Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor

• Published in: Journal of medicinal chemistry Vol. 60; no. 9; pp. 3851 - 3865
• Main Authors: Mandal, Mihirbaran, Tan, Zheng, Madsen-Duggan, Christina, Buevich, Alexei V, Caldwell, John P, Dejesus, Reynalda, Flattery, Amy, Garlisi, Charles G, Gill, Charles, Ha, Sookhee Nicole, Ho, Ginny, Koseoglu, Sandra, Labroli, Marc, Basu, Kallol, Lee, Sang Ho, Liang, Lianzhu, Liu, Jenny, Mayhood, Todd, McGuinness, Debra, McLaren, David G, Wen, Xiujuan, Parmee, Emma, Rindgen, Diane, Roemer, Terry, Sheth, Payal, Tawa, Paul, Tata, James, Yang, Christine, Yang, Shu-Wei, Xiao, Li, Wang, Hao, Tan, Christopher, Tang, Haifeng, Walsh, Paul, Walsh, Erika, Wu, Jin, Su, Jing
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.05.2017; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Female; Life Sciences & Biomedicine; Lipids - chemistry; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - growth & development; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pharmacology & Pharmacy; Science & Technology; Small Molecule Libraries; Solubility; Structure-Activity Relationship; IN-VITRO; ANALOGS; WALL TEICHOIC-ACID; CHARGES; MRSA; OXAZOLIDINONES; DISCOVERY; CHALLENGES

We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and p...