Structure-Activity Relationship for the Oxadiazole Class of Antibacterials

MEISEL, JAYDA E.; PENG, ZHIHONG; TESTERO, SEBASTIAN A.; LASTOCHKIN, ELENA; WOLTER, WILLIAM R.; CHANG, MAYLAND; DING, DERONG; SPINK, EDWARD; YAMAGUCHI, TAKAO; LEEMANS, ERIKA; SCHROEDER, VALERIE A.; MOBASHERY, SHAHRIAR; BOUDREAU, MARC A.; JANARDHANAN, JESHINA; QIAN, YUANYUAN; O'DANIEL, PETER I.; SONG, WEI; SUCKOW, MARK A.

ACS Medicinal Chemistry Letters

American Chemical Society

Año: 2019 p. 322 - 326

1948-5875

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 showed potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.