Abstract
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.
Original language | English |
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Pages (from-to) | 322-326 |
Number of pages | 5 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 11 |
Issue number | 3 |
DOIs | |
State | Published - Mar 12 2020 |
Bibliographical note
Funding 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.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
Keywords
- Antibacterials
- oxadiazoles
- penicillin-binding proteins
- structure-activity relationship
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry