Tri- and Diterpenoids from Stillingia loranthacea as Inhibitors of Zika Virus Replication

Abstract

This study represents the first phytochemical analysis of Stillingia loranthacea (S. loranthacea) and describes new terpenoids obtained from the root bark of this species. The fractionation of the hexane extract from the root bark led to the isolation of two new 28-nor-taraxarenes derivatives, loranthones A and B (1 and 2), four new tigliane diterpenes (5−8), three known tigliane diterpenes (9−11), and three known flexibilene diterpenes, tonantzitlolones A−C (12−14). The investigation of these compounds and the use of a molecular networking-based prioritization approach afforded two other new 28-nor-taraxarenes, loranthones C and D (3 and 4). The cytotoxicity of compounds 1, 2, and 5−14 was evaluated against Vero cells, and their 20% cytotoxic concentration (CC 20 ) values varied from 8.7 to 328 μM; antiviral activity was tested against an epidemic Zika virus (ZIKV) strain circulating in Brazil. Six out of 12 compounds (2, 5, 9−11, and 14) exhibited significant antiviral effects against ZIKV. Specifically, compounds 2 and 5 offered the most promise as lead compounds as they had a 1.7 and 1.8 log 10 TCID 50 /mL reduction in ZIKV replication, respectively. Together, the present findings have identified S. loranthacea terpenoids as potent anti-ZIKV inhibitors and pave the way to the development of possible new treatments against this devastating pathogen.

Antimicrobial Diterpenes: Recent Development From Natural Sources

“…[Euphorbiaceae]. The compounds were tested for antiviral activity against the Zika virus PE243 strain where only 134 exhibited significant inhibition of Zika virus replication by reducing viral titer by approximately 1.0 log 10 TCID 50 /ml ( Abreu et al, 2019 ).…”

Anti-viral triterpenes: a review

“…Compound loranthones B ( 342 ) exhibited significant anti-viral activity with 1.7 log10 TCID 50 /mL reduction in ZIKV replication against an epidemic Zika virus (ZIKV) strain circulating in Brazil (ZIKV/H. sapiens/Brazil/PE243/2015) (Abreu et al 2019 ). …”

Antitumor and antiangiogenic effects of Tonantzitlolone B, an uncommon diterpene from Stillingia loranthacea

“…Kits and reagents for biochemical and hematological analysis were purchased from Labtest (Lagoa Santa, MG, Brazil). Tonantzitlolone B (TNZ-B) was obtained from Stillingia loranthacea as described previously (Abreu et al 2019).…”

“…Tonantzitlolones (TNZ) A and B are diterpenes based on a rare 15-membered flexibilane skeleton obtained from Stillingia species, and few literature reports describe their pharmacological properties (Abreu et al 2019;Dräger et al 2007;Pfeffer et al 2016). The anti-CHIKV effect for TNZ-A has been described (Olivon et al 2015;Techer et al 2015;Wardana et al 2021).…”

“…Nevertheless, there is no data in the literature related to their in vivo anticancer effect. Recently, Tonantzitlolone B (TNZ-B) was obtained in sufficient quantity for in vivo assays from Stillingia loranthacea collected in Bahia, Northeastern Brazil (Abreu et al 2019). This prompted us to investigate the antitumor effect of TNZ-B on Ehrlich ascites carcinoma model in mice and the involvement of the antiangiogenic action and modulation of oxidative stress, in addition to toxicological effects.…”