Development of novel Schiff Base-triazole hybrids with potent antimicrobial agent: Design, synthesis, in-silico and biological evaluation.

Abstract

The rise of microbes resistant to nearly all classes of antimicrobial drugs has become a severe public health problem in recent years. In this study, a new series of Schiff-base triazole hybrid derivatives was designed and synthesized and their in silico and biological evaluations were conducted to explore their antimicrobial potential. To gain deeper mechanistic insight, the synthesized compounds were subjected to a comprehensive computational workflow that included molecular docking, ADME profiling, DFT calculations, and MD simulations. Molecular docking studies revealed promising binding affinities ranging from -7.00 to -10.8 kcal/mol, placing these compounds on par with clinically established reference drugs in terms of target engagement. Among the series, compound 6j emerged as electronically favourable, exhibiting the lowest HOMO-LUMO energy gap (-0.15163 Hartree) as determined by DFT analysis, a characteristic often associated with enhanced chemical reactivity and biological interaction potential. The dynamic behaviour of the most promising protein-ligand complexes was further interrogated through 100 ns MD simulations, which confirmed robust structural stability throughout the simulation trajectory. Complementing these findings, ADME profiling established that the compounds fulfil the criteria outlined by Lipinski's Rule of Five, underscoring their suitability as orally bioavailable drug candidates. On the biological front, in vitro antimicrobial evaluation against a panel of clinically relevant bacterial and fungal strains yielded encouraging results. Compound 6j demonstrated meaningful antifungal activity, with MIC values spanning 500-1000 μg/mL, while compound 6d stood out for its potent antibacterial performance, achieving an MIC of 500 μg/mL. Collectively, these findings position Schiff-base triazole hybrids as structurally versatile and biologically promising scaffolds, warranting accelerated pharmacological exploration toward the development of next-generation antimicrobial therapeutics.