Discovery and structure–activity relationship study of novel isoxazole-based small molecules targeting Zika virus infections†

The Zika virus (ZIKV), a significant public health threat, is transmitted by Aedes aegypti mosquitoes and is associated with severe neurological disorders, particularly in newborns. Currently, there are no approved vaccines or specific therapeutics for ZIKV. Our study focuses on the identification and optimization of isoxazole-based small molecules, specifically through the structural modification of KR-26827, to combat ZIKV infections. Among the synthesized derivatives, 7l emerged as the most promising candidate, showing potent antiviral activity against ZIKV strains and an improved safety profile in vitro. This research underlines the potential of 7l for further development as a ZIKV therapeutic agent.