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 EC 50 between 5.0 and 10.0 μM against Colombian Zika virus strains and EC 50 = 9.8 μM against Chikungunya virus. Knowing that this ferruginol analogue is also active against Dengue virus type 2 (EC 50 = 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.

Antiviral Effect of Natural and Semisynthetic Diterpenoids against Adenovirus Infection in vitro

“…Some abietane diterpenes have shown antiviral activity, including ferruginol and carnosic acid. Carnosic acid inhibits HIV-1 virus and HIV-1 protease and shows the effect of human respiratory syncytial virus 44 . The diindolacetate 9 was the most active from our carnosic acid derivatives, with an EC 50 value of 15 µM toward HAdV-V.…”

Host Cell Targets for Unconventional Antivirals against RNA Viruses

“…It does inhibit in vitro infection by Zika virus in Vero [ 19 ], PC3, and HeLa cells at concentrations below 10 μM. Likewise, this molecule has antiviral activity in Vero cells infected with CHIKV (Alphavirus genus) [ 138 ]. Further unpublished studies related to the antiviral mechanism of action of this molecule strongly suggest that 18-(phthalimide-2-yl)-ferruginol has an HTA-related mechanism of action by disrupting the DENV-2 polyprotein translation via the alteration of actin remodeling and other related cellular and viral processes involved in the replicative complex formation.…”

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

“…During our compound screening program designed to search for new antivirals derived from natural products, we discovered a broad-spectrum antiviral analog of the bioactive abietane-type diterpene ferruginol (1, Figure 1) [16,17], which we later named 12hydroxy-N,N-phthaloyldehydroabietylamine or 18-(phthalimid-2-yl)ferruginol (1a, henceforth abbreviated as phthFGL, Figure 1) based on the abietane carbon skeleton numbering (Figure 1) [18][19][20][21]. PhthFGL (1a) has exhibited relevant in vitro antiviral activity against herpes and dengue [18], Brazilian Zika strains [19], Colombian Zika and chikungunya strains [20], and very recently, against the human coronavirus 229E (HCoV-229E) [21]. With the aim of gaining insight into the possible mechanism of action of phthFGL, we previously carried out a basic computational study using a molecular docking approach [20].…”

“…PhthFGL (1a) has exhibited relevant in vitro antiviral activity against herpes and dengue [18], Brazilian Zika strains [19], Colombian Zika and chikungunya strains [20], and very recently, against the human coronavirus 229E (HCoV-229E) [21]. With the aim of gaining insight into the possible mechanism of action of phthFGL, we previously carried out a basic computational study using a molecular docking approach [20]. In that work, it was found that phthFGL has a good affinity for key viral targets, including chikungunya nonstructural protein 2 (nsP2), Zika and dengue virus NS5 methyltransferase, and herpesvirus thymidine kinase (TK) with a higher binding energy value than that of acyclovir itself [20].…”

“…With the aim of gaining insight into the possible mechanism of action of phthFGL, we previously carried out a basic computational study using a molecular docking approach [20]. In that work, it was found that phthFGL has a good affinity for key viral targets, including chikungunya nonstructural protein 2 (nsP2), Zika and dengue virus NS5 methyltransferase, and herpesvirus thymidine kinase (TK) with a higher binding energy value than that of acyclovir itself [20]. Additionally, like IVM, phthFGL showed features suggesting potential inhibition towards cellular therapeutic targets, as demonstrated by its high free energy value with G-Actin and tubulin [20,22].…”