Design, Synthesis, and Structure‐Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase

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.