Harnessing Natural Products by a Pharmacophore‐Oriented Semisynthesis Approach for the Discovery of Potential Anti‐SARS‐CoV‐2 Agents
Yuan‐Fei Zhou, Bing‐Chao Yan, Qian Yang, Xin‐Yan Long, Dan‐Qi Zhang, Rong‐Hua Luo, Hanyu Wang, Han‐Dong Sun, Xiao‐Song Xue, Yong‐Tang Zheng, Pema‐Tenzin Puno
Abstract
Abstract 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 EC 50 value (19±1 nM) and a high TI value (>1000), both values better than those of remdesivir.