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 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.
Stiff
Cory M
CM
Medicinal Chemistry, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49001, USA.
Zhong
Min
M
Sarver
Ronald W
RW
Gao
Hua
H
Ho
Andrea M
AM
Sweeney
Michael T
MT
Zurenko
Gary E
GE
Romero
Donna L
DL
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002151:Calorimetry; D053801:Capillary Electrochromatography; D002264:Carboxylic Acids / Q000737:chemistry*; D002417:Cattle; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects*; D012710:Serum Albumin, Bovine; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D012710:Serum Albumin, Bovine