Miniaturized click chemistry and direct screening facilitate the discovery of triazole piperazine SARS-CoV-2 M inhibitors with improved metabolic stability.

The continuous mutational nature of SARS-CoV-2 and its inter-species' similarities emphasize the urgent need to design and develop more direct-acting antiviral agents against highly infectious variants. Herein, we report on the efficient discovery of potent non-covalent non-peptide-derived M inhibitors using miniaturized click chemistry and direct screening. Based on the privileged piperazine scaffold, 68 triazole-containing derivatives were assembled and screened.