole based inhibitors. Bioorg. Med. Chem., 2017, 25(10), 2761-2771.
Chikhale, R.; Menghani, S.; Babu, R.; Bansode, R.; Bhargavi, G.; Karodia, N.; Rajasekharan, M.V.; Paradkar, A.; Khedekar, P. Development of selective DprE1 inhibitors: Design, synthesis, crystal structure and antitubercular activity of benzothiazolylpyrimidine-5-carboxamides. Eur. J. Med. Chem., 2015, 96, 30-46.
Landge, S.; Mullick, A.B.; Nagalapur, K.; Neres, J.; Subbulakshmi, V.; Murugan, K.; Ghosh, A.; Sadler, C.; Fellows, M.D.; Humnabadkar, V.; Mahadevaswamy, J.; Vachaspati, P.; Sharma, S.; Kaur, P.; Mallya, M.; Rudrapatna, S.; Awasthy, D.; Sambandamurthy, V.K.; Pojer, F.; Cole, S.T.; Balganesh, T.S.; Ugarkar, B.G.; Balasubramanian, V.; Bandodkar, B.S.; Panda, M.; Ramachandran, V. Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-beta-D-ribose 2′-oxidase. Bioorg. Med. Chem., 2015, 23(24), 7694-7710.
Mehra, R.; Rajput, V.S.; Gupta, M.; Chib, R.; Kumar, A.; Wazir, P.; Khan, I.A.; Nargotra, A. Benzothiazole derivative as a novel Mycobacterium tuberculosis Shikimate kinase inhibitor: Identification and elucidation of its allosteric mode of inhibition. J. Chem. Inf. Model., 2016, 56(5), 930-940.
Venugopala, K.N.; Albericio, F.; Coovadia, Y.M.; Kruger, H.G.; Maguire, G.E.M.; Pillay, M.; Govender, T. Total synthesis of a depsidomycin analogue by convergent solid-phase peptide synthesis and macrolactonization strategy for antitubercular activity. J. Pept. Sci., 2011, 17(10), 683-689.
Venugopala, K.N.; Nayak, S.K.; Pillay, M.; Prasanna, R.; Coovadia, Y.M.; Odhav, B. Synthesis and antitubercular activity of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(met-hoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium chlorides. Chem. Biol.Drug. Des., 2013, 81(2), 219-227.
Venugopala, K.N.; Dharma, R.G.B.; Bhandary, S.; Pillay, M.; Chopra, D.; Aldhubiab, B.E.; Attimarad, M.; Alwassil, O.I.; Harsha, S.; Mlisana, K. Design, synthesis, and characterization of (1-(4-aryl)-1H-1,2,3-triazol-4-yl) methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against Mycobacterium tuberculosis. Drug Des. Devel. Ther., 2016, 10, 2681-2690.
Khedr, M.A.; Pillay, M.; Chandrashekharappa, S.; Chopra, D.; Aldhubiab, B.E.; Attimarad, M.; Alwassil, O.I.; Mlisana, K.; Odhav, B.; Venugopala, K.N. Molecular modeling studies and anti-TB activity of trisubstituted indolizine analogues; molecular docking and dynamic inputs. J. Biomol. Struct. Dyn., 2018, 36, 2163-2178.
Palmer, P.J.; Trigg, R.B.; Warrington, J.V. Benzothiazolines as antituberculous agents. J. Med. Chem., 1971, 14(3), 248-251.
Panini, P.; Venugopala, K.N.; Odhav, B.; Chopra, D. Polymorphism in two biologically active dihydropyrimidinium hydrochloride derivatives: quantitative inputs towards the energetics associated with crystal packing. Acta Crystallogr. B Struct. Sci. Cryst.Sect. B Eng. Mater., 2014, 70, 681-696.
Panini, P.; Venugopala, K.N.; Odhav, B.; Chopra, D. Quantitative analysis of intermolecular interactions in 7-hydroxy-4-methyl-2H-chromen-2-one and its hydrate. P. Natl. A. Sci. India A., 2014, 84(2), 281-295.
Munshi, P.; Venugopala, K.N.; Jayashree, B.S.; Guru, R.T.N. Concomitant polymorphism in 3-acetylcoumarin: Role of weak C−H···O and C−H···π interactions. Cryst. Growth Des., 2004, 4(6), 1105-1107.
Siemens, S.S. Siemens Analytical X-ray Instruments Inc; Madison, MI, 1995.
Apex2, Version 2 User Manual M86-E01078; Bruker Analytical X-ray Systems Madison: WI, 2006.
Burla, M.C.; Caliandro, R.; Carrozzini, B.; Cascarano, G.L.; Cuocci, C.; Giacovazzo, C.; Mallamo, M.; Mazzone, A.; Polidori, G. Crystal structure determination and refinement via SIR2014. J. Appl. Cryst., 2015, 48(1), 306-309.
Sheldrick, G. A short history of SHELX. Acta. Crystallographica. Sec. C., 2015, 71, 3-8.
Farrugia, L. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Cryst., 1999, 32(4), 837-838.
Sheldrick, G.M. SHELXS-97, SHELXL-2014 and SADABS version 2.05; University of Göttingen: Germany, 1997.
Macrae, C.F.; Bruno, I.J.; Chisholm, J.A.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P.A. Mercury CSD 2.0 - new features for the visualization and investigation of crystal structures. J. Appl. Cryst., 2008, 41(2), 466-470.
Nardelli, M. PARST95 - an update to PARST: a system of Fortran routines for calculating molecular structure parameters from the results of crystal structure analyses. J. Appl. Cryst., 1995, 28(5), 659.
Spek, A. Single-crystal structure validation with the program PLATON. J. Appl. Cryst., 2003, 36(1), 7-13.
Martin, A.; Morcillo, N.; Lemus, D.; Montoro, E.; Telles, M.A.; Simboli, N.; Pontino, M.; Porras, T.; Leon, C.; Velasco, M.; Chacon, L.; Barrera, L.; Ritacco, V.; Portaels, F.; Palomino, J.C. Multicenter study of MTT and resazurin assays for testing susceptibility to first-line anti-tuberculosis drugs. Int. J. Tuberc. Lung Dis., 2005, 9(8), 901-906.
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
Tripathi, S.M.; Agarwal, A.; Ramachandran, R. Mutational analysis of Mycobacterium tuberculosis lysine varepsilon-aminotransferase and inhibitor co-crystal structures, reveals distinct binding modes. Biochem. Biophys. Res. Commun., 2015, 463(1-2), 154-160.
Tripathi, S.M.; Ramachandran, R. Direct evidence for a glutamate switch necessary for substrate recognition: crystal structures of lysine ε-aminotransferase (Rv3290c) from Mycobacterium tuberculosis H37Rv. J. Mol. Biol., 2006, 362, 877-886.
Batt, S.M.; Jabeen, T.; Bhowruth, V.; Quill, L.; Lund, P.A.; Eggeling, L.; Alderwick, L.J.; Futterer, K.; Besra, G.S. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc. Natl. Acad. Sci. USA, 2012, 109(28), 11354-11359.
Blanco, B.; Prado, V.; Lence, E.; Otero, J.M.; Garcia-Doval, C.; van Raaij, M.J.; Llamas-Saiz, A.L.; Lamb, H.; Hawkins, A.R.; González-Bello, C. Mycobacterium tuberculosis Shikimate kinase inhibitors: Design and simulation studies of the catalytic turnover. J. Am. Chem. Soc., 2013, 135(33), 12366-12376.
Alnazawi, M.; Altaher, A.; Kandeel, M. Comparative genomic analysis MERS CoV i solated from humans and camels with special reference to virus encoded helicase. Biol. Pharm. Bull., 2017, 40(8), 1289-1298.
Kandeel, M.; Kitade, Y. In silico molecular docking analysis of the human Argonaute 2 PAZ domain reveals insights into RNA interference. J. Comput. Aided Mol. Des., 2013, 27(7), 605-614.

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