Benzothiazole–thiazole hybrids as broad-spectrum antimicrobial agents: synthesis, SAR analysis, and molecular docking against bacterial and fungal targets

Abstract

The persistent threat of pathogenic microorganisms demands the development of innovative scaffolds with dual antibacterial and antifungal activities. Herein, we report the synthesis and characterization of a novel series of benzothiazole–thiazole hybrids (4a–4f) via a three-step route, confirmed by NMR and MS analyses. The compounds were screened against Gram-positive, Gram-negative, mycobacterial, and fungal strains using disk diffusion and REMA assays. Compounds 4b, 4c, 4d, and 4f showed strong inhibition zones and low MIC values (3.90–15.63 μg mL⁻¹), with 4b emerging as the most potent. Structure–activity relationship (SAR) analysis revealed that electron-withdrawing groups such as nitro and halogens enhanced antimicrobial activity. Molecular docking studies against Staphylococcus aureus and Mycobacterium tuberculosis DNA gyrase and fungal cytochrome P450 14α-demethylase supported the in vitro findings, with key interactions including hydrogen bonding, π–π stacking, and hydrophobic contacts. These results underscore the potential of benzothiazole–thiazole hybrids as multi-target antimicrobial agents and promising candidates for further development.