Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity

Overexpression of aldehyde dehydrogenase 1A1 (ALDH1A1) is associated with the occurrence and development of obesity and insulin resistance. Herein, a series of coumarin-based ALDH1A1 inhibitors were designed, synthesized and evaluated. Among them, compounds 10, 14 and 26 exhibited potent inhibitory activity against ALDH1A1 and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Optimized compound 10 showed markedly improved pharmacokinetic characters and ADME profiles comparing to the lead compound 1. In vitro study demonstrated that 10 alleviated palmitic acid-induced impairment of glucose consumption in HepG2 cells. [Display omitted] •A series of coumarin derivatives were identified as potent and highly selective ALDH1A1 inhibitors.•Compound 10 demonstrated good pharmacokinetic characters and ADME profiles.•Compound 10 can significantly alleviate palmitic acid-induced impairment of glucose metabolism in HepG2 cells.