Tick-borne flavivirus reproduction inhibitors based on isoxazole core linked with adamantane

Infections caused by flaviviruses pose a huge threat for public health all over the world. The search for therapeutically relevant compounds targeting tick-borne flaviviruses requires the exploration of novel chemotypes. In the present work a large series of novel polyfunctionalized isoxazole derivatives bearing substituents with various steric and electronic effects was obtained by our unique versatile synthetic procedure and their antiviral activity against tick-borne encephalitis, Omsk hemorrhagic fever, and Powassan viruses was studied in vitro. The majority of studied isoxazoles showed activity in low micromolar range. No appreciable cytotoxicity was observed for tested compounds. The lead compounds, 5-aminoisoxazole derivatives containing adamantyl moiety, exhibited strong antiviral activity and excellent therapeutic index.