Abstract
OBJECTIVE: The aim of the study is to design N-5-(1H-pyrazol-3-yl)-3H-ben-zo[d]imidazole-2,5-diamine derivatives and evaluate its anti-obesity activity. MATERIALS AND METHODS: A few pyrazole-fused benzimidazole derivatives were de-signed as potential Pancreatic Lipase (PL) inhibitors. The designed N-5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives have been screened using the Lipinski rule of five, ADMET analysis, acute toxicity prediction, and molecular docking. Later on, the derivatives which possess the most drug-likeness properties and displayed the most potent inhibition of the enzyme in molecular docking were synthesized. Then, in vitro enzyme assay was performed. RESULTS: Orlistat used as the standard exhibited 91 +/- 1.68% inhibition of the enzyme, dis-played binding affinity (BA) of only-4.5 kcal/mol with Pancreatic Lipase (PL), and made only one salt bridge attractive charge and carbon -hydro-gen bond with ASP79 and TRP252, respectively. Compound 9 displayed the most potent activity (93 +/- 1.12% inhibition of P.L. and-9.5 kcal/mol BA). It has formed five conventional H -bonds with GLU253, ILE78, ASP79, PHE258, and one Pi-donor H-bond with ILE78. From the present investigation, we hereby reported (E)- N-2-((naphthalene-1-yl)methylene)-N-5-(1H-pyra-zol-3-yl)-3H-benzo[d]imidazole-2,5-diamine as most potent PL inhibitor for the treatment of obesity, which can be further optimized by undergoing more studies using in vivo and in vitro models. CONCLUSIONS: (E)-N-2-((naphthalene-1-yl)methylene)-N-5-(1H-pyrazol-3-yl)-3H-benzo[d]imidaz-ole-2,5-diamine as most potent PL inhibitor for the treatment of obesity which can be further optimized better using more in vivo and in vitro models. PL plays a critical role in digesting dietary fat. Therefore, PL inhibitors are verified as a potential therapy for treating obesity.