Correlation of carboxylic acid pK_a to protein binding and antibacterial activity of a novel class of bacterial translation inhibitors

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• 作者：Cory M. Stiff ; Min Zhong ; Ronald W. Sarver ; Hua Gao ; Andrea M. Ho ; Michael T. Sweeney ; Gary E. Zurenko ; Donna L. Romero
• 关键词：Translation inhibitors ; Protein binding ; Antibacterial ; Capillary electrophoresis ; Acidity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 October 2007
• 卷：17
• 期：19
• 页码：5479-5482
• 文件大小：140 K

摘要

Previously we reported the discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents which suffered from extensive protein binding. This report describes efforts directed toward understanding the relationship of the acidity of the carboxylic acid with the extent of protein binding. The pK_a of the acid was modified via the synthesis of a number of anthranilic acid analogs which vary the aromatic ring substituent at the 4-position. The pK_a and HSA binding constants have been determined for each of the analogs. Our results indicate a correlation between pK_a and HSA K_d. The physical properties and antibacterial activities will be discussed as well as how these results help address the protein binding issue with this series of compounds.