Anti-Zika virus activity of several abietane-type ferruginol analogues

Abietane diterpenoids are naturally occurring plant metabolites with a broad spectrum of biological effects including antibacterial, antileishmanial, antitumor, antioxidant, as well as antiinflammatory activities. Recently, we found that some analogues of natural ferruginol ( 2 ) actively inhibited dengue virus 2 (DENV-2) replication. Due to the similarity with DENV, we envisaged that abietane diterpenoids would also be active against Zika virus (ZIKV). Six selected semi-synthetic abietane derivatives of (+)-dehydroabietylamine ( 3 ) were tested. Cytotoxicity was determined by MTT assay in Vero cells. In vitro anti-ZIKV (clinical isolate, IMT17) activity was evaluated by plaque assay. Interestingly, these molecules showed potential as anti-ZIKV agents, with EC(50) values ranging from 0.67 to 18.57 µM, and cytotoxicity (CC(50) values) from 2.56 to 35.09 µM. The 18-Oxoferruginol (8) (EC(50) = 2.60 µM, SI = 13.51) and 12-nitro-N-benzoyldehydroabietylamine (9) (EC(50)= 0.67 µM, SI = 3.82) were the most active compounds, followed by 12-hydroxy-N-tosyldehydroabietylamine ( 7 ) (EC(50) = 3.58 µM, SI = 3.20) and 12-hydroxy-N,N-phthaloyldehydroabietylamine ( 5 ) (EC(50) = 7.76 µM, SI = 1.23). To the best of our knowledge, this is the first report on anti-Zika virus properties of abietanes.