Synthesis and biological evaluation of 2‐benzylaminoquinazolin‐4(3H)‐one derivatives as a potential treatment for SARS‐CoV‐2

Despite the continuing global crisis caused by coronavirus disease 2019 (COVID‐19), there is still no effective treatment. Therefore, we designed and synthesized a novel series of 2‐benzylaminoquinazolin‐4(3H)‐one derivatives and demonstrated that they are effective against SARS‐CoV‐2. Among the synthesized derivatives, 7‐chloro‐2‐(((4‐chlorophenyl)(phenyl)methyl)amino)quinazolin‐4(3H)‐one (Compound 39) showed highest anti‐SARS‐CoV‐2 activity, with a half‐maximal inhibitory concentration value greater than that of remdesivir (IC50= 4.2 μM vs. 7.6 μM, respectively), which gained urgent approval from the U.S. Food and Drug Administration. In addition, Compound 39showed good results in various assays measuring metabolic stability, human ether a‐go‐go, Cytochromes P450 (CYPs) inhibition, and plasma protein binding (PPB), and showed better solubility and pharmacokinetics than our previous work. Lead optimization of 2‐benzylaminoquinazolin‐4(3H)‐one derivatives