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

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.