Antiviral Profiling of C-18- or C-19-Functionalized Semisynthetic Abietane Diterpenoids

Abstract

Viral infections affect several million patients annually. Although hundreds of viruses are known to be pathogenic, only a few can be treated in the clinic with available antiviral drugs. Naturally based pharmacotherapy may be a proper alternative for treating viral diseases. Several natural and semisynthetic abietane-type diterpenoids have shown important antiviral activities. In this study, a biological evaluation of a number of either C-18- or C-19-functionalized known semisynthetic abietanes against Zika virus, Dengue virus, Herpes virus simplex type 1, and Chikungunya virus are reported. Semisynthetic abietane ferruginol and its analogue 18-(phthalimid-2-yl)ferruginol displayed broad-spectrum antiviral properties. The scale-up synthesis of this analogue has been optimized for further studies and development. This molecule displayed an EC₅₀ between 5.0 and 10.0 μM against Colombian Zika virus strains and EC₅₀ = 9.8 μM against Chikungunya virus. Knowing that this ferruginol analogue is also active against Dengue virus type 2 (EC₅₀ = 1.4 μM, DENV-2), we can conclude that this compound is a promising broad-spectrum antiviral agent paving the way for the development of novel antivirals.

Scheme 1. Synthetic Route for the Preparation of Tested Molecules 12–26

Scheme 2. Optimized Synthesis of Antiviral Compound 6, Starting from DHAA (ca. 60%)

Scheme 3. Synthesis of Antiviral Compound 6, Starting from DHAA (ca. 90%)

Figure 1

Antiviral effects on compound 6 on cultures treated and posteriorly infected with ZIKV/Col. (A) Effect on release of viral infectious particles. Infection percentage calculated according to the results obtained by plaque assay (PFU/mL) of the supernatants collected. (B) Effect on intracellular genomic copies. The replication percentage was calculated according to the results obtained by qRT-PCR of monolayers infected. (C) Effect on intracellular viral protein. Viral protein percentage was calculated according to the results obtained by cell-ELISA on monolayers infected. The asterisks indicate statistically significant differences with respect to the control without compound (*p < 0.05; Student’s t test), and error bars indicate the standard error of the mean; n = 6. In all cases ribavirin (100 μM) was used as the positive control of inhibition.