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Medicinal Chemistry

Editor-in-Chief

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

General Research Article

Design, Synthesis and Biological Evaluation of Anti-tuberculosis Agents based on Bedaquiline Structure

Author(s): Chengjun Wu, Jinghan Luo, Mengtong Wu, Fanzhen Meng, Zhiqiang Cai, Yu Chen* and Tiemin Sun*

Volume 16, Issue 5, 2020

Page: [703 - 714] Pages: 12

DOI: 10.2174/1573406415666190613094433

Price: $65

Abstract

Background: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial ATP synthase. However, studies have found that bedaquiline has serious side effects due to high lipophilicity. Recently, the complete structure of ATP synthase was first reported in the Journal of Science.

Objective: The study aimed to design, synthesise and carry out biological evaluation of antituberculosis agents based on the structure of bedaquiline.

Methods: The mode of action of bedaquiline and ATP synthase was determined by molecular docking, and a series of low lipophilic bedaquiline derivatives were synthesized. The inhibitory activities of bedaquiline derivatives towards Mycobacterium phlei 1180 and Mycobacterium tuberculosis H37Rv were evaluated in vitro. A docking study was carried out to elucidate the structureactivity relationship of the obtained compounds. The predicted ADMET properties of the synthesized compounds were also analyzed.

Results: The compounds 5c3, 6a1, and 6d3 showed good inhibitory activities (MIC=15.62 ug.mL-1). At the same time, the compounds 5c3, 6a1, and 6d3 also showed good drug-like properties through molecular docking and ADMET properties prediction.

Conclusion: The results of in vitro anti-tuberculosis activity assays, docking studies and ADMET predictions indicate that the synthesized compounds have potential antifungal activity, with compounds 6a1 being further optimized and developed as lead compounds.

Keywords: Bedaquiline derivatives, anti-tuberculosis, ATP synthase, molecular docking ADMET, Mycobacterium tuberculosis.

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[1]
Geneva: World Health Organization. Licence: CC BY-NCSA 3.0 IGO., 2017.
[2]
Andries, K.; Verhasselt, P.; Guillemont, J.; Göhlmann, H.W.; Neefs, J.M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science, 2005, 307(5707), 223-227.
[http://dx.doi.org/10.1126/science.1106753] [PMID: 15591164]
[3]
Mase, S.; Chorba, T.; Lobue, P.; Castro, K. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm. Rep., 2013, 62(RR-09), 1-12.
[PMID: 24157696]
[4]
Mahajan, R. Bedaquiline: First FDA-approved tuberculosis drug in 40 years. Int. J. Appl. Basic Med. Res., 2013, 3(1), 1-2.
[http://dx.doi.org/10.4103/2229-516X.112228] [PMID: 23776831]
[5]
Patel, R.V.; Riyaz, S.D.; Park, S.W. Bedaquiline: a new hope to treat multi-drug resistant tuberculosis. Curr. Top. Med. Chem., 2014, 14(16), 1866-1874.
[http://dx.doi.org/10.2174/1568026614666140929114822] [PMID: 25262806]
[6]
Kim, C.T.; Kim, T.O.; Shin, H.J.; Ko, Y.C.; Hun Choe, Y.; Kim, H.R.; Kwon, Y.S. Bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis: a multicentre cohort study in Korea. Eur. Respir. J., 2018, 51(3) 1702467
[http://dx.doi.org/10.1183/13993003.02467-2017] [PMID: 29545276]
[7]
Kakkar, A.K.; Dahiya, N. Bedaquiline for the treatment of resistant tuberculosis: promises and pitfalls. Tuberculosis (Edinb.), 2014, 94(4), 357-362.
[http://dx.doi.org/10.1016/j.tube.2014.04.001] [PMID: 24841672]
[8]
Pym, A.S.; Diacon, A.H.; Tang, S.J.; Conradie, F.; Danilovits, M.; Chuchottaworn, C.; Vasilyeva, I.; Andries, K.; Bakare, N.; De Marez, T.; Haxaire-Theeuwes, M.; Lounis, N.; Meyvisch, P.; Van Baelen, B.; van Heeswijk, R.P.; Dannemann, B. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur. Respir. J., 2016, 47(2), 564-574.
[http://dx.doi.org/10.1183/13993003.00724-2015] [PMID: 26647431]
[9]
Fox, G.J.; Menzies, D. A review of the evidence for using bedaquiline (TMC207) to treat multi-drug resistant tuberculosis. Infect. Dis. Ther., 2013, 2(2), 123-144.
[http://dx.doi.org/10.1007/s40121-013-0009-3] [PMID: 25134476]
[10]
Diacon, A.H.; Pym, A.; Grobusch, M.P.; Jm, D.L.R.; Gotuzzo, E.; Vasilyeva, I.; Leimane, V.; Andries, K.; Bakare, N.; De, M.T. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. In: Kluwer Academic Pub; , 2014.
[http://dx.doi.org/10.1056/NEJMoa1313865]
[11]
Tong, A.S.T.; Choi, P.J.; Blaser, A.; Sutherland, H.S.; Tsang, S.K.Y.; Guillemont, J.; Motte, M.; Cooper, C.B.; Andries, K.; Van den Broeck, W.; Franzblau, S.G.; Upton, A.M.; Denny, W.A.; Palmer, B.D.; Conole, D. Andries, K.; Broeck, W.V.D. 6-Cyano analogues of bedaquiline as less lipophilic and potentially safer diarylquinolines for tuberculosis. ACS Med. Chem. Lett., 2017, 8(10), 1019-1024.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00196] [PMID: 29057044]
[12]
Svensson, E.M.; Murray, S.; Karlsson, M.O.; Dooley, K.E. Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug. J. Antimicrob. Chemother., 2015, 70(4), 1106-1114.
[PMID: 25535219]
[13]
Diacon, A.H.; Donald, P.R.; Pym, A.; Grobusch, M.; Patientia, R.F.; Mahanyele, R.; Bantubani, N.; Narasimooloo, R.; De Marez, T.; van Heeswijk, R.; Lounis, N.; Meyvisch, P.; Andries, K.; McNeeley, D.F. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob. Agents Chemother., 2012, 56(6), 3271-3276.
[http://dx.doi.org/10.1128/AAC.06126-11] [PMID: 22391540]
[14]
Makula, A.; Maddela, S. Design, synthesis and docking study of some novel isatin-quinoline hybrids as potential antitubercular agents. Antiinfect. Agents, 2016, 14, 53.
[http://dx.doi.org/10.2174/221135251401160302151229]
[15]
Srivastava, A.P.; Luo, M.; Zhou, W.; Symersky, J.; Bai, D.; Chambers, M.G.; Faraldo-Gómez, J.D.; Liao, M.; Mueller, D. High resolution cryo-EM analysis of the yeast ATP synthase in a lipid membrane. Science, 2018, 360(6389) eaas9699
[http://dx.doi.org/10.1126/science.aas9699]
[16]
Kumar, S.; Mehra, R.; Sharma, S.; Bokolia, N.P.; Raina, D.; Nargotra, A.; Singh, P.P.; Khan, I.A. Screening of antitubercular compound library identifies novel ATP synthase inhibitors of Mycobacterium tuberculosis. Tuberculosis (Edinb.), 2018, 108, 56-63.
[http://dx.doi.org/10.1016/j.tube.2017.10.008] [PMID: 29523328]
[17]
Preiss, L.; Langer, J.D.; Yildiz, Ö.; Eckhardt-Strelau, L.; Guillemont, J.E.; Koul, A.; Meier, T. Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci. Adv., 2015, 1(4) e1500106
[http://dx.doi.org/10.1126/sciadv.1500106] [PMID: 26601184]
[18]
Zhang, Z.H.; Chen, Y.; Yan, X.J.; Sun, Y.; Yang, X.M.; Cai, X.Y.; You, S. Synthesis and evaluation of novel urea and amide derivatives of 2-amino-4-phenylthiazole as potential antibacterial agents. Med. Chem. Res., 2017, 26, 2080-2087.
[http://dx.doi.org/10.1007/s00044-017-1910-1]
[19]
Consortium, U.P. UniProt: a hub for protein information. Nucleic Acids Res., 2015, 43(Database issue), D204-D212.
[http://dx.doi.org/10.1093/nar/gku989] [PMID: 25348405]
[20]
Ramachandran, G.N.; Ramakrishnan, C.; Sasisekharan, V. Stereochemistry of polypeptide chain configurations. J. Mol. Biol., 1963, 7, 95-99.
[http://dx.doi.org/10.1016/S0022-2836(63)80023-6] [PMID: 13990617]
[21]
Gengenbacher, M.; Rao, S.P.S.; Pethe, K. Nutrient-starved, non-replicating mycobacterium tuberculosis requires respiration, atp synthase and isocitrate lyase for maintenance of atp homeostasis and viability. Microbiology, 2010, 156(1), 81-87.
[http://dx.doi.org/10.1099/mic.0.033084-0] [PMID: 19797356]
[22]
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.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[23]
Pathak, R.; Madapa, S.; Batra, S. Trifluoroacetic acid: a more effective and efficient reagent for the synthesis of 3-arylmethylene-3,4-dihydro-1 H -quinolin-2-ones and 3-arylmethyl-2-amino-quinolines from Baylis–Hillman derivatives via Claisen rearrangement. Tetrahedron, 2007, 63, 451-460.
[http://dx.doi.org/10.1016/j.tet.2006.10.053]
[24]
Upadhayaya, R.S.; Vandavasi, J.K.; Vasireddy, N.R.; Sharma, V.; Dixit, S.S.; Chattopadhyaya, J. Design, synthesis, biological evaluation and molecular modelling studies of novel quinoline derivatives against Mycobacterium tuberculosis. Bioorg. Med. Chem., 2009, 17(7), 2830-2841.
[http://dx.doi.org/10.1016/j.bmc.2009.02.026] [PMID: 19285414]
[25]
Wang, Z.; Zhao, L.; Chen, Y.; Xu, W.; Sun, T. Determination of absolute configurations of bedaquiline analogs by quantum chemical electronic circular dichroism calculations and an x‐ray diffraction study. Eur. J. Org. Chem., 2014, 2014, 3814-3821.
[http://dx.doi.org/10.1002/ejoc.201400135]
[26]
Tonelli, M.; Cichero, E.; Mahmoud, A.M.; Rabbito, A.; Tasso, B.; Fossa, P.; Ligresti, A. Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction. MedChemComm, 2018, 9(12), 2045-2054.
[http://dx.doi.org/10.1039/C8MD00461G] [PMID: 30647880]
[27]
Nisha, C.M.; Kumar, A.; Vimal, A.; Bai, B.M.; Pal, D.; Kumar, A. Docking and ADMET prediction of few GSK-3 inhibitors divulges 6-bromoindirubin-3-oxime as a potential inhibitor. J. Mol. Graph. Model., 2016, 65, 100-107.
[http://dx.doi.org/10.1016/j.jmgm.2016.03.001] [PMID: 26967552]

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