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

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 pKa 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 pKa and HSA binding constants have been determined for each of the analogs. Our results indicate a correlation between pKa and HSA Kd. 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.

Graphical abstractA study of the relationship between pKa of a compound containing a carboxylic acid, and its antibacterial activity and protein binding is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide