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

• Published in: Bioorganic & medicinal chemistry letters 2007-10, Vol.17 (19), p.5479-5482
• Main Authors: STJFF, Cory M, MIN ZHONG, SARVER, Ronald W, HUA GAO, HO, Andrea M, SWEENEY, Michael T, ZURENKO, Gary E, ROMEROA, Donna L
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Calorimetry; Capillary Electrochromatography; Carboxylic Acids - chemistry; Cattle; Medical sciences; Pharmacology. Drug treatments; Protein Binding; Protein Biosynthesis - drug effects; Serum Albumin, Bovine; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.05.006

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.