MOLECULAR DOCKING STUDIES AND SYNTHESIS OF 3, 4 - DISUBSTITUTED TRIAZOLES AS MYCOBACTERIUM TUBERCULOSIS ENOYL-ACP REDUCTASE AND CYP-51 INHIBITORS
Objective: To design, synthesize and in vitro antitubercular, antifungal and antioxidant evaluation of some novel mercapto 1, 2, 4â€“triazole derivatives.
Methods: New derivatives were designed by using various software like ACD Lab chemsketch, molinspiration and autodock. Designed molecules are obeying Lipinskiâ€™s rule of five and having highest binding score was selected for the synthesis. The synthesized compounds were subjected to TLC, melting point determination, FTIR, 1H NMR,Â 13C NMR and mass spectral analysis. The newly synthesized compounds were investigated for in vitro antitubercular evaluation by MABA method, antifungal evaluation by cup plate method and antioxidant evaluation by DPPH scavenging assay.
Results: A virtual screening was carried out through docking designed compounds into the InhA and CYP-51 binding site to predict if these compounds have an analogous binding mode of the enoylÂ ACP reductase (InhA) and CYP-51 inhibitors. Three derivatives (4a1, 4a2 and 4a3) were selected for the synthesis with the help of in silico modeling. The selected derivatives were synthesized by a conventional method. All the synthesized compounds showed a characteristic peak in FT IR, 1H and 13C NMR and mass spectroscopic studies. All the selected derivatives showed antitubercular, antifungal and antioxidant activity.
Conclusion: The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields. Newer derivatives possess good antitubercular, antifungal and antioxidant activity.
2. Lengauer T, Rarey M. Computational methods for biomolecular docking. Curr Opin Struct Biol 1996;6:402â€“6.
3. Dolin, Gerald Mandell L, John Bennett E, Raphael Mandell. Douglas and bennett's principles and practice of infectious diseases. 7th ed. Philadelphia PA: Churchill Livingstone/Elsevier; 2010.
4. Ling LL, Xian J, Ali S, Geng B, Fan J, Mills DM, et al. Identification and characterization of inhibitors of bacterial enoyl-acyl carrier protein reductase. Antimicrob Agents Chemother 2004; 48:1541-7.
5. Oliveira JS, Vasconcelos IB, Moreira IS, Santos DS, Basso LA. Enoyl reductases as targets for the development of anti-tubercular and anti-malarial agents. Curr Drug Targets 2007;8:399-411.
6. Zhongjun Guan, Xiaoyun Chai, Shichong Yu, Honggang Hu, Yuanying Jiang, Qingguo Meng, et al. Synthesis, molecular docking and biological evaluation of novel triazole derivatives as antifungal agents. Chem Biol Drug Des 2010;76:496â€“504.
7. Stefania Felicia Barbuceanu, Diana Carolina Ilies, Gabriel Saramet, Valentina Uivarosi, Constantin Draghici, Valeria Radulescu. Synthesis and antioxidant activity evaluation of new compounds from hydrazinecarbothioamide and 1, 2, 4-triazole class containing diaryl sulfone and 2,4-difluoro-phenyl moieties. Int J Mol Sci 2014;15:10908-25.
8. Ahmet Cetin, Ibrahim Halil Gecibesler. Evaluation as antioxidant agents of 1,2,4-triazole derivatives: essential functional group effects. J Appl Pharm Sci 2015;5:120-6.
9. Nareshvarma Seelam, Shrivastava SP, Prasanthi S, Supriya Gupta. Synthesis and in vitro study of some fused 1, 2, 4-triazole derivatives as antimycobacterial agents. J Saudi Chem Soc 2016;20:411â€“8.
10. Sheng CQ, Zhang WN, Ji HT, Zhang M, Song YL, Xu H, et al. Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA and molecular docking. J Med Chem 2006;49:2512â€“25.
11. Wang Z, Wu B, Kuhen KL, Bursulaya B, Nguyen TN, Nguyen DG, et al. Synthesis and biological evaluations of sulfanyl triazoles as novel HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem Lett 2006;16:4174â€“7.
12. Navidpour L, Shafaroodi H, Abdi K, Amini M, Ghahremani MH, Dehpour AR, et al. Design, synthesis, and biological evaluation of substituted 3-alkylthio-4,5-diaryl-4H-1, 2, 4-triazoles as selective COX-2 inhibitors. Bioorg Med Chem 2006;14:2507â€“17.
13. Prabhu Jalihal C, Vaibhav Rajoriya, Varsha Kashaw. Design, synthesis, and evaluation of new derivative of 1,2,4-triazoles for antimicrobial and anti-inflammatory activity. Int J Curr Pharm Res 2018;10:29-35.
14. Jeetendra Kumar Gupta, Pradeep Mishra. Antimicrobial and anthelmintic activities of some newly synthesized triazoles. Asian J Pharm Clin Res 2017;10:139-45.
15. Yasodakrishna Sajja, Sowmya Vanguru, Hanmanth Reddy Vulupala, Rajashaker Bantu, Perumal Yogeswari, Dharmarajan Sriram, et al. Design, synthesis and in vitro anti-tuberculosis activity of benzo [6, 7] cyclohepta [1,2-b]pyridine-1,2,3-triazole derivatives. Bioorg Med Chem Lett 2017;27:5119-21.
16. Arif Mermer, Neslihan Demirbas, Yakup Sirin, Harun Uslu, Zeynep Ozdemir, Ahmet Demirbas. Conventional and microwave prompted synthesis, antioxidant, anticholinesterase activity screening and molecular docking studies of new quinolone triazole hybrids. Bioorg Chem 2018;78:236-48.
17. Bakunov SA, Bakunova SM, Wenzler T, Ghebru M, Werbovetz KA, Brun R. Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3-triazoles. J Med Chem 2010;53:254-72.
18. Guimaraes TT, Pinto FR, Lanza JS, Melo MN, Monte-Neto RL, Melo IMM. Potent naphthoquinones against antimony sensitive and resistant Leishmania parasites: synthesis of novel Î±-and nor-Î±-lapachone based 1,2,3-triazoles by copper catalyzed azide-alkyne cycloaddition. Eur J Med Chem 2013;63:523-30.
19. Zhou CH, Wang Y. Recent researches in triazole compounds as medicinal drugs. Curr Med Chem 2012;19:239-80.
20. Rucha Wadapurkar M, Shilpa MD, Anil Kumar Katti S, Sulochana MB. In silico drug design for Staphylococcus aureus and development of host-pathogen interaction network. Informatics Medicine Unlocked 2018;10:58â€“70.
21. He X, Alian A, Stroud RM, Ortiz de Montellano PR. Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J Med Chem 2006;19:6308-23.
22. Podust LM, Poulos TL, Waterman MR. Crystal structure of cytochrome P450 14alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc Natl Acad Sci USA 2001;13:3068-73.
23. Schroeder EK, Basso LA, Santos DS, de Souza ON. Molecular dynamics simulation studies of the wild-type, 121V and I16T mutants of isoniazid-resistant Mycobacterium tuberculosis enoyl reductase (InhA) in complex with NADH: toward the understanding of NADH-InhA different affinities. Biophys J 2005;89:876-84.
24. Bellamine A, Lepesheva GI, Waterman MR. Fluconazole binding and sterol demethylation in three CYP 51 isoforms indicate defferences in active site topology. J Lipid Res 2004;45:2000-7.
25. Tian W, Chen C, Lei X, Zhao J, Liang J. CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res 2018;2:W363-7.
26. Shashikanth Pattan, Priyanka Gadhave, Vishal Tambe. Synthesis and evaluation of some novel 1,2,4-triazole derivatives for antimicrobial, antitubercular and anti-inflammatory activities. Indian J Chem 2012;51B:297-301.
27. Holla BS, Mahalinga M, Karthikeyan MS, Akberali PM, Shetty NS. Synthesis of some novel pyrazolo[3,4-d]pyrimidine derivatives as potential antimicrobial agents. Bioorg Med Chem 2006;14:2040-7.
28. Sethupandian Geetha, Kokkaiah Irulandi, Palanichamy Mehalingam. Evaluation of antioxidant and free radical scavenging activities of different solvent extracts of leaves of piper umbellatum. Asian J Pharm Clin Res 2017;10:274-6.
29. Xini Zhang, Michael Breslav, Jeffrey Grimm, Kailin Guan. A new procedure for preparation of carboxylic acid hydrazides. J Org Chem 2002;67:9471â€“4.
30. Hitchcock CA, Dickinson K, Brown SB, Evans EGV, Adams DJ. Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14 alpha-sterol demethylase purified from Candida albicans. Biochem J 1990;266:475-80.