SYNTHESIS AND EVALUATION OF ANTITUBERCULAR ACTIVITY OF 1, 3, 4-OXADIAZOLE DERIVATIVES
DOI:
https://doi.org/10.22159/ajpcr.2026v19i2.56395Keywords:
Oxadiazole, Antitubercular activity, Pyrrolidine carboxamideAbstract
Objective: The present study aimed to design, synthesize, and evaluate two novel series of 1,3,4-oxadiazole derivatives for their antitubercular activity against Mycobacterium tuberculosis H37Rv, supported by molecular docking and absorption, bio-distribution, metabolism, and excretion (ADME) predictions to identify potential lead molecules.
Methods: Two series of oxadiazole derivatives2-(3-phenoxybenzylideneamino)-5-(4-substituted phenyl)-1,3,4-oxadiazoles (Series 1a-1e) and N-[5- (4-substituted phenyl)-1,3,4-oxadiazol-2-yl]-5-oxo-1-phenylpyrrolidine-3-carboxamides (Series2a-2e)were synthesized and structurally confirmed using melting point analysis, Ultraviolet-Visible, IR, ¹H-NMR, and mass spectrometry. Antitubercular activity was assessed using the Alamar Blue Assay against M. tuberculosis H37Rv, with isoniazid (INH) as the standard. Molecular docking studies were performed against Enoyl-Acyl Carrier Protein Reductase (InhA), and ADME properties were predicted using an online computational server.
Results: Docking studies indicated strong binding affinities for compounds 1e and 2c, with docking scores of −10.7 and −10.5, respectively, suggesting potent interaction with InhA. ADME analysis showed that most derivatives possessed favorable drug-like properties, although compounds 1c and 1d exhibited Lipinski’s rule violations. Biological screening revealed that compound 2b demonstrated the most significant antitubercular activity, with a minimum inhibitory concentration of 1.6 μg/mL compared with the standard drug INH.
Conclusion: The synthesized oxadiazole derivatives exhibited moderate to strong antitubercular activity, supported by promising docking scores and acceptable ADME properties. These findings identify derivatives such as 2b as potential leads for further optimization and development of novel antitubercular agents.
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References
1. WHO. Report on Tuberculosis. W.H.O. Fact Sheet at 14th March; 2025.
2. Kadi AA, El-Brollosy NR, Al-Deeb OA, Habib EE, Ibrahim TM, El- Emam AA. Synthesis, antimicrobial and anti-inflammatory activities of 1,3,4-oxadiazole derivatives. Eur J Med Chem. 2010;45(12):5006-11. doi: 10.1016/j.ejmech.2010.08.020.
3. Khazi IM, Koti RS, Mahajanshetti CS, Somani RR. Synthesis and antimicrobial activity of some 2-(N-substituted carboxamidomethyl/ ethylthio)-5-(2′-thienyl)-1,3,4-oxadiazoles. Indian J Heterocycl Chem. 2003 Jul 1;13(1):87-8.
4. Edward LH. U.S. Patent. Chem Abstract, 95. 1981;4(259):25078f.
5. Liberman D, Rist N. Congress Intern Biochemistry Resumés Communs. 3rd Vol. 51. Chemistry, Brussels; 1957. p. 14137f. 6. Bondock S, Fadaly W, Metwally MA. Synthesis and antimicrobial activity of some new 1,3,4-oxadiazole derivatives. Eur J Med Chem. 2010;45(9):3692-701. doi: 10.1016/j.ejmech.2010.05.062[GM3]
7. Sonar VN, Hadimani MB. Synthesis of pyrazolylindoles and oxadiazolylindoles-their anti-inflammatory activity. Indian J Heterocycl Chem. 1998 Oct 1;8:125-8.
8. Donawade DS, Raghu AV, Gadaginamath GS. Synthesis and antimicrobial activity of some new 1-substituted-3-pyrrolyl aminocarbonyl/oxadiazolyl/triazolyl/5-methoxy-2-methylindoles and benz [g] indoles. Indian J Chem B. 2006 Mar 1;45(3):689.
9. Küçükgüzel SG, Oruç EE, Rollas S, Sahin F, Ozbek A. Synthesis, characterisation and biological activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and some related compounds. Eur J Med Chem. 2002 Mar;37(3):197-206. doi: 10.1016/s0223-5234(01)01326-5, PMID 11900864
10. Kučerová-Chlupáčová M. Systematic review on 1,2,3-oxadiazoles, 1,2,4-oxadiazoles, and 1,2,5-oxadiazoles in the antimycobacterial drug discovery. ChemMedChem. 2025 May 5;20(9):e202400971. doi: 10.1002/cmdc.202400971, PMID 39846226
11. Pflégr V, Stolaříková J, Karabanovich G, Maixnerová J, Pál A, Korduláková J, et al. 5-(3,5-dinitrophenyl)-1,3,4-oxadiazol-2- amine derivatives, their precursors, and analogues: synthesis and evaluation of novel highly potent antitubercular agent. PLOS One. 2025 May 29;20(5):e0324608. doi: 10.1371/journal.pone.0324608, PMID 40440331, PMCID PMC12121777
12. Asif M, Farhan SS. An overview on antitubercular activity profile of fluoroquinolone derivatives and their molecular hybridization. J Med Chem. 2020;3:145-53. doi: 10.26655/jmchemsci.2020.2.6
13. Jasim SF, Mustafa YF. Synthesis and antidiabetic assessment of new coumarin-disubstituted benzene conjugates: An in silico in virto study. J Med Chem Sci. 2022;5(6):887-99. doi: 10.26655/ JMCHEMSCI.2022.6.3
14. Lihumis HS, Alameri AA, Zaooli RH. A review on recent development and biological applications of benzothiazole derivatives. Prog Chem Biochem Res. 2022;5:147-64. doi: 10.22034/pcbr.2022.330703.1214
15. He X, Alian A, Stroud R, 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 Oct 19;49(21):6308-23. doi: 10.1021/jm060715y, PMID 17034137, PMCID PMC2517584
16. Aye KS, Nakajima C, Yamaguchi T, Win MM, Shwe MM, Win AA, et al. Genotypic characterization of multi-drug-resistant Mycobacterium tuberculosis isolates in Myanmar. J Infect Chemother. 2016 Mar;22(3):174-9. doi: 10.1016/j.jiac.2015.12.009, PMID 26806152
17. Van Rie A, Warren R, Mshanga I, Jordaan AM, Van Der Spuy GD, Richardson M, et al. Analysis for a limited number of gene codons can predict drug resistance of Mycobacterium tuberculosis in a high-incidence community. J Clin Microbiol. 2001 Feb;39(2):636- 41. doi: 10.1128/JCM.39.2.636-641.2001, PMID 11158121, PMCID PMC87790
18. Zhang Y, Vilchèze C, Jacobs WR. Mechanisms of drug resistance in Mycobacterium tuberculosis. In: Cole ST, Eisenach KD, McMurray DN, Jacobs WR, editors. Tuberculosis and the Tubercle Bacillus. Chichester: John Wiley and Sons; 2004. p. 115-40. doi: 10.1128/9781555817657.ch8
19. Unissa AN, Subbian S, Hanna LE, Selvakumar N. Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis. Infect Genet Evol. 2016 Nov;45:474-92. doi: 10.1016/j. meegid.2016.09.004, PMID 27612406
20. Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis. 1998;79(1):3-29. doi: 10.1054/tuld.1998.0002, PMID 10645439
21. Spindola De Miranda S, Kritski A, Filliol I, Mabilat C, Panteix G, Drouet E. Mutations in the rpoB gene of rifampicin-resistant Mycobacterium tuberculosis strains isolated in Brazil and France. Mem Inst Oswaldo Cruz. 2001 Feb;96(2):247-50. doi: 10.1590/s0074- 02762001000200019, PMID 11285505
22. Hillemann D, Kubica T, Rüsch-Gerdes S, Niemann S. Disequilibrium in distribution of resistance mutations among Mycobacterium tuberculosis Beijing and Non-Beijing strains isolated from patients in Germany. Antimicrob Agents Chemother. 2005 Mar;49(3):1229-31. doi: 10.1128/ AAC.49.3.1229-1231.2005, PMID 15728936, PMCID PMC549281
23. Bollela VR, Namburete EI, Feliciano CS, Macheque D, Harrison LH, Caminero JA. Detection of katG and inhA mutations to guide isoniazid and ethionamide use for drug-resistant tuberculosis. Int J Tuberc Lung Dis. 2016 Aug;20(8):1099-104. doi: 10.5588/ijtld.15.0864, PMID 27393546, PMCID PMC5310937
24. Aiswariya BV, Satya MS, Satya MS. Molecular docking and ADMET studies of benzotriazole derivatives tethered with isoniazid for antifungal activity. Int J Curr Pharm Res. 2022;14(4):78-80. doi: 10.22159/ijcpr.2022v14i4.2004
25. Dhawale S, Gawale S, Jadhav A, Gethe K, Raut P, Hiwarale N, et al. In silico approach targeting polyphenol as FabH inhibitor in bacterial infection. Int J Pharm Pharm Sci. 2022;14(11):25-30. doi: 10.22159/ ijpps.2022v14i11.45816
26. Madriwala B, Suma BV, Jays J. Molecular docking study of hentriacontane for anticancer and antitubercular activity. Int J Chem Res. 2022 Oct;6(4):1-4. doi: 10.22159/ijcr.2022v6i4.208
27. Kachkure D, Sa D, Tapadiya G, Pawar C, Bharad J. Synthesis and evaluation of diazo-triazole hybrid as anti-tubercular agents. Int J Chem Res. 2025;9(4):34-9. doi: 10.22159/ijcr.2025v9i4.281
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