Novel 1-Methylquinazoline and 1-Methylquinoxaline derivatives targeting FtsZ protein: Potent antibacterial agents against gram-positive bacteria.

The continuous increase in bacterial resistance and the emergence of multi-drug resistant bacteria pose a great threat to the public healthcare industry. To address this challenge, we designed and synthesized a series of novel 1-methylquinazoline and 1-methylquinoxaline derivatives, which exhibited significant inhibitory activity against gram-positive bacteria. The bioactivity assay results showed that the dominant compounds, C1 and C9, were significantly better than the positive control drugs, linezolid and vancomycin, against typical gram-positive bacteria (Staphylococcus. Aureus ATCC 25923, MIC = 0.125 μg/mL; Bacilus. Subtilis ATCC 9372, MIC = 0.0625 μg/mL). Further studies revealed that C9 has the multiple advantages of low hemolytic toxicity, rapid bactericidal kinetic characteristics and low tendency to induce bacterial resistance. In vivo studies using a mouse model of bacteremia indicated that the therapeutic effect of C9 was comparable to that of linezolid. Mechanism studies confirmed that C9 interfereed with the normal division of bacteria by promoting the polymerization of FtsZ protein to inhibit the bacterial cell division, thus exerting highly effective antibacterial effects. The findings suggest that C9 is a promising candidate molecule that provides a new strategy to solve the problems posed by multidrug-resistant bacteria in the public healthcare industry.