Identification of 1,2-dihydroquinazolin-2-ones kinase inhibitors as anti-coronavirus agents.

Abstract

The growing threat of viral pandemics, along with the emergence and re-emergence of various viruses, highlights an urgent need for innovative antiviral strategies. Traditional antivirals typically target viral proteins, but this approach often faces challenges like drug resistance and specificity. In contrast, host-based antivirals present a promising alternative by focusing on cellular factors essential for viral replication, which can potentially limit viral adaptation and resistance. Kinase inhibitors are a notable class within these therapies, as viruses frequently exploit kinases to aid in their replication, making them a crucial therapeutic target. By blocking these signalling pathways, kinase inhibitors can disrupt viral replication, broadening their range of use and providing effective defences against multiple pathogens. To search for effective inhibitory agents, we performed a high-content screen (HCS) of a 406-compound library of kinase inhibitor chemotypes using human coronavirus OC43 (HCoV-OC43). The compounds were selected based on their favourable cytotoxicity profile from a larger kinase library. In the primary screen, 57 hits were identified that belong to 9 chemical families. Of these, dose response analysis distinguished 20 compounds that exhibited EC50 < 10 μM. Four compounds with EC50 < 3 μM and favourable selectivity belong to a series of 1,2-dihydroquinazolin-2-ones, representing a novel class of antivirals.