Tryptanthrin Analogues as Inhibitors of Enoyl-acyl Carrier Protein Reductase: Activity against Mycobacterium tuberculosis, Toxicity, Modeling of Enzyme Binding

Author(s): Gheorghe Duca, Serghei Pogrebnoi, Veaceslav Boldescu, Fatma Aksakal, Andrei Uncu, Vladimir Valica, Livia Uncu, Simona Negres, Florica Nicolescu, Fliur Macaev*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 8 , 2019

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Graphical Abstract:


Background: High numbers of infection with resistant forms of Micobacterium tuberculosis (Mtb) contribute to a constant growing demand in new highly active and effective therapeutics. Current drug discovery efforts directed towards new antituberculosis agents include the development of new inhibitors of enoyl-acyl carrier protein reductase (InhA) that do not require activation by the specific enzymes. Tryptanthrin is a known inhibitor of Mtb InhA and its analogues are investigated as potential agents with antimycobacterial efficiency.

Objective: The main objective of the presented research was to develop a new group of tryptanthrin analogues with good inhibition properties against Mtb.

Methods: Synthesis of new derivatives of 5H-[1,3,4]thiadiazolo[2,3- b]quinazolin-5-one and evaluation of their activity against Mtb, as well as acute and chronic toxicity studies were carried out. Molecular modeling studies were performed to investigate the binding mechanisms of the synthesized ligands with InhA. Binding energies and non-covalent interactions stabilizing the ligand-receptor complexes were obtained from the results of molecular docking.

Results: The most active compound in the obtained series, 2-(propylthio)-5H-[1,3,4]thiadiazolo[2,3- b]quinazolin-5-one, exhibited the superior inhibition activity (up to 100%) against mycobacterial growth at MIC 6.5 µg/mL, showed good affinity to the InhA enzyme in docking studies and demonstrated a very low per oral toxicity in animals falling under the category 5 according to GHS classification.

Conclusion: 2-(propylthio)-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one can be further explored for the development of a new series of compounds active against Mtb.

Keywords: Tryptanthrin, Mycobacterium tuberculosis, Enoyl-acyl carrier protein reductase, Drug design, Enzyme models, Thiadiazole, Quinazolinone.

World Health Organization Regional Office for South-East Asia. Bending the curve - Ending TB. Annual Report, 2017, 2017, 1-76.
Lu, X.Y.; You, Q.D.; Chen, Y.D. Recent progress in the identification and development of InhA direct inhibitors of Mycobacterium Tuberculosis. Mini Rev. Med. Chem., 2010, 10(3), 182-193.
North, E.J.; Jackson, M.; Lee, R.E. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics. Curr. Pharm. Des., 2014, 20(27), 4357-4378. []. [PMID: 24245756].
Zhang, Y.; Xie, L.; Xie, J. Progress on the discovery of inhibitors of InhA, the FAS II Enoyl-ACP reductase TB drug discovery targeted on InhA. Lett. Drug Des. Discov., 2016, 13(6), 539-546. [].
Pan, P.; Tonge, P.J. Targeting InhA, the FASII enoyl-ACP reductase: SAR studies on novel inhibitor scaffolds. Curr. Top. Med. Chem., 2012, 12(7), 672-693. [ 156802612799984535]. [PMID: 22283812].
Sullivan, T.J.; Truglio, J.J.; Boyne, M.E.; Novichenok, P.; Zhang, X.; Stratton, C.F.; Li, H-J.; Kaur, T.; Amin, A.; Johnson, F.; Slayden, R.A.; Kisker, C.; Tonge, P.J. High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem. Biol., 2006, 1(1), 43-53. [ 10.1021/cb0500042]. [PMID: 17163639].
Freundlich, J.S.; Wang, F.; Vilchèze, C.; Gulten, G.; Langley, R.; Schiehser, G.A.; Jacobus, D.P.; Jacobs, W.R., Jr; Sacchettini, J.C. Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. ChemMedChem, 2009, 4(2), 241-248. []. [PMID: 19130456].
Stec, J.; Vilchèze, C.; Lun, S.; Perryman, A.L.; Wang, X.; Freundlich, J.S.; Bishai, W.; Jacobs, W.R., Jr; Kozikowski, A.P. Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein reductase InhA in drug-sensitive and drug-resistant strains of mycobacterium tuberculosis. ChemMedChem, 2014, 9(11), 2528-2537. [ 201402255]. [PMID: 25165007].
Pan, P.; Knudson, S.E.; Bommineni, G.R.; Li, H.J.; Lai, C.T.; Liu, N.; Garcia-Diaz, M.; Simmerling, C.; Patil, S.S.; Slayden, R.A.; Tonge, P.J. Time-dependent diaryl ether inhibitors of InhA: Structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy. ChemMedChem, 2014, 9(4), 776-791. []. [PMID: 24616444].
Kuo, M.R.; Morbidoni, H.R.; Alland, D.; Sneddon, S.F.; Gourlie, B.B.; Staveski, M.M.; Leonard, M.; Gregory, J.S.; Janjigian, A.D.; Yee, C.; Musser, J.M.; Kreiswirth, B.; Iwamoto, H.; Perozzo, R.; Jacobs, W.R., Jr; Sacchettini, J.C.; Fidock, D.A. Targeting tuberculosis and malaria through inhibition of Enoyl reductase: Compound activity and structural data. J. Biol. Chem., 2003, 278(23), 20851-20859. []. [PMID: 12606558].
Zanzoul, A.; Chollet, A.; Piedra-Arroni, E.; Stigliani, J-L.; Bernardes-Génisson, V.; Essassi, E.M.; Pratviel, G. Synthesis of an Indoloquinoxaline derivative as potential inhibitor of InhA enzyme of Mycobacterium Tuberculosis. Lett. Org. Chem., 2015, 12(10), 727-733. [].
He, X.; Alian, A.; Stroud, R.; Ortiz de Montellano, P.R. Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J. Med. Chem., 2006, 49(21), 6308-6323. [ jm060715y]. [PMID: 17034137].
Guardia, A.; Gulten, G.; Fernandez, R.; Gómez, J.; Wang, F.; Convery, M.; Blanco, D.; Martínez, M.; Pérez-Herrán, E.; Alonso, M.; Ortega, F.; Rullás, J.; Calvo, D.; Mata, L.; Young, R.; Sacchettini, J.C.; Mendoza-Losana, A.; Remuiñán, M.; Ballell Pages, L.; Castro-Pichel, J. N-Benzyl-4-((heteroaryl)methyl)benzamides: A new class of direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors with antitubercular activity. ChemMedChem, 2016, 11(7), 687-701. [ cmdc.201600020]. [PMID: 26934341].
He, X.; Alian, A.; Ortiz de Montellano, P.R. Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg. Med. Chem., 2007, 15(21), 6649-6658. []. [PMID: 17723305].
Baker, W.R.; Lester, A.M. Indolo [2, 1-Biquinazoline-6, 12-Dione antibacterial compounds and methods of use thereof. US Patent 5,441,955., May 26, 1995.
Mitscher, L.A.; Baker, W. Tuberculosis: A search for novel therapy starting with natural products. Med. Res. Rev., 1998, 18(6), 363-374. [<363:AID-MED1>3.0.CO;2-I]. [PMID: 9828037].
Hwang, J-M.; Oh, T.; Kaneko, T.; Upton, A.M.; Franzblau, S.G.; Ma, Z.; Cho, S-N.; Kim, P. Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents. J. Nat. Prod., 2013, 76(3), 354-367. [ np3007167]. [PMID: 23360475].
Tripathi, A.; Wadia, N.; Bindal, D.; Jana, T. Docking studies on novel alkaloid tryptanthrin and its analogues against enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis. Indian J. Biochem. Biophys., 2012, 49(6), 435-441. [PMID: 23350278].
Honda, G.; Tabata, M. Isolation of antifungal principle tryptanthrin, from Strobilanthes cusia O. Kuntze. Planta Med., 1979, 36(1), 85-90. []. [PMID: 461559].
Honda, G.; Tosirisuk, V.; Tabata, M. Isolation of an antidermatophytic, tryptanthrin, from indigo plants, Polygonum tinctorium and Isatis tinctoria. Planta Med., 1980, 38(3), 275-276. []. [PMID: 7367492].
Bergman, J.; Lindström, J-O.; Tilstam, U.L.F. The structure and properties of some indolic constituents in Couroupita Guianensis Aubl. Tetrahedron, 1985, 41(14), 2879-2881. [ 10.1016/S0040-4020(01)96609-8].
Schindler, F.; Zähner, H. Mitteilung tryptanthrin, ein von tryptophan abzuleitendes antibioticum aus dandida lipolytica. Arch. Mikrobiol., 1968, 6(25), 224-239.
Jahng, Y. Progress in the studies on tryptanthrin, an alkaloid of history. Arch. Pharm. Res., 2013, 36(5), 517-535. []. [PMID: 23543631].
Frisch, M.J.E.A. G. W, Trucks.; Hs B, Schlegel.; G. E, Scuseria.; M. A. Robb, J. R.; Cheeseman, G. S. Gaussian 09, Revision a. 02; Gaussian. Inc.: Wallingford, CT, 2009, p. 200.
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789. []. [PMID: 9944570].
Becke, A.D. Densityϋfunctional thermochemistry. III. The role of exact exchange. J. Chem. Phys., 1993, 98, 5648-5652. [].
Shattuck, T.W. Molecular Operating Environment (MOE). Chemical Computing Group; Canada, 2013.
Collins, L.; Franzblau, S.G. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents Chemother., 1997, 41(5), 1004-1009. []. [PMID: 9145860].
Yao, Z-J.; Dong, J.; Che, Y-J.; Zhu, M-F.; Wen, M.; Wang, N-N.; Wang, S.; Lu, A-P.; Cao, D-S. TargetNet: A web service for predicting potential drug-target interaction profiling via multi-target SAR models. J. Comput. Aided Mol. Des., 2016, 30(5), 413-424. []. [PMID: 27167132].
El-Azab, A.S.; Abdel-Aziz, A.A-M.; Al-Swaidan, I.A.; Ng, S.W.; Tiekink, E.R.T. 2-Methyl-sulfanyl-9H-1,3,4-thia-diazolo[2,3-b]quinazolin-9-one. Acta Crystallogr. Sect. E Struct. Rep. Online, 2012, 68(Pt 7), o2134. [ S1600536812026189]. [PMID: 22798810].
Macaev, F.; Rusu, G.; Pogrebnoi, S.; Gudima, A.; Stingaci, E.; Vlad, L.; Shvets, N.; Kandemirli, F.; Dimoglo, A.; Reynolds, R. Synthesis of novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure-anti-mycobacterial activities. Bioorg. Med. Chem., 2005, 13(16), 4842-4850. [ 05.011]. [PMID: 15993090].
Macaev, F.; Ribkovskaia, Z.; Pogrebnoi, S.; Boldescu, V.; Rusu, G.; Shvets, N.; Dimoglo, A.; Geronikaki, A.; Reynolds, R. The structure-antituberculosis activity relationships study in a series of 5-aryl-2-thio-1,3,4-oxadiazole derivatives. Bioorg. Med. Chem., 2011, 19(22), 6792-6807. [ 2011.09.038]. [PMID: 22001325].
Pogrebnoi, S.; Chiriţă, C.; Valica, V.; Macaev, F.; Chifiriuc, M.C.; Kamerzan, C.; Uncu, L. Studies on the antimycobacterial action of a novel compound of the thiadiazole class. Farmacia, 2017, 65(1), 69-74.
Rychtarčíková, Z.; Krátký, M.; Gazvoda, M.; Komlóová, M.; Polanc, S.; Kočevar, M.; Stolaříková, J.; Vinšová, J. N-substituted 2-isonicotinoylhydrazinecarboxamides--new antimycobacterial active molecules. Molecules, 2014, 19(4), 3851-3868. [ 10.3390/molecules19043851]. [PMID: 24686575].

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Year: 2019
Page: [609 - 619]
Pages: 11
DOI: 10.2174/1568026619666190304125740
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