# Targeted Isolation of Coumarins From Sideritis Species Based on Antiviral Screening and Untargeted Metabolomics

## TL;DR

This study investigates antiviral properties of Sideritis plant extracts against SARS-CoV-2 and identifies coumarin compounds as potential contributors.

## Contribution

First-time isolation of a trimethoxy-dimethyl-coumarin from the Sideritis genus using a combined metabolomics and screening approach.

## Key findings

- Dichloromethane extract of Sideritis cypria showed notable protective effect against SARS-CoV-2.
- Coumarins were identified as key compounds in Sideritis species, with varying concentrations.
- A new trimethoxy-dimethyl-coumarin derivative was isolated and structurally characterized.

## Abstract

The SARS‐CoV‐2 pandemic has revealed a deficiency in antiviral agents. Plants, traditionally used for respiratory infections, are valuable sources of antiviral compounds. Such a plant is the Sideritis L. taxa (mountain tea), traditionally used against cold and cough.

Accordingly, this study aimed to investigate the potential protective effects of dichloromethane extracts from Sideritis species against SARS‐CoV‐2.

Eight Sideritis extracts were tested in an in vitro pretreatment assay to assess the protective effect against SARS‐CoV‐2. Therefore, infectious virus particles were pre‐incubated with the extract, then incubated with Vero E6 cells to finally measure cell viability as a surrogate for virus infection. Untargeted analyses (GC–MS and LC‐PDA‐HRESIMS) were performed to determine metabolite profiles.

Using an orthogonal approach that combines untargeted metabolomics and biological data from a screening assay, we characterized the phytochemical profiles of the different extracts and prioritized samples for targeted isolation. The dichloromethane extract of Sideritis cypria exhibited a notable protective effect. Untargeted analysis revealed coumarins as key compounds, with varying amounts across Sideritis species. Accordingly, fractionation of extract resulted in the isolation of two coumarin derivatives. Structure elucidation was performed using one‐ and two‐dimensional nuclear magnetic resonance experiments. The coumarin, more abundant in
S. cypria
, demonstrated a slight protective effect in the SARS‐CoV‐2 pretreatment assay.

This study highlights the antiviral effects of Sideritis taxa, although further investigations are necessary to clarify the full potential of the herb. Additionally, the methodology presented herein can serve as a valuable resource for future phytochemical investigations focused on coumarin content within Sideritis genus.

This study explores the antiviral efficacy of eight Sideritis taxa, evaluating the potential protective effects of the dichloromethane extracts against SARS‐CoV‐2 in vitro. Combining untargeted metabolomics with biological screening data, the phytochemical profiles of the extracts were analyzed. This approach identified two coumarin derivatives and led to the first‐time isolation of a trimethoxy‐dimethyl‐coumarin from the Sideritis genus, highlighting the plants' potential in antiviral applications and contributing to the understanding of the medicinal properties.