title: Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Bouley
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Derong
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Bastian
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Elena
authors.initials: E
authors.lastname: Lastochkin
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.affiliation: Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.affiliation: Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology*; D052999:Quinazolinones / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D052999:Quinazolinones; C061339:4-hydroxyquinazoline