Structure-Activity Relationship for the Oxadiazole Class of Antibacterials

  • ACS Med Chem Lett. 2019 Oct 3;11(3):322-326. doi: 10.1021/acsmedchemlett.9b00379.
Marc A Boudreau  1 ,  Derong Ding  1 ,  Jayda E Meisel  1 ,  Jeshina Janardhanan  1 ,  Edward Spink  1 ,  Zhihong Peng  1 ,  Yuanyuan Qian  1 ,  Takao Yamaguchi  1 ,  Sebastian A Testero  1 ,  Peter I O'Daniel  1 ,  Erika Leemans  1 ,  Elena Lastochkin  1 ,  Wei Song  1 ,  Valerie A Schroeder  2 ,  William R Wolter  2 ,  Mark A Suckow  2 ,  Shahriar Mobashery  1 ,  Mayland Chang  1
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
  • 2. Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, United States.
PMID: 32184964 DOI: 10.1021/acsmedchemlett.9b00379
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.