Design, synthesis, in silico, and in vitro evaluation of benzylbenzimidazolone derivatives as potential drugs on -glucosidase and glucokinase as pharmacological targets

Benzimidazolones have shown biological activities, including antihyperglycemic and hypoglycemic, by inhibiting or activating of alpha-glu and GK. The aim of this study is the rational design of compounds using in silico assays to delimitate the selection of structures to synthesize and the in vitro evaluation of benzimidazolone derivatives in blood glucose control. A docking of 23 benzimidazolone derivatives was performed; selecting the compounds with better in silico profiles to synthesize by microwaveirradiation/conventional heat and evaluate in enzymatic in vitro evaluation. Compounds 2k, 2m, 2r, and 2s presented the best in silico profiles, showing good affinity energy (-10.9 to -8.6 kcal mol(-1)) and binding with catalytic-amino acids. They were synthesized at 70 degrees C and 24 h using DMF as the solvent and potassium carbonate (yield: 22-38%). The results with alpha-glu showed moderate inhibition of 2k (14 +/- 1.23-29 +/- 0.45), 2m (12 +/- 2.21-36 +/- 0.30), 2r (7 +/- 2.21-13 +/- 1.34), and 2s (11 +/- 0.74-35 +/- 2.95) at evaluated concentrations (0.1 to 100 mu g mL(-1)). The GK activation assay showed an enzymatic activity increase; compound 2k increased 1.31 and 2.83 more than normal activity, 2m (2.13-fold), 2s (2.86 and 3.74-fold) at 100 and 200 mu g mL(-1) respectively. The present study showed that the 2s derivative presents moderate potential as an alpha-glu inhibitor and a good activator potential of GK, suggesting that this compound is a good candidate for blood glucose control through antihyperglycemic and hypoglycemic mechanisms.