Design, synthesis, and structure-activity relationships of a novel class of quinazoline derivatives as coronavirus inhibitors.

There remain great unmet needs to treat coronavirus infections in clinic, and the development of novel antiviral agents is highly demanded. In this work, a phenotypic screening against our in-house compound library identified several cajanine derivatives with moderate antiviral activity against HCoV-OC43. Based on the scaffold of cajanine, a series of quinazoline derivatives were designed employing a scaffold-hopping strategy. After an iterative structural optimization campaign, several quinazoline derivatives with potent antiviral efficacy (EC50: ∼0.1 μM) and high selectivity (SI > 1000) were successfully identified. The preliminary mechanism of action study indicated that such quinazoline derivatives functioned at the early stage of infection. In aggregate, this work delivered a new chemical type of coronavirus inhibitors, which could be employed not only for further development of antiviral drugs but also as important chemical tools to delineate the target of action.