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

• Published in: European journal of medicinal chemistry 2018-08, Vol.156, p.126-136
• Main Authors: Liu, Qi, Shi, Wei-Kang, Ren, Shen-Zhen, Ni, Wei-Wei, Li, Wei-Yi, Chen, Hui-Min, Liu, Pei, Yuan, Jing, He, Xiao-Su, Liu, Jia-Jia, Cao, Peng, Yang, Pu-Zhen, Xiao, Zhu-Ping, Zhu, Hai-Liang
• Format: Article
• Language: English
• Subjects: Arylamino containing hydroxamic acid; Gastritis and gastric ulcer; H. pylori urease inhibitor; Kinetics study; Therapeutic efficacy
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.06.065

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 IC50 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 LD50s 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. [Display omitted] •N-arylaminoacylhydroxamic acids were designed by structural improvement of 3-aryl-3-hydroxypropionylhydroxamic acid.•N-arylaminoacylhydroxamic acids were firstly reported as urease inhibitors.•Significant improvement of potency.•A dual site binding mode of these compounds was firstly disclosed.