Arylamino containing hydroxamic acids as potent urease inhibitors for the treatment of Helicobacter pylori infection

Abstract A novel series of aniline-containing hydroxamic acids were designed, synthesized and evaluated as anti-virulence agents for the treatment of gastritis and gastric ulcer caused by Helicobacter pylori . In vitro enzyme-based screen together with in vivo assays and structure−activity relationship (SAR) studies led to the discovery of three potent urease inhibitors 3-(3,5-dichlorophenylamino) N -hydroxypropanamide ( 3a ), 3-(2-chlorophenylamino) N -hydroxypropanamide ( 3d ) and 3-(2,4-dichlorophenylamino) N -hydroxypropanamide ( 3n ). Compounds 3a , 3d and 3n showed excellent urease inhibition with IC 50 values 0.043 ± 0.005, 0.055 ± 0.008 and 0.018 ± 0.002 μM, and significantly depressed gastritis developing at the dose of 32 mg/kg b. i.d with eradication rates of H. pylori reaching 92.3, 84.6 and 100%, respectively. Preliminary safety studies (acute toxicity in mice) disclosed that 3a , 3d and 3n was well-tolerated in KM mice with LD 50 s of 2982.8, 3349.4 and 3126.9 mg/kg, respectively. Collectively, the data obtained in this study indicate that 3a , 3d and 3n , in particular 3n , could considered as promising candidates for the potential treatment of H. pylori caused gastritis and gastric ulcer, and hence merit further studies.