Article ; Online: 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.
European review for medical and pharmacological sciences
2022 Volume 26, Issue 19, Page(s) 7245–7255
Abstract: 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 ... ...
| Abstract | 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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| MeSH term(s) | Molecular Docking Simulation ; Lipase ; Diamines ; Orlistat/pharmacology ; Pyrazoles/pharmacology ; Imidazoles ; Benzimidazoles/pharmacology ; Naphthalenes ; Dietary Fats ; Carbon ; Structure-Activity Relationship |
| Chemical Substances | Lipase (EC 3.1.1.3) ; Diamines ; Orlistat (95M8R751W8) ; Pyrazoles ; Imidazoles ; Benzimidazoles ; Naphthalenes ; Dietary Fats ; Carbon (7440-44-0) |
| Language | English |
| Publishing date | 2022-10-20 |
| Publishing country | Italy |
| Document type | Journal Article |
| ZDB-ID | 605550-3 |
| ISSN | 2284-0729 ; 1128-3602 ; 0392-291X |
| ISSN (online) | 2284-0729 |
| ISSN | 1128-3602 ; 0392-291X |
| DOI | 10.26355/eurrev_202210_29917 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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