# Searching for Novel Antiviral Agents as COVID19 Treatments: Guanidino Diaryl Thioureas

## TL;DR

This study explores guanidino diaryl thioureas as potential treatments for COVID-19 by targeting the TMPRSS2 enzyme, but finds that reversible inhibitors are less effective than irreversible ones.

## Contribution

The study identifies a hit compound and evaluates its derivatives as potential TMPRSS2 inhibitors, highlighting the limitations of reversible inhibition.

## Key findings

- A hit compound with reversible TMPRSS2 inhibitory activity was identified.
- Synthesized derivatives showed good drug-likeness but no improvement in inhibitory activity.
- Irreversible inhibitors like camostat are more effective than reversible ones for TMPRSS2.

## Abstract

The COVID‐19 pandemic highlighted the urgent need for effective antiviral treatments targeting SARS‐CoV‐2. TMPRSS2, a serine protease essential for viral entry into host cells, represents a promising therapeutic target, and this study explores guanidino diaryl thioureas as potential TMPRSS2 inhibitors. Initial screening identified a “hit‐compound” (1) with reversible inhibitory activity against TMPRSS2. Computational studies, including docking and molecular dynamics simulations, were conducted to optimize derivatives of compound 1. Twenty‐five derivatives were synthesized, and their pharmacokinetic properties and cytotoxicity assessments indicated favorable drug‐likeness and minimal toxicity. However, biochemical studies revealed that none of the derivatives improved TMPRSS2 inhibitory activity compared to the original “hit‐compound”. The findings suggest that reversible inhibitors may be suboptimal for TMPRSS2 targeting, as camostat and nafamostat exert their effects through irreversible covalent binding. Future efforts should focus on developing irreversible TMPRSS2 inhibitors to enhance antiviral efficacy against SARS‐CoV‐2.

Structure of the "hit‐compound" found and the proposed interaction with the active site of the TMPRSS2 protease, involving a reversible mechanism of action, are shown. © 2026 WILEY‐VCH GmbH