Structure–activity relationships of heteroaromatic esters as human rhinovirus 3C protease inhibitors

Abstract

Human rhinovirus 3C protease (HRV 3C pro) is known to be a promising target for development of therapeutic agents against the common cold because of the importance of the protease in viral replication as well as its expression in a large number of serotypes. To explore non-peptidic inhibitors of HRV 3C pro, a series of novel heteroaromatic esters was synthesized and evaluated for inhibitory activity against HRV 3C pro, to determine the structure–activity relationships. The most potent inhibitor, 7, with a 5-bromopyridinyl group, had an IC 50 value of 80 nM. In addition, the binding mode of a novel analog, 19, with the 4-hydroxyquinolinone moiety, was explored by molecular docking, suggesting a new interaction in the S1 pocket.