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

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

Authors :
Bouley R
Ding D
Peng Z
Bastian M
Lastochkin E
Song W
Suckow MA
Schroeder VA
Wolter WR
Mobashery S
Chang M
Source :
Journal of medicinal chemistry [J Med Chem] 2016 May 26; Vol. 59 (10), pp. 5011-21. Date of Electronic Publication: 2016 May 05.
Publication Year :
2016

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
59
Issue :
10
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
27088777
Full Text :
https://doi.org/10.1021/acs.jmedchem.6b00372