Derivatives of 6-Nitrobenzimidazole Inhibit Fructose-Mediated Protein Glycation and Intracellular Reactive Oxygen Species Production

Benzimidazoles are important pharmacophores in drug discovery, and currently its derivatives such as flubendazole, omeprazole, and astemizole are used for the treatment of anthelmintic, ulcerative, and histaminic diseases, respectively.The aim of the current study was to investigate the antiglycation activity of nitrobenzimidazole derivatives against fructose-mediated human serum albumin (HSA) glycation. The study was also aimed at investigating the effects of newly identified antiglycation inhibitors on AGEsinduced intracellular reactive oxygen species (ROS) production, and associated impaired proliferation of the hepatocytes.The present study focuses on the antiglycation activity of 6-nitrobenzimidazole derivatives 1-13 in in-vitro human serum albumin (HSA)- fructose model. These derivatives were also identified as non-toxic against 3T3 mouse fibroblast cell-line in MTT-based assay. The effect of the most promising derivative 5, 4-(6-nitro-1H-benzimidazol-2-yl)-1,2,3-benzenetriol, was studied in a dose dependent manner, co-incubated with fructose-derived AGEs (0- 200 μg/mL) on rat hepatocytes proliferation and associated intracellular generation of ROS via MTT-based assay and DCFHDA technique, respectively.We found that derivative 5 ameliorates the elevated intracellular oxidative stress and associated diminished proliferation of the hepatocytes in response to AGEs.In conclusion, we identified novel 6-nitrobenzimidazole derivatives as antiglycation agents through in-vitro, and cell-based models.