Biological and Medicinal Chemistry

Identification and Semisynthesis of (–)-Anisomelic Acid as an Oral Antiviral Agent against SARS-CoV-2 in Mice



(–)-Anisomelic acid (AA), isolated from Anisomeles indica (L.) Kuntze (Labiatae) leaves, is a macrocyclic cembranolide with a trans-fused α-methylene-β-lactone motif. Cytopathic effect assays showed that the anti-SARS-CoV-2 effect of AA (IC50 = 4.3 μM) is comparable to that of remdesivir (IC50 = 2.1 μM), and more potent than that of molnupiravir (IC50 = 27.8 μM). Challenge studies in SARS-CoV-2-infected K18-hACE2 mice showed that oral administration of AA and remdesivir can both reduce the viral titers in the lung tissue at the same level. To facilitate drug discovery, we used a semisynthetic approach to shorten the project timelines. The enantioselective semisynthesis of AA from the naturally enriched and commercially available starting material (+)-costunolide was achieved in five steps with a 27% overall yield. The developed chemistry provides opportunities for developing AA-based novel ligands for selectively targeting proteins involved in viral infection.

Version notes

Added a missing reagent in the synthetic route.


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Supplementary material

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Supplementary Materials
This document contains the supplementary materials for <Identification and Semi-synthesis of (−)-Anisomelic Acid as an Oral Antiviral Agent against SARS-CoV-2>, including in vitro antiviral activity assays, in vivo antiviral activity assays, materials and methods, Figs. S1 to S3, spectral data, single-crystal XRD data and references.