Design, Synthesis, and Biological Evaluation of 1,4-Bis(2,3-dihydro-5-oxopyrrol-4-yl)-1,3-butadienes as Potential Chk1 Inhibitors

Abstract

A series of 1,4-bis(2,3-dihydro-5-oxopyrrol-4-yl)-1,3-butadienes were designed as inhibitors of checkpoint kinase 1 (Chk1), based on the structure‒activity relationships for known inhibitors through docking simulations. The docking results suggested that the title compounds were similar to known inhibitors in interaction with the catalytic site of Chk1. Twelve compounds were synthesized by a one-pot procedure from amines, dimethyl acetylenedicarboxylate, and glyoxal in water in the presence of catalytic amounts of γ-cyclodextrin. The inhibitory activities of the synthesized compounds were evaluated in vitro using EC9706 esophageal cancer cells. The results indicated that 1,4-bis(2,3-dihydro-5-oxopyrrol-4-yl)-1,3-butadienes significantly inhibited Chk1 (IC₅₀ 10.45 μM).