Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase: Structure鈥揂ctivity Relationships and Chiral Preference of a New Hydrophobic Binding Region

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• 作者：Sameer P. Kawatkar ; Thomas A. Keating ; Nelson B. Olivier ; John N. Breen ; Oluyinka M. Green ; Satenig Y. Guler ; Martin F. Hentemann ; James T. Loch ; Andrew R. McKenzie ; Joseph V. Newman ; Linda G. Otterson ; Gabriel Mart铆nez-Botella
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4584-4597
• 全文大小：616K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound <b>39b>, with 3 nM ICb>50b> against S. aureus TMK and 2 渭g/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like <b>39b> are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.