Ligand-Based Design of Novel Thiazole-Quinazolinone Hybrids with Dual Antimicrobial and Anti-Virulence Activity Targeting Staphylococcal Sortase A

Abstract

The escalating prevalence of antimicrobial resistance necessitates the pursuit of therapeutic strategies that specifically target bacterial virulence factors. Here, we describe the design, synthesis, and biological evaluation of novel thiazole-quinazolinone hybrid compounds with dual antimicrobial and anti-virulence activities. We initially designed a hybrid scaffold that rationally integrates thiazole and quinazolinone moieties as antimicrobial motifs, using structure-activity relationship (SAR) analysis and ligand-based pharmacophore modeling derived from established staphylococcal sortase A (SrtA) inhibitors. All the synthesized compounds were evaluated for their antimicrobial activity against six clinically relevant pathogens (Staphylococcus aureus, Bacillus subtilis, Acinetobacter baumannii, Klebsiella pneumoniae, Candida albicans, and Aspergillus fumigatus). Notably, compounds 4c and 4e were the most potent candidates, with minimum inhibitory concentration (MIC) values ranging from 0.125 to 4 μg/mL and 0.125 to 8 μg/mL, respectively. Compounds 4c and 4e also demonstrated anti-virulence activity by inhibiting biofilm formation, reducing preformed biofilm biomass, inhibiting SrtA, and effectively blocking S. aureus adhesion to immobilized fibrinogen. Molecular docking studies further confirmed efficient non-covalent binding within the SrtA catalytic pocket. Moreover, the minimal cytotoxicity of both compounds toward mammalian cells underscored promising safety profiles. The two compounds exhibited chemical stability under the sterilizing doses of gamma irradiation used.