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.
Bibliographical noteFunding Information:
This project is supported by Grant AI116548 from the National Institutes of Health (to M.C.). R.B. was supported by Training Grant T32GM075762 and by an individual Ruth L. Kirschstein National Research Service Award F31AI115851 from the National Institutes of Health and by an American Chemical Society Division of Medicinal Chemistry Predoctoral Fellowship. The antisense strains were generous gifts from Dr. Terry Roemer of Merck.