SAR exploration for 4-aminotetrahydroquinazolines with adamantyl moiety against orthoflaviviruses.

4-Aminotetrahydroquinazoline N-oxides form a prominent chemotype of orthoflavivirus reproduction inhibitors, attractive for the search of lead compounds for development as direct-action antiviral agents. Here we explored the relationship between the structure and antiviral activity within an extended series of adamantyl-containing 4-aminotetrahydroquinazolines, synthesized via SNAr reactions of 4-chlorotetrahydroquinazolines with adamantyl-containing amines. Most of the obtained compounds inhibited the reproduction of tick-borne encephalitis, yellow fever, and West Nile viruses in phenotypic assays with micromolar EC50s. The most favorable substituents at 4-amino group were 2-adamant-(1/2)-ylethyls, while the position 2 of heterocyclic core served as a toxicity switch, 2-chlorotetrahydroquinazolines being much less toxic than other analogues. Time-of-addition experiments for hit compounds against West Nile virus revealed a possibility for multi-factorial mechanism of action in the 4-aminotetrahydroquinazoline series.