linezolid and 4-hydroxyquinazoline

We report herein the syntheses of 79 derivatives of the 4(3

Topics: Animals; Anti-Bacterial Agents; Female; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Quinazolinones; Staphylococcus aureus; Structure-Activity Relationship

We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity against Staphylococcus aureus. The first structure-activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model.

Topics: Animals; Anti-Bacterial Agents; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Gram-Positive Bacteria; Hep G2 Cells; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Molecular Structure; Peritonitis; Quinazolinones; Structure-Activity Relationship