Exploring novel aryl/heteroaryl-isosteres of phenylthiazole against multidrug-resistant bacteria

Antimicrobial resistance has become a concern as a worldwide threat. A novel scaffold of phenylthiazoles was recently evaluated against multidrug-resistant Staphylococci to control the emergence and spread of antimicrobial resistance, showing good results. Several structural modifications are needed based on the structure-activity relationships (SARs) of this new antibiotic class. Previous studies revealed the existence of two key structural features essential for the antibacterial activity, the guanidine head and lipophilic tail. In this study, a new series of twenty-three phenylthiazole derivatives were synthesized utilizing the Suzuki coupling reaction to explore the lipophilic part. The in vitro antibacterial activity was evaluated against a range of clinical isolates. The three most promising compounds, 7d, 15d and 17d, with potent MIC values against MRSA USA300 were selected for further antimicrobial evaluation. The tested compounds exhibited potent results against the tested MSSA, MRSA, and VRSA strains (concentration: 0.5 to 4 μg mL^-1). Compound 15d inhibited MRSA USA400 at a concentration of 0.5 μg mL^-1 (one-fold more potent than vancomycin) and showed low MIC values against ten clinical isolates, including linezolid-resistant strain MRSA NRS119 and three vancomycin-resistant isolates VRSA 9/10/12. Moreover, compound 15d retained its potent antibacterial activity using the in vivo model by the burden reduction of MRSA USA300 in skin-infected mice. The tested compounds also showed good toxicity profiles and were found to be highly tolerable to Caco-2 cells at concentrations of up to 16 μg mL^-1, with 100% of the cells remaining viable.