# Allosteric Inhibitors of SARS‐CoV‐2 RNA‐Dependent RNA Polymerase Based on N,N′‐Diphenylurea

## TL;DR

Researchers developed new antiviral compounds targeting the SARS-CoV-2 virus's RNA polymerase to improve solubility and reduce toxicity.

## Contribution

A new class of N,N′-diphenylurea-based RdRp inhibitors with improved solubility and reduced activity was designed and synthesized.

## Key findings

- Seven analogs showed enhanced aqueous solubility (kinetic solubility > 10 µM).
- Nine compounds exhibited residual RdRp activity below 50% at 10 µM.
- Cytotoxicity remains a challenge despite improvements in solubility and activity.

## Abstract

The COVID‐19 pandemic, caused by the highly transmissible SARS‐CoV‐2 virus, has highlighted the urgent need for effective small‐molecule antivirals. To date, only a few such agents, including molnupiravir and remdesivir, have been approved by the FDA. In our previous study, a novel class of SARS‐CoV‐2 RNA‐dependent RNA polymerase (RdRp) inhibitors based on an N,N′‐diphenylurea scaffold was identified; however, these compounds exhibited poor aqueous solubility and significant cytotoxicity. Herein, the design, synthesis, and evaluation of twenty‐seven new derivatives aimed at improving solubility and reducing cytotoxicity through targeted scaffold modifications are reported. Seven analogs display enhanced aqueous solubility (kinetic solubility > 10 µM), and nine compounds show residual RdRp activity (RA—determined at 10 μM concentration of screened compounds) below 50%, with the most potent analog achieving an RA value of 34%. Despite these improvements, cytotoxicity remains a limitation across the series. These findings provide valuable structure–activity relationship insights and direct ongoing optimization efforts toward developing less toxic, soluble RdRp inhibitors with improved antiviral profiles.

Inhibitors of SARS‐CoV‐2 RdRp activity based on N,N′‐diphenylurea scaffold have been identified. Several compounds exhibit residual activity (RA) below 50% in an enzymatic assay (at 10 µM concentration) and improved aqueous solubility compared to the previously reported series of inhibitors.© 2026 WILEY‐VCH GmbH