Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity.
Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity.
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DOI：
10.3390/molecules25184154
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发表时间：
2020-09-11
期刊：
影响因子：
--
通讯作者：
Chavasiri W
中科院分区：
文献类型：
--
作者：
Boonyasuppayakorn S;Saelee T;Visitchanakun P;Leelahavanichkul A;Hengphasatporn K;Shigeta Y;Huynh TNT;Chu JJH;Rungrotmongkol T;Chavasiri W
登革热感染是危害最大的公共卫生问题之一，全世界有20亿人口面临感染风险。继发性异型感染引起的免疫功能紊乱可引起血浆漏出、出血和休克。黄酮，常见于药用植物中，由于其直接抗病毒作用和抑制登革热免疫发病机制中的促炎细胞因子，先前显示出作为抗登革热抑制剂的潜力。在这里，我们通过卤化化学修饰了黄酮，匹诺松素和pinostrobin，并将它们表征为潜在的登革热2型抑制剂，并在人源性细胞和体内动物模型中进行了毒性试验。二溴生菌素和二溴生菌素抑制登革热血清型2的ec50分别为2.0640±0.7537和5.8567±0.5074µM， cc50分别为67.2082±0.9731和bbb100µM。在静脉给药后第1天、第3天和第8天，通过ALT和Cr水平评估，这两种化合物对成年C57BL/6小鼠的毒性也很小。计算研究表明，潜在的靶点可能是sam结合口袋上的NS5甲基转移酶。综上所述，这两种溴化黄酮是进一步药物发现研究的潜在线索。
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 EC50s of 2.0640 ± 0.7537 and 5.8567 ± 0.5074 µM with at the CC50s 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.
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