Rational design and synthesis of novel bis-azole hybrids: biological evaluation and computational insights

Abstract

The increasing prevalence of drug-resistant microbial infections demands the development of novel antimicrobial agents with improved efficacy and safety profiles. In this study, a new series of bis-azole derivatives (5a–5m) was designed and synthesized via a click chemistry strategy to explore their antimicrobial potential. Structural confirmation was achieved using NMR, FTIR, and HRMS analyses. The resulting hybrids were evaluated for their antimicrobial efficacy against two Gram ( +) bacteria i.e. B. subtilis, S. aureus and two Gram (-) bacteria i.e. P. aeruginosa, E. coli, two animal fungal strains (A. niger and C. albicans), and three cotton-based plant pathogens (M. phasolina, R. solani, and F. oxysporum). Among the series, compound 5b displayed the highest activity against the tested animal fungal pathogens, with a MIC value of 0.0206 µmol/mL, and also demonstrated potent activity against plant pathogens (MIC: 0.0412 µmol/mL) relative to reference drug Fluconazole. Compound 5f displayed prominent antibacterial efficacy against E. coli, B. subtilis, and P. aeruginosa, with a MIC value of 0.0258 µmol/mL, comparable to the standard drug Norfloxacin. Molecular docking studies further confirmed favorable binding interactions of compound 5f with the E. coli DNA gyrase target exhibiting a binding energy of − 8.6 kcal/mol, and of compound 5b with the C. albicans sterol 14-alpha demethylase target, with a binding energy of − 10.5 kcal/mol. In silico ADMET predictions indicated favorable drug-likeness and low toxicity profiles.

Graphical abstract