A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c shows potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.
|Number of pages||5|
|Journal||ACS Medicinal Chemistry Letters|
|State||Published - Mar 12 2020|
Bibliographical noteFunding Information:
This work was supported by grants AI090818 (to MC and SM) and by AI104987 (to SM) from the National Institutes of Health. YQ is a Ruth L. Kirschstein National Research Service Award Fellow of the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, supported by training grant T32 GM075762 from the National Institutes of Health.
Copyright © 2019 American Chemical Society.
- penicillin-binding proteins
- structure-activity relationship
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry