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

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.