Conventional and microwave-assisted synthesis of pyridine-linked 1,3,4-oxadiazole derivatives as promising antimicrobial agents: Structure-activity relationship and computational investigations using molecular docking, molecular dynamics simulation, MM-GBSA and DFT.

A novel series of pyridine-linked 2,2,5-trisubstituted 1,3,4-oxadiazole derivatives 4(a-o) was synthesized through conventional and microwave-assisted approaches using N-acylhydrazone intermediates derived from isoniazid and substituted acetophenones. Microwave irradiation significantly reduced reaction time while affording moderate to good product yields. The synthesized compounds were structurally characterized by FT-IR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. Biological evaluation demonstrated promising antibacterial and antifungal activities, with the nature and position of aromatic substituents markedly influencing antimicrobial potency. Molecular docking studies against E. coli DNA gyrase B, S. aureus dihydrofolate reductase and C. albicans lanosterol 14α-demethylase revealed favourable binding interactions consistent with the experimental antimicrobial results. In silico ADMET prediction indicated acceptable pharmacokinetic characteristics and the absence of significant toxicity liabilities, while Density Functional Theory (DFT) calculations provided insights into the electronic properties governing molecular reactivity. Furthermore, molecular dynamics simulation of the most promising DNA gyrase B complex confirmed stable ligand binding through sustained structural stability, compact protein architecture, coordinated residue motions, energetically favourable conformational states, and an effective MM-GBSA binding free energy predominantly driven by van der Waals interactions. Collectively, these findings identify pyridine-linked 1,3,4-oxadiazole derivatives as promising lead scaffolds for the development of new antimicrobial agents.