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. A pharmacophore‐oriented semisynthesis (POSS) approach was applied to (−)‐maoelactone A (1) and oridonin (2) for the discovery of anti‐SARS‐CoV‐2 agents. A Wolff rearrangement/lactonization cascade (WRLC) was developed to install the unprecedented scaffold during semisynthesis of 1. Further assembly of the pharmacophore of 1 and scaffold of 2 by WRLC reaction led to the discovery of a potential anti‐SARS‐CoV‐2 agent with EC50 at 19 nM.