Eur Rev Med Pharmacol Sci 2022; 26 (19): 7245-7255
DOI: 10.26355/eurrev_202210_29917

Design, in silico study, synthesis and in vitro evaluation of some N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives as potential pancreatic lipase inhibitors for anti-obesity activity

A. Unnisa, B. Huwaimel, S. Almahmoud, A.S. Abouzied, K.M. Younes, B. Anupama, P.K. Kola, N.V.K.C. Lakshmi

Department of Pharmaceutical Chemistry, College of Pharmacy, Hail University, Hail, Saudi Arabia. Khushiazeez@yahoo.co.in


OBJECTIVE: The aim of the study is to design N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives and evaluate its anti-obesity activity.

MATERIALS AND METHODS: A few pyrazole-fused benzimidazole derivatives were designed as potential Pancreatic Lipase (PL) inhibitors. The designed N5-(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, displayed binding affinity (BA) of only -4.5 kcal/mol with Pancreatic Lipase (PL), and made only one salt bridge attractive charge and carbon-hydrogen 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)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-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)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-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.

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A. Unnisa, B. Huwaimel, S. Almahmoud, A.S. Abouzied, K.M. Younes, B. Anupama, P.K. Kola, N.V.K.C. Lakshmi
Design, in silico study, synthesis and in vitro evaluation of some N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives as potential pancreatic lipase inhibitors for anti-obesity activity

Eur Rev Med Pharmacol Sci
Year: 2022
Vol. 26 - N. 19
Pages: 7245-7255
DOI: 10.26355/eurrev_202210_29917