Allosteric Inhibitors of SARS‐CoV‐2 RNA‐Dependent RNA Polymerase Based on <i>N</i> , <i>N′</i> ‐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.