A reverse method for diversity introduction of benzimidazole to synthesize H +/K +-ATP enzyme inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2011-07, Vol.21 (14), p.4189-4192
• Main Authors: Yan, Yu, Liu, Zijie, Zhang, Jianjun, Xu, Ruiming, Hu, Xiao, Liu, Gang
• Format: Article
• Language: English
• Subjects: Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; chemistry; DFDNB; Digestive system; enzyme inhibitors; H +/K +-ATP enzyme inhibitors; H(+)-K(+)-Exchanging ATPase - metabolism; Medical sciences; Pharmacology. Drug treatments; Proton Pump Inhibitors - chemical synthesis; Proton Pump Inhibitors - chemistry; Proton Pump Inhibitors - pharmacology; Solution phase synthesis; Structure-Activity Relationship; Sulfoxides - chemical synthesis; Sulfoxides - chemistry; Sulfoxides - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.05.080

We have devolped a reverse method to synthesize benzimidazole derivatives that inhibits H +/K +-ATP enzymatic activity as potential proton pump inhibitors. A series of 2-[(2-pyridylmethyl)sulfinyl]benzimidazole derivatives were synthesized via a solution phase synthetic route using a reversal method of diversity introduction. Using this synthetic strategy, we obtained two key intermediates ( 4-A and 4-B) simultaneously, which allows us to introduce diversity points onto the benzimidazole part of the final product under reliable reaction conditions to identify potent H +/K +-ATP enzyme inhibitors. Compound 14l (IC 50 = 1.6 × 10 −5 M) was comparable with H +/K +-ATP enzyme inhibitor in vitro.