Harnessing Natural Products by a Pharmacophore-Oriented Semisynthesis Approach for the Discovery of Potential Anti-SARS-CoV-2 Agents

Natural products possessing unique scaffolds may have antiviral activity but their complex structures hinder facile synthesis. A pharmacophore-oriented semisynthesis approach was applied to (-)-maoelactone A (1) and oridonin (2) for the discovery of anti-SARS-CoV-2 agents. The Wolff rearrangement/lactonization cascade (WRLC) reaction was developed to construct the unprecedented maoelactone-type scaffold during semisynthesis of 1. Further mechanistic study suggested a concerted mechanism for Wolff rearrangement and a water-assisted stepwise process for lactonization. The WRLC reaction then enabled the creation of a novel family by assembly of the maoelactone-type scaffold and the pharmacophore of 2, whereby one derivative inhibited SARS-CoV-2 replication in HPA EpiC cells with a low EC50 value (19 +/- 1 nM) and a high TI value (>1000), both values better than those of remdesivir.

Automated summary

A pharmacophore-oriented semisynthesis approach was used to discover anti-SARS-CoV-2 agents by modifying (-)-maoelactone A and oridonin. The WRLC reaction was developed to construct the maoelactone-type scaffold, and further mechanistic study revealed the mechanisms of Wolff rearrangement and lactonization. The creation of a novel family by combining the maoelactone-type scaffold and the pharmacophore of oridonin resulted in a derivative with potent anti-SARS-CoV-2 activity.