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Derivados de 2-hidróxi-3-anilino-1,4-naftoquinona: atividade antiplasmodial in vitro, toxicidade e interferência na biossíntese de isoprenóides

机译:2-羟基-3-苯胺基-1,4-萘醌衍生物:体外抗血浆活性,毒性和对类异戊二烯生物合成的干扰

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摘要

The resistance to antimalarial drugs available on the market leads to the need for the development of new compounds with novel pharmacological targets. The naphthoquinone derivatives are described as promising compounds leading to the development of antimalarial drugs. That said, we evaluated the antiplasmodial in vitro activity of three derivatives of hydroxy-naphthoquinones against asexual intraeritrocitic stage of Plasmodium falciparum, as well as toxicological in vitro and in vivo parameters and investigate a possible mechanism of action related to the isoprenoid pathway through metabolic markers via the precursors of radioactive tritium, complete with docking studies with a template of octaprenil pyrophosphate synthase. Hydroxy-naphthoquinones derivatives analyzed had good antiplasmodial activity with IC50 less than 20 μM for 3D7 strain and less than 50 μM for Dd2 strain. The therapeutic window is safe with selectivity index ranging between 36.7 and 143.0. The compounds did not cause hemolysis at the doses tested (10 and 50 times greater than their IC50), and not triggered signs of toxicity in acute toxicity test in vivo even though the compound 4a have promoted hepatic steatosis and haemorrhage in kidney tissue. Whereas a likely mechanism of action, the hydroxy-naphthoquinones derivatives appear to inhibit the synthesis of isoprenic precursors, especially menaquinone and tocopherol and docking studies revealed nine possible interactions with high energy in four different binding sites with a template of octaprenil pyrophosphate synthase. In our results, the compound 4c was the most promising, since it possessed the lowest IC50 in antiplasmodial test in vitro, lower cytotoxicity in vitro and in vivo acute toxicity, and has inhibited the three via the tested isoprenoid products, might be considered a standard candidate for the process "hit-to-lead.
机译:市场上对抗疟药的抗性导致需要开发具有新颖药理学靶标的新化合物。萘醌衍生物被描述为导致抗疟药发展的有前途的化合物。就是说,我们评估了羟基萘醌的三种衍生物对恶性疟原虫无性生殖内阶段的抗血浆体外活性以及体外和体内毒理学参数,并通过代谢标记物研究了与类异戊二烯途径有关的可能作用机制通过放射性tri的前体,完成与辛普萘尼焦磷酸合酶模板的对接研究。分析的羟基萘醌衍生物具有良好的抗血浆活性,对于3D7菌株,IC50小于20μM,对于Dd2菌株,IC50小于50μM。治疗窗口是安全的,选择性指数在36.7和143.0之间。即使化合物4a促进了肾组织的肝脂肪变性和出血,该化合物在所测试的剂量下(不会引起其IC50的10和50倍)都不会引起溶血,并且在体内急性毒性测试中也未引发毒性迹象。尽管有可能的作用机理,但是羟基萘醌衍生物似乎抑制了异戊二烯前体的合成,尤其是甲萘醌和生育酚,对接研究显示,在以十八烯酚焦磷酸合酶为模板的四个不同结合位点,九种可能的高能相互作用。在我们的结果中,化合物4c是最有前途的,因为它在体外抗血浆试验中具有最低的IC50,在体外和体内的急性细胞毒性较低,并且已经通过测试的类异戊二烯产品抑制了这三种化合物,因此可以认为是标准化合物候选人的过程“命中率领先。

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