Anti‐Dengue‐Virus Activity and Structure–Activity Relationship Studies of Lycorine Derivatives

Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. No vaccines or specific therapeutics are currently available for dengue. Lycorine, which is a natural plant alkaloid, has been shown to possess antiviral activities against flaviviruses. In this study, a series of novel lycorine derivatives were synthesized and assayed for their inhibition of dengue virus (DENV) in cell cultures. Among the lycorine analogues, 1-acetyllycorine exhibited the most potent anti-DENV activity (EC50 =0.4 μM) with a reduced cytotoxicity (CC50 >300 μM), which resulted in a selectivity index (CC50 /EC50 ) of more than 750. The ketones 1-acetyl-2-oxolycorine (EC50 =1.8 μM) and 2-oxolycorine (EC50 =0.5 μM) also exhibited excellent antiviral activities with low cytotoxicity. Structure-activity relationships for the lycorine derivatives against DENV are discussed. A three-dimensional quantitative structure-activity relationship model was established by using a comparative molecular-field analysis protocol in order to rationalize the experimental results. Further modifications of the hydroxy group at the C1 position with retention of a ketone at the C2 position could potentially lead to inhibitors with improved overall properties.