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Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials.
Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials.
- 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.
- Subjects :
- Animals
Anti-Bacterial Agents administration & dosage
Anti-Bacterial Agents therapeutic use
Cell Proliferation drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Hep G2 Cells
Humans
Mice
Mice, Inbred ICR
Microbial Sensitivity Tests
Molecular Structure
Quinazolinones administration & dosage
Quinazolinones therapeutic use
Structure-Activity Relationship
Anti-Bacterial Agents chemistry
Anti-Bacterial Agents pharmacology
Gram-Positive Bacteria drug effects
Peritonitis drug therapy
Peritonitis microbiology
Quinazolinones chemistry
Quinazolinones pharmacology
Subjects
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