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Design,Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase |
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| Authors: | Jing Zhang Yang Yang Xing-Kai Qian Pei-Fang Song Yi-Shu Zhao Dr Xiao-Qing Guan Prof Li-Wei Zou Dr Xiaoze Bao Prof Hong Wang |
| Affiliation: | 1. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 P. R. China
These authors contributed equally to this work;2. College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014 P. R. China These authors contributed equally to this work;3. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 P. R. China;4. College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014 P. R. China |
| Abstract: | Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure–activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC50=0.30 μM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R1) and hydrophobic interactions of phenyl moiety (R3) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolones-type PL inhibitors for biomedical applications. |
| Keywords: | inhibitors pancreatic lipases pyrazolones structure-activity relationships |