Synthesis, Cannabinoid Receptor Targeted Molecular Docking of Some New Pyrazole Derivatives as Hypolipidemic and Anti- Obesity Agents

Abstract

Obesity is a serious health problem of 21st century. Around 1 billion adults are overweight and more than 300 million people are found to be obese globally. In fact 2.6 million people die per year due to obesity and thus it has now become a major reason of morbidity and mortality. In line to this few novel pyrazole derivatives (Z)-3-(4-subtituted phenyl)-2-(3, 5-dimethyl-1H-pyrazol-1-yl)-1-phenylprop-2-en-1-one (4a-f) were synthesized from 3, 5 dimethyl pyrazole by a simple inexpensive, rapid method. All compounds were authenticated using different physical and analytical techniques such as Infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry. Hypolipidemic activity was carried out for all the compounds using Triton WR 1339 induced hyperlipidemia model in rodents. Further, molecular docking was performed to understand the receptor-ligand interactions of synthesized compounds with cannabinoid receptor (protein data bank code: 5TGZ) using Argus lab 4.0, followed by anti-obesity studies of the selected compound (Z)-3-(4-chlorophenyl)-2-(3, 5-dimethyl-1H-pyrazol-1-yl)-1-phenylprop-2-en-1-one (4b). Amongst six compounds four compounds showed significant reduction in cholesterol levels in along with triglyceride levels in hyperlipidemic rats. Compound 4b also caused significant elevation in % high density lipoprotein levels of rats comparable to the standard Gemfibrozil. All these compounds showed good interactions with the target protein. Compound 4b (5 mg/kg and 10 mg/kg orally), caused notable reduction in body weight of high fat diet rats. Compound 4b i.e. (Z)-3-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1- yl)-1-phenylprop-2-en-1-one has ability to reduce body weight and improve lipid profile in rats and requires further studies to establish its safety and efficacy in preclinical and clinical subjects.