Synthesis and structure-activity relationship of 3-arylisoquinolone analogues as novel highly specific hCES2A inhibitors.

In this study, 3-arylisoquinolone 3h was found with potent inhibitory effect on hCES2A (IC 50 = 0.68 μΜ, K i =0.36 μΜ) and excellent specificity (more than 147.05 fold over hCES1A). Moreover, brominated product 4a exhibited 3-fold improvement inhibition on intracellular hCES2A in living HepG2 cells compared with 3h , with the IC 50 value of 0.41 μΜ. The inhibition kinetics results and molecular docking simulations demonstrated that both 3h and 4a could bind to multiple sites of hCES2A, functioning as mixed inhibitors. The SAR (structure-activity relationship) analysis revealed that the lactam moiety on B ring is crucial to the specificity towards hCES2A, while the benzyloxy group is the optimal group for hCES2A inhibition potency, and the introduction of bromine atom may enhance the permeability to increase the intracellular hCES2A inhibitory activity.
PMID: 32935462 [PubMed - as supplied by publisher]

Source: ChemMedChem - September 15, 2020 Category: Chemistry Authors: Li B, Zhao Y, Xiong Y, Dong S, Guan X, Song Y, Yang Y, Zou K, Li Z, Zhang Y, Fang S, Zhu W, Chen K, Jia Q, Ge G Tags: ChemMedChem Source Type: research