Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials

Renee Bouley, Derong Ding, Zhihong Peng, Maria Bastian, Elena Lastochkin, Wei Song, Mark A. Suckow, Valerie A. Schroeder, William R. Wolter, Shahriar Mobashery, Mayland Chang

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5011-5021
Number of pages11
JournalJournal of medicinal chemistry
Volume59
Issue number10
DOIs
StatePublished - May 26 2016

Bibliographical note

Funding 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.

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