Exploration of Multicomponent Triazole-Oxadiazole Clubbed Imidazole Hybrids: Design, Synthesis, In Silico Docking, and DFT Analysis as Potent Pharmacological Agents

Despite significant progress in controlling infectious microbe-borne diseases worldwide, the growing problem of resistance to existing antibacterial drugs highlights the urgent need for new antimicrobial agents that are both affordable and effective. As part of our ongoing efforts to identify a novel class of antibacterials, we synthesized and evaluated imidazole-based triazole-oxadiazole molecular hybrids for their in vitro antibacterial and antitubercular activities. The synthesized compounds were characterized using various spectroscopic techniques, including 1H, 13C NMR, and mass spectrometry. Among the synthesized triazoles bearing meta-chlorophenyl (MIC = 3.99±2.4 μg/mL) and para-nitrophenyl (MIC = 3.85±1.5 μg/mL) exhibited the most potent antibacterial activity against S. aureus, as evident from the minimum inhibitory concentration (MIC) values. Additionally, compound para-nitrophenyl substituted triazole demonstrated significant antitubercular activity against Mycobacterium tuberculosis H37Rv, with an MIC of 2.82±1.6 μg/mL. These biological activities are further substantiated by in silico molecular modeling studies, which revealed strong binding affinities of meta-chlorophenyl, para-nitrophenyl, and m,p-dihydroxyphenyl triazole compounds to the bacterial target proteins of S. aureus (PDB ID: 3FYW) and M. tuberculosis (PDB ID: 1DF7). Binding mode analysis of para-nitrophenyl triazole compound revealed a favorable hydrogen-bonding interaction within the active pocket of the M. tuberculosis target, involving key amino acid residues Arg55(A), Ser74(A), Trp47(A), Met72(A), and Gln68(A). To support these findings, Density Functional Theory (DFT) calculations were performed using the B3LYP method with the 6-31G(d,p) basis set. The calculated HOMO–LUMO energy gap indicated favorable electronic properties consistent with bioactivity. These in silico predictions were further validated through experimental pharmacological analysis. Moreover, drug-likeness and ADMET profiling demonstrated that the newly synthesized scaffolds possess desirable pharmacokinetic properties, including good oral bioavailability, low toxicity, and efficient absorption.