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

• Published in: Angewandte Chemie International Edition Vol. 61; no. 28; pp. e202201684 - n/a
• Main 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
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 11.07.2022; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Anti-SARS-CoV-2 Agents; Antiviral activity; Chemistry; Chemistry, Multidisciplinary; Domino Reactions; Natural Products; Pharmacology; Physical Sciences; Scaffolds; Science & Technology; Semisynthesis; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Wolff Rearrangement; Anti-SARS-CoV-2 Agents; Natural Products; ORIDONIN; Semisynthesis; Wolff Rearrangement; ANALOGS; STRATEGY; Domino Reactions
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202201684

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.