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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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Research Article

Synthesis of Novel NSAIDs Linked to Triazolyl-oxadiazole Heterocyclic Compounds as more Comprehensive Antimicrobial Agents: A Computational Molecular Docking

Author(s): Shaik Adamshafi, Venkatarao Veera, Mohan Rao S.V.M. and Kishore Pilli V.V.N.*

Volume 18, Issue 2, 2022

Published on: 23 November, 2021

Article ID: e251121195214 Pages: 14

DOI: 10.2174/1381612827666210803113506

Price: $65

Abstract

Introduction: Progress in the development of triazolyl-oxadiazoles, a bisphosphonate- 700 inhibitor, is still continuing with an outcome of the good scaffold as oxadiazole as well as triazoles individually for antibacterial activity. Hence, we have proposed a suitable approach for the synthesis of dual heterocyclic analogues consisting of the therapeutically used non-steroidal anti- inflammatory drugs in a combined form and evaluated their antibacterial and antifungal activities, and conducted docking studies.

Methods: The chemical structures were confirmed by various spectroscopic methods like IR, 1H NMR, 13C NMR, mass, and elemental analysis. The antibacterial and antifungal activities of these compounds were screened against Gram-positive and Gram-negative bacteria, and fungal stains, by the agar well diffusion method. The crystal structure of S. aureus complexed with the active site of bisphosphonate BPH-700 (2ZCS) was obtained from the Protein Database (PDB, http://www.rcsb.org). Molecular properties, drug-likeness score, lipophilicity and solubility parameters were assessed by the Molinspiration and Molsoft software 7f (2-NO2, 5-Ome), 7g (3-Cl, 4-Cl), 7a (2-NO2).

Results: The synthesised NSAID-triazolyl-oxadiazoles containing 2-nitro-5-methoxy (7f), 3,4- dichloro (7g) derivatives were found to be highly active antibacterial agents against S. aureus and E. coli with MIC values of 16 and 19 μg/mL, respectively. 2-nitro-5-methoxy (7f), 4-bromo (7h) and 2-nitro (7a) derivatives displayed superior antifungal activity against A. niger with MIC values of 56, 76, and 130 μg/mL, respectively. From molecular docking, NSAID linked to 3,4-dichloro analogue (7g) revealed stronger binding interaction (ΔG =7.90 Kcal/Mol) with amino acids Asp49 (1.19 A◦), Arg45 (2.17 A◦), Lys17, and Lys46 in the active site of S. aureus complexed with bisphosphonate Bph-700 (2ZCS). The compounds following the Lipinski ‘Rule of five’ were synthesized for antimicrobial screening as oral bioavailable drugs/leads. Maximum drug-likeness model score 0.49 and 0.41 was found for compounds 7h and 7b.

Discussion: An efficient combination of molecular modeling and biological activity provided an insight into QSAR guidelines that could aid in the further development of these derivatives.

Conclusion: The present work, through simple synthetic approaches, led to the development of novel hybrids of triazole-oxadiazole pharmacophores that exhibited remarkable biological activities against different microorganisms. The compounds showed suitable drug-like properties and are expected to present good bioavailability pro□le.

Keywords: Mefenamic acid, 1, 2, 3-triazole, 3, 4-oxadiazole, antibacterial properties, rule of five, molecular modeling.

Graphical Abstract

[1]
McGettigan, P.; Henry, D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: An examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med., 2013, 10(2), e1001388.
[http://dx.doi.org/10.1371/journal.pmed.1001388] [PMID: 23424288]
[2]
Patrono, C. Baigent. Coxibs, traditional NSAIDs, and cardiovascular safety post-precision: What we thought we knew then and what we think we know now. Clin. Pharmacol. Ther., 2017, 102, 238-245.
[http://dx.doi.org/10.1002/cpt.696] [PMID: 28378879]
[3]
Bhala, N.; Emberson, J.; Merhi, A.; Abramson, S.; Arber, N.; Baron, J.A.; Bombardier, C.; Cannon, C.; Farkouh, M.E.; FitzGerald, G.A.; Goss, P.; Halls, H.; Hawk, E.; Hawkey, C.; Hennekens, C.; Hochberg, M.; Holland, L.E.; Kearney, P.M.; Laine, L.; Lanas, A.; Lance, P.; Laupacis, A.; Oates, J.; Patrono, C.; Schnitzer, T.J.; Solomon, S.; Tugwell, P.; Wilson, K.; Wittes, J.; Baigent, C. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet, 2013, 382(9894), 769-779.
[http://dx.doi.org/10.1016/S0140-6736(13)60900-9] [PMID: 23726390]
[4]
Meek, I.L.; Van de Laar, M.A.F.J.; E Vonkeman, H. Non-steroidal anti-inflammatory drugs: An overview of cardiovascular risks. Pharmaceuticals (Basel), 2010, 3(7), 2146-2162.
[http://dx.doi.org/10.3390/ph3072146] [PMID: 27713346]
[5]
Dannhardt, G.; Kiefer, W. Cyclooxygenase inhibitors-current status and future prospects. Eur. J. Med. Chem., 2001, 36(2), 109-126.
[http://dx.doi.org/10.1016/S0223-5234(01)01197-7] [PMID: 11311743]
[6]
Praveen Rao, P.N.; Knaus, E. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J. Pharm. Sci., 2008, 11, 81-110.
[http://dx.doi.org/10.18433/J3T886]
[7]
Khalid M., Khan; Nosheen A., Rao.; Zia, Ullah; Muhammad, Ali.; Shahnaz, Perveen.; Muhammad, Iqbal Choudhary.; Atta, UrRahman. Wolfgang, voelter. Nat. Prod. Res., 2009, 23, 5-9.
[http://dx.doi.org/10.1080/ 14786410601129887]
[8]
Parikh, K.; Joshi, D. Med. Chem. Res., 2013, 22, 3688-3697.
[http://dx.doi.org/10.1007/s00044-012-0369-3]
[9]
Amir, M.; Shikha, K. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2,6-dichloroanilino) phenyl]acetic acid derivatives. Eur. J. Med. Chem., 2004, 39(6), 535-545.
[http://dx.doi.org/10.1016/j.ejmech.2004.02.008] [PMID: 15183912]
[10]
Li, Y.; Liu, J.; Zhang, H.; Yang, X.; Liu, Z. Stereoselective synthesis and fungicidal activities of (E)-alpha-(methoxyimino)-benzeneacetate derivatives containing 1,3,4-oxadiazole ring. Bioorg. Med. Chem. Lett., 2006, 16(8), 2278-2282.
[http://dx.doi.org/10.1016/j.bmcl.2006.01.026] [PMID: 16455246]
[11]
Gaonkar, S.L.; Rai, K.M.; Prabhuswamy, B. Synthesis and antimicrobial studies of a new series of 2-[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]-5-substituted-1,3,4-oxadiazoles. Eur. J. Med. Chem., 2006, 41(7), 841-846.
[http://dx.doi.org/10.1016/j.ejmech.2006.03.002] [PMID: 16616395]
[12]
Kumar, D.; Sundaree, S.; Johnson, E.O.; Shah, K. An efficient synthesis and biological study of novel indolyl-1,3,4-oxadiazoles as potent anticancer agents. Bioorg. Med. Chem. Lett., 2009, 19(15), 4492-4494.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.172] [PMID: 19559607]
[13]
Loetchutinat, C.; Chau, F.; Mankhetkorn, S. Synthesis and evaluation of 5-Aryl-3-(4-hydroxyphenyl)-1,3,4-oxadiazole-2-(3H)-thiones as P-glycoprotein inhibitors. Chem. Pharm. Bull. (Tokyo), 2003, 51(6), 728-730.
[http://dx.doi.org/10.1248/cpb.51.728] [PMID: 12808255]
[14]
Khan, M.T.H.; Choudhary, M.I.; Khan, K.M.; Rani, M.; Atta-ur-Rahman, Structure-activity relationships of tyrosinase inhibitory combinatorial library of 2,5-disubstituted-1,3,4-oxadiazole analogues. Bioorg. Med. Chem., 2005, 13(10), 3385-3395.
[http://dx.doi.org/10.1016/j.bmc.2005.03.012] [PMID: 15934142]
[15]
Vardan, S.; Smulyan, H.; Mookherjee, S.; Eich, R. Effects of tiodazosin, a new antihypertensive, hemodynamics and clinical variables. Clin. Pharmacol. Ther., 1983, 34(3), 290-296.
[http://dx.doi.org/10.1038/clpt.1983.170] [PMID: 6883905]
[16]
Sahin, G.; Palaska, E.; Kelicen, P.; Demirdamar, R.; Altinok, G. Synthesis of some new 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones and their anti-inflammatory activities. Arzneimittelforschung, 2001, 51(6), 478-484.
[http://dx.doi.org/10.1055/s-0031-1300066] [PMID: 11455679]
[17]
Piala, J.; Yale, H. Chem Abstr. US Patent: 3, 141, 022, 1964, 61, 8317.
[18]
Yale, H.L.; Losee, K. 2-amino-5-substituted 1,3,4-oxadiazoles and 5-imino-2-substituted delta-2-1,3,4-oxadiazolines. A group of novel muscle relaxants. J. Med. Chem., 1966, 9(4), 478-483.
[http://dx.doi.org/10.1021/jm00322a007] [PMID: 5968010]
[19]
Palmer, J.T.; Hirschbein, B.L.; Cheung, H.; McCarter, J.; Janc, J.W.; Yu, Z.W.; Wesolowski, G. Keto-1,3,4-oxadiazoles as cathepsin K inhibitors. Bioorg. Med. Chem. Lett., 2006, 16(11), 2909-2914.
[http://dx.doi.org/10.1016/j.bmcl.2006.03.001] [PMID: 16546382]
[20]
Johns, B. 2004.PCT Int. WO 2004101512,
[21]
Baxendale, I.R.; Ley, S.V.; Martinelli, M. The rapid preparation of 2-aminosulfonamide-1,3,4-oxadiazoles using polymer-supported reagents and microwave heating. Tetrahedron, 2005, 61, 5323-5349.
[http://dx.doi.org/10.1016/j.tet.2005.03.062]
[22]
Coppo, F.T.; Evans, K.A.; Graybill, T.L.; Burton, G. Efficient one-pot preparation of 5-substituted-2-amino-1,3,4-oxadiazoles using resin-bound reagents. Tetrahedron Lett., 2004, 45, 3257-3260.
[http://dx.doi.org/10.1016/j.tetlet.2004.02.119]
[23]
Chinthala, Y.; Thakur, S.; Tirunagari, S.; Chinde, S.; Domatti, A.K.; Arigari, N.K.; K v N S, S.; Alam, S.; Jonnala, K.K.; Khan, F.; Tiwari, A.; Grover, P. Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity. Eur. J. Med. Chem., 2015, 93, 564-573.
[http://dx.doi.org/10.1016/j.ejmech.2015.02.027] [PMID: 25743216]
[24]
Bock, V.D.; Speijer, D.; Hiemstra, H.; van Maarseveen, J.H. 1,2,3-Triazoles as peptide bond isosteres: Synthesis and biological evaluation of cyclotetrapeptide mimics. Org. Biomol. Chem., 2007, 5(6), 971-975.
[http://dx.doi.org/10.1039/b616751a] [PMID: 17340013]
[25]
Zou, Y.; Zhao, Q.; Liao, J.; Hu, H.; Yu, S.; Chai, X.; Xu, M.; Wu, Q. New triazole derivatives as antifungal agents: Synthesis via click reaction, in vitro evaluation and molecular docking studies. Bioorg. Med. Chem. Lett., 2012, 22(8), 2959-2962.
[http://dx.doi.org/10.1016/j.bmcl.2012.02.042] [PMID: 22437114]
[26]
Shafi, S.; Alam, M.M.; Mulakayala, N.; Mulakayala, C.; Vanaja, G.; Kalle, A.M.; Pallu, R.; Alam, M.S. Synthesis of novel 2-mercapto benzothiazole and 1,2,3-triazole based bis-heterocycles: Their anti-inflammatory and anti-nociceptive activities. Eur. J. Med. Chem., 2012, 49, 324-333.
[http://dx.doi.org/10.1016/j.ejmech.2012.01.032] [PMID: 22305614]
[27]
Whiting, M.; Tripp, J.C.; Lin, Y.C.; Lindstrom, W.; Olson, A.J.; Elder, J.H.; Sharpless, K.B.; Fokin, V.V. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. J. Med. Chem., 2006, 49(26), 7697-7710.
[http://dx.doi.org/10.1021/jm060754+] [PMID: 17181152]
[28]
Ma, L.Y.; Pang, L.P.; Wang, B.; Zhang, M.; Hu, B.; Xue, D.Q.; Shao, K.P.; Zhang, B.L.; Liu, Y.; Zhang, E.; Liu, H.M. Design and synthesis of novel 1,2,3-triazole-pyrimidine hybrids as potential anticancer agents. Eur. J. Med. Chem., 2014, 86, 368-380.
[http://dx.doi.org/10.1016/j.ejmech.2014.08.010] [PMID: 25180925]
[29]
Alam, M.S.; Huang, J.; Ozoe, F.; Matsumura, F.; Ozoe, Y. Synthesis, 3D-QSAR, and docking studies of 1-phenyl-1H-1,2,3-triazoles as selective antagonists for beta3 over alpha1beta2gamma2 GABA receptors. Bioorg. Med. Chem., 2007, 15(15), 5090-5104.
[http://dx.doi.org/10.1016/j.bmc.2007.05.039] [PMID: 17544280]
[30]
Perion, R.; Ferroeres, V.; Moreno, M.I.G.; Mellet, C.O.; Duval, R.; Fernandez, J.M.G.; Plusqullec, D. 1,2,3-Triazoles and related glycoconjugates as new glycosidase inhibitors. Tetrahedron, 2005, 61, 9118-9128.
[31]
Pinhua, L.; Lei, W. One-Pot Synthesis of 1,2,3-Triazoles from benzyl and alkyl halides, sodium azide and alkynes in water under transition-metal-catalyst free reaction conditions. Lett. Org. Chem., 2007, 4, 23-26.
[32]
Neeraja, P.; Srinivas, S.; Mukkanti, K.; Pramod Kumar, D. Sarbani Pal. 1H-1,2,3-Triazolyl-substituted 1,3,4-oxadiazole derivatives containing structural features of ibuprofen/naproxen: Their synthesis and antibacterial evaluation. Bioorg. Med. Chem. Lett., 2016, 26, 5212-5217.
[http://dx.doi.org/10.1016/j.bmcl.2016.09.059] [PMID: 27727124]
[33]
Available from: http://www.molinspiration.com
[34]
Zhao, Y.H.; Abraham, M.H.; Le, J.; Hersey, A.; Luscombe, C.N.; Beck, G.; Sherborne, B.; Cooper, I. Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res., 2002, 19(10), 1446-1457.
[http://dx.doi.org/10.1023/A:1020444330011] [PMID: 12425461]
[35]
Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem., 2000, 43(20), 3714-3717.
[http://dx.doi.org/10.1021/jm000942e] [PMID: 11020286]
[36]
CLSI document M07-A9: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, approved standard. Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2012.
[37]
Adriano, M.; Giorgia, M.; Azzurra, S.; Roberto, C.; Simone, C.; Valentina, C.; Mara, Di.; Luigina, C.; Romano, S.; Cesare, G.; Anita, S.; Stefano, M.; Pasqualina, P.; Sako, M. Arginine- and lysine-rich peptides: Synthesis, characterization and antimicrobial activity. Lett. Drug Des. Discov., 2017, 14, 1-7.
[38]
Reference method for broth dilution antifungal susceptibility testing of yeasts: Approved standard—third edition clsi document M27-A3. Clinical and Laboratory Standard Institute: Wayne, PA, USA, 2008.
[39]
Roman, A. Laskowski. PDBsum new things. Nucleic Acids Res., 2009, 37, D355-D359.
[40]
Genheden, S.; Ryde, U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov., 2015, 10(5), 449-461.
[http://dx.doi.org/10.1517/17460441.2015.1032936] [PMID: 25835573]
[41]
Garrett, M.M.; Ruth, H.; William, L.; Michel, F.S.; Richard, K.B.; David, S.G.; Arthur, J.O. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30, 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[42]
Harder, E.; Damm, W.; Maple, J.; Wu, C.; Reboul, M.; Xiang, J.Y.; Wang, L.; Lupyan, D.; Dahlgren, M.K.; Knight, J.L.; Kaus, J.W.; Cerutti, D.S.; Krilov, G.; Jorgensen, W.L.; Abel, R.; Friesner, R.A. OPLS3: A force field providing broad coverage of drug- like small molecules and proteins. J. Chem. Theory Comput., 2016, 12(1), 281-296.
[http://dx.doi.org/10.1021/acs.jctc.5b00864] [PMID: 26584231]
[43]
4ZCS. Crystal structure of the C-terminal catalytic domain of Plasmodium falciparum CTP: Phosphocholine cytidylyltransferase in complex with CDP-choline. Available from: https://www.rcsb.org/structure/4zcs.

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