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 1 H‐/ 13 C‐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.