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

[EN] Abietane diterpenoids are naturally occurring plant metabolites with a broad spectrum of biological effects including antibacterial. antileishmanial, antitumor, antioxidant, as well as antiinfiammatory activities. Recently, we found that some analogues of natural ferruginol (2) actively inhibited dengue virus 2 (DENV-2) replication. Due to the similarity with DENY, we envisaged that abietane diteipenoids would also be active against Zika virus (ZIKV). Six selected semi-synthetic abietane derivatives of (+)-dehydroabietylatnine (3) were tested. Cytotoxicity was determined by Mn' 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 EC50 values ranging from 0.67 to 18.57 mu M. and cytotoxicity (CC50 values) from 256 to 35.09 mu M. The 18-Oxoferruginol (8) (EC50 = 2.60 mu M, SI = 13.51) and 12-nitro-N-benzoyldehydroabietylamine (9) (ECG 0.67 mu M, SI = 3.82) were the most active compounds, followed by 12-hydroxy-N-tosyldehydroabietylamine (7) (EC50 = 3.58 mu M, SI = 3.20) and 12-hydroxy-N,N-phthaloyldehydroabietylamine (5) (EC50 = 7.76 mu M, SI = 1.23). To the best of our knowledge, this is the first report on anti-Zika virus properties of abietanes.Financial support from the Universitat Politecnica de Valencia, under a cooperation "ADSIDEO" research grant (AD1902), is gratefully acknowledged. We are also gratefully to the financial support of the Sao Paulo Research Foundation (FAPESP), grants No 2013/01690-0, No 2019/03859-9, and FAPESP Scholarship No 2013/017029 to FTGS.Sousa, FTG.; Nunes, C.; Malta Romano, C.; Cerdeira Sabino, E.; González-Cardenete, MA. (2020). Anti-Zika virus activity of several abietane-type ferruginol analogues. Revista do Instituto de Medicina Tropical de São Paulo. 62:1-4. https://doi.org/10.1590/S1678-9946202062097S1462Newman, D. J., & Cragg, G. M. (2020). Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. Journal of Natural Products, 83(3), 770-803. doi:10.1021/acs.jnatprod.9b01285Hanson, J. R., Nichols, T., Mukhrish, Y., & Bagley, M. C. (2019). Diterpenoids of terrestrial origin. Natural Product Reports, 36(11), 1499-1512. doi:10.1039/c8np00079dGonzález, M. A. (2015). Aromatic abietane diterpenoids: their biological activity and synthesis. Natural Product Reports, 32(5), 684-704. doi:10.1039/c4np00110aBrandt, C. W., & Neubauer, L. G. (1939). 221. Miro resin. Part I. Ferruginol. Journal of the Chemical Society (Resumed), 1031. doi:10.1039/jr9390001031González, M. A., Clark, J., Connelly, M., & Rivas, F. (2014). Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group. Bioorganic & Medicinal Chemistry Letters, 24(22), 5234-5237. doi:10.1016/j.bmcl.2014.09.061Balasubramanian, A., Teramoto, T., Kulkarni, A. A., Bhattacharjee, A. K., & Padmanabhan, R. (2017). Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus. Antiviral Research, 137, 141-150. doi:10.1016/j.antiviral.2016.11.015Roa-Linares, V. C., Brand, Y. M., Agudelo-Gomez, L. S., Tangarife-Castaño, V., Betancur-Galvis, L. A., Gallego-Gomez, J. C., & González, M. A. (2016). Anti-herpetic and anti-dengue activity of abietane ferruginol analogues synthesized from (+)-dehydroabietylamine. European Journal of Medicinal Chemistry, 108, 79-88. doi:10.1016/j.ejmech.2015.11.009González, M. A., & Pérez-Guaita, D. (2012). Short syntheses of (+)-ferruginol from (+)-dehydroabietylamine. Tetrahedron, 68(47), 9612-9615. doi:10.1016/j.tet.2012.09.055Dea-Ayuela, M. A., Bilbao-Ramos, P., Bolás-Fernández, F., & González-Cardenete, M. A. (2016). Synthesis and antileishmanial activity of C7- and C12-functionalized dehydroabietylamine derivatives. European Journal of Medicinal Chemistry, 121, 445-450. doi:10.1016/j.ejmech.2016.06.004Cory, A. H., Owen, T. C., Barltrop, J. A., & Cory, J. G. (1991). Use of an Aqueous Soluble Tetrazolium/Formazan Assay for Cell Growth Assays in Culture. Cancer Communications, 3(7), 207-212. doi:10.3727/095535491820873191Chattopadhyay, D., Sarkar, M. C.-, Chatterjee, T., Sharma Dey, R., Bag, P., Chakraborti, S., & Khan, M. T. H. (2009). Recent advancements for the evaluation of anti-viral activities of natural products. New Biotechnology, 25(5), 347-368. doi:10.1016/j.nbt.2009.03.00