Bisbenzylisoquinoline Alkaloids of Cissampelos Sympodialis With in Vitro Antiviral Activity Against Zika Virus

Abstract

In search of new antiviral compounds against Zika virus we conducted a bioassay-guided fractionation of bisbenzyilisoquinoline alkaloids isolated from Cissampelos sympodialis (Menispermaceae), a medicinal plant species endemic to Brazil. Six subfractions were obtained from a tertiary alkaloidal fraction of the rhizomes (TAFrz) using preparative high-performance liquid chromatography. All the subfractions were tested against Zika virus-infected Vero cells as the cellular model to evaluate cytotoxicity and antiviral effective concentrations. The results showed that three of the six TAFrz subfractions tested were active. The most active ones were the subfraction 6 (that consisted of the alkaloids methylwarifteine and warifteine present as a mixture at a ratio of 8.8:1.2 respectively) and the subfraction 5, that was later identified as warifteine, the major tertiary alkaloid of this species. Warifteine was able to significantly reduce virus titer in Zika virus-infected Vero cells with an IC50 of 2.2 μg/ml and this effect was selective (selectivity index, SI = 68.3). Subfraction 6 had an IC50 = 3.5 μg/ml and was more cytotoxic than pure warifteine, with SI = 6.14. Fraction 5 and fraction 6 were more potent in decreasing the viral titer of Zika virus-infected Vero cells than 6-methylmercaptopurine riboside (IC50 = 24.5 μg/ml and SI = 11.9), a mercaptopurine riboside with ZIKV antiviral activity used as a positive control. Our data demonstrate that alkaloids of the bisbenzylisoquinoline type may be explored as new antiviral agents or as an useful pharmacophore for investigating ZIKV antiviral activity.

Natural Products and Derivatives as Potential Zika virus Inhibitors: A Comprehensive Review

“…The alkaloids lycorine and cherylline, isolated from Crinum jagus , were active against ZIKV in Huh 7.5 cells (SI = 35.4 and SI >12.3, respectively) [ 99 ], along with warifteine, isolated from Cissampelos sympodialis , tested in ZIKV-infected Vero cells (SI = 68.3) [ 100 ].…”

Research progress on the antiviral activities of natural products and their derivatives: Structure–activity relationships

“…Silva and colleagues extracted a bisbenzylisoquinoline alkaloid, warifteine (24A), from the rhizomes of Cissampelos sympodialis , which proved to be an anti-DENV ( da Silva et al, 2021a ). Subsequently, they found that (24A) and methylwarifteine (25A) had strong effects against the Zika virus in vitro , and could be used as a pharmacophore or lead compounds to counteract Zika-virus infection ( da Silva et al, 2021b ). Zeng’s team identified that dehydrocheilanthifoline (26A) had anti-hepatitis B virus (HBV) activity in vitro , making it a promising drug candidate for the treatment of HBV infection ( Zeng et al, 2013 ).…”