Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CL Inhibitors as anti-SARS-CoV-2 Drug Candidate.

SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound that displayed good 3CL inhibitory activity. Here, an in-depth structural optimization for was launched to obtain more desirable drug candidates for the therapy of SARS-CoV-2 infection, in which 54 novel derivatives were designed and synthesized by a structure-based drug design strategy. Among them, 24 compounds show significantly enhanced 3CL inhibitory potencies with IC values less than 100 nM, and 11 compounds dose-dependently inhibit the replication of the SARS-CoV-2 delta variant. In particular, compound has the most desirable antiviral activity with EC of 0.272 ± 0.013 μM against the delta variant, which was more than 20 times stronger than . Oral administration of could significantly reduce the lung viral copies of mice, exhibiting a more favorable therapeutic potential. Overall, this investigation presents a promising drug candidate for further development to treat SARS-CoV-2 infection.