nTZDpa (non-thiazolidinedione PPAR gamma partial agonist) derivatives retain antimicrobial activity without improving renal toxicity

• Authors: Madeline M Dekarske, Emory University; Lewis Oscar Felix, Rhode Island Hospital; Carlos Monteagudo Ortiz, Emory University; Erika E Csatary, Emory University; Elefterios Mylonakis, Rhode Island Hospital; William Wuest, Emory University
• Journal Title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• Volume: Volume 64
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD | 2022-03-17, Pages 128678-128678
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.bmcl.2022.128678
• Subjects: Chemistry, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Physical Sciences; Chemistry, Medicinal; Chemistry, Organic; Pharmacology & Pharmacy; Chemistry; nTZDpa; Renal toxicity; Antibiotic resistance; ANTIBIOTICS; MECHANISMS

Abstract

nTZDpa kills both growing and persister Staphylococcus aureus. However, due to toxicity liabilities, our lab conducted two structure–activity relationship (SAR) studies focusing on the core scaffold and obtained a new lead compound that was more potent and less hemolytic. Despite these favorable changes, the new lead displayed toxicity to renal cells. In this SAR study, we sought to improve this renal toxicity by derivatization via changes to sp3 character, the acid moiety, and halogenation of the aryl rings. Presented herein are our efforts that produced potent compounds albeit with no improvement to renal cell toxicity.