Schiff Base Derivatives of Benzothiazole and Benzamide as Promising Antimicrobial Agents: Integrated In Silico and In Vitro Evaluation.

Abstract

Antimicrobial resistance (AMR) remains a critical global health challenge, demanding new scaffolds with potent and broad-spectrum activity. In this work, a library of Schiff-base derivatives of benzothiazoles (2a-2f) and benzamides (5a-5i) was designed, synthesised via a microwave-assisted approach, and comprehensively characterised by 1H-/13C-NMR, FT-IR, and UV-Vis spectroscopy. In silico ADMET profiling predicted favourable pharmacokinetics and low toxicity. Molecular docking of the compounds against E. coli glucosamine-6-phosphate synthase (2VF5) and C. albicans lanosterol 14α-demethylase (5V5Z) revealed strong binding affinities, surpassing ciprofloxacin and fluconazole. Compounds 5f and 2f (-8.1 and -8.0 kcal/mol) for 2VF5, while 2a and 5h had good binding affinity (-9.7 and -9.6 kcal/mol) for 5V5Z, showing optimal interactions with key catalytic residues, maintaining structural stability in molecular dynamics simulations. Consistent with these predictions, compounds 5h, 5f, and 2a exhibited potent antibacterial activity (MIC: 3.13-12.5 µg/mL) against both Gram-positive and Gram-negative strains, and antifungal activity (MIC: 6.25-12.5 µg/mL against C. albicans and A. fumigatus). Structure-activity relationship (SAR) analysis revealed that aryl substitution influenced bioactivity, with 4-ethoxy (5h), 2-hydroxy (5f), and 2-fluoro (2a) groups being active, whereas unsubstituted analogues were inactive. These compounds are highlighted as promising antimicrobial leads requiring further in vivo evaluation.