Design, synthesis and pharmacological evaluation of omeprazole-like agents with anti-inflammatory activity

• Published in: Bioorganic & medicinal chemistry 2013-04, Vol.21 (7), p.1661-1670
• Main Authors: El-Nezhawy, Ahmed O.H., Biuomy, Ayman R., Hassan, Fatma S., Ismaiel, Ayman K., Omar, Hany A.
• Format: Article
• Language: English
• Subjects: 2-Methyl-1H-benzimidazole; adverse effects; Animals; Anti-inflammatory activity; anti-inflammatory agents; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; anti-ulcer activity; Anti-Ulcer Agents - chemical synthesis; Anti-Ulcer Agents - chemistry; Anti-Ulcer Agents - therapeutic use; Anti-ulcerogenic activity; Antiinflammatory agents; Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - therapeutic use; Carrageenan; chemistry; Cyclic sulfate; Diclofenac; Drug Design; Edema; Edema - chemically induced; Edema - drug therapy; Gastric mucosa; Inflammation; Mice; Omeprazole; Omeprazole - analogs & derivatives; Omeprazole - chemical synthesis; Omeprazole - therapeutic use; Rats; Rats, Sprague-Dawley; Side effects; Stomach Ulcer - drug therapy; stomach ulcers; Sugar; sugars; Ulcers
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.01.070

Novel benzimidazole derivatives containing substituted pyrid-2-yl moiety and polyhydroxy sugar conjugated to the N-benzimidazole moiety. A new series of novel benzimidazole derivatives containing substituted pyrid-2-yl moiety and polyhydroxy sugar conjugated to the N-benzimidazole moiety has been synthesized and evaluated as orally bioavailable anti-inflammatory agents with anti-ulcerogenic activity. The anti-inflammatory and anti-ulcerogenic activities of these compounds were compared to diclofenac and omeprazole, respectively. In carrageenan-induced paw oedema assay, 2-methyl-N-((3,4-dimethoxypyridin-2-yl)methyl)-1H-benzimidazol-5-amine (12d) and 1-(1,2,3,5-tetrahydroxy-α-d-mannofuranose)-5-(((3,4-dimethoxypyridin-2yl)methyl)amino)-2-methyl-1H-benzimidazole (15d) displayed dose-dependent anti-inflammatory activities by decreasing the inflammation by 62% and 72%, respectively which is comparable to that of diclofenac (73%). In contrast to diclofenac, the anti-inflammatory activity of these compounds was not only free from any side effects on the gastric mucosa but also showed significant anti-ulcerogenic activity in rat pyloric ligation and ethanol-induced gastric ulcer models similar to that of omeprazole. Together, these findings suggest that 12d and 15d are potent anti-inflammatory agents with concurrent anti-ulcerogenic activity and support its clinical promise as a component of therapeutic strategies for inflammation, for which the gastric side effects are always a major limitation.