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- Title
Harnessing Natural Products by a Pharmacophore‐Oriented Semisynthesis Approach for the Discovery of Potential Anti‐SARS‐CoV‐2 Agents.
- Authors
Zhou, Yuan‐Fei; Yan, Bing‐Chao; Yang, Qian; Long, Xin‐Yan; Zhang, Dan‐Qi; Luo, Rong‐Hua; Wang, Han‐Yu; Sun, Han‐Dong; Xue, Xiao‐Song; Zheng, Yong‐Tang; Puno, Pema‐Tenzin
- 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 EC50 value (19±1 nM) and a high TI value (>1000), both values better than those of remdesivir.
- Subjects
NATURAL products; WOLFF rearrangement; REMDESIVIR; BIOMIMETIC materials; SARS-CoV-2
- Publication
Angewandte Chemie, 2022, Vol 134, Issue 28, p1
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.202201684