Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-09, Vol.25 (18), p.4154
• Main Authors: Boonyasuppayakorn, Siwaporn, Saelee, Thanaphon, Visitchanakun, Peerapat, Leelahavanichkul, Asada, Hengphasatporn, Kowit, Shigeta, Yasuteru, Huynh, Thao Nguyen Thanh, Chu, Justin Jang Hann, Rungrotmongkol, Thanyada, Chavasiri, Warinthorn
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; antiviral drug; Binding sites; Biocompatibility; Bromination; Bromine - chemistry; Computer applications; Cytotoxicity; Dengue - drug therapy; dengue methyltransferase; dengue virus; Dengue Virus - drug effects; Drug Design; Drug Discovery; flavanone; Flavanones - pharmacology; Flavanones - toxicity; flavonoid; Flavonoids; Halogenation; HEK293 Cells; Hemorrhage; Hep G2 Cells; Herbal medicine; Humans; Immunology; Immunopathogenesis; In vivo methods and tests; Infections; Inflammation; Infusions, Intravenous; Inhibitors; Intravenous administration; Iodine - chemistry; Magnetic Resonance Spectroscopy; Medicinal plants; Methyltransferase; Methyltransferases - metabolism; Mice; Mice, Inbred C57BL; Protein Binding; Proteins; Public health; RNA polymerase; Toxicity; Toxicity testing; Vector-borne diseases; World population; Zika virus
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25184154

Dengue infection is one of the most deleterious public health concerns for two-billion world population being at risk. Plasma leakage, hemorrhage, and shock in severe cases were caused by immunological derangement from secondary heterotypic infection. Flavanone, commonly found in medicinal plants, previously showed potential as anti-dengue inhibitors for its direct antiviral effects and suppressing the pro-inflammatory cytokine from dengue immunopathogenesis. Here, we chemically modified flavanones, pinocembrin and pinostrobin, by halogenation and characterized them as potential dengue 2 inhibitors and performed toxicity tests in human-derived cells and in vivo animal model. Dibromopinocembrin and dibromopinostrobin inhibited dengue serotype 2 at the EC s of 2.0640 ± 0.7537 and 5.8567 ± 0.5074 µM with at the CC s of 67.2082 ± 0.9731 and >100 µM, respectively. Both of the compounds also showed minimal toxicity against adult C57BL/6 mice assessed by ALT and Cr levels in day one, three, and eight post-intravenous administration. Computational studies suggested the potential target be likely the NS5 methyltransferase at SAM-binding pocket. Taken together, these two brominated flavanones are potential leads for further drug discovery investigation.