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首页> 外文期刊>RSC Advances >Synthesis, antimalarial activity, heme binding and docking studies of 4-aminoquinoline-pyrimidine based molecular hybrids
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Synthesis, antimalarial activity, heme binding and docking studies of 4-aminoquinoline-pyrimidine based molecular hybrids

机译：基于4-氨基喹啉-嘧啶的分子杂种的合成，抗疟活性，血红素结合和对接研究

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摘要

A series of novel 4-aminoquinoline-pyrimidine hybrids was synthesized and evaluated for their antimalarial activity. Several compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum with no cytotoxicity against Vero cell lines. The selected compound 7f, when evaluated for in vivo activity showed mild suppression of parasites in the P. berghei-mouse malaria model. The heme binding studies were conducted to determine the probable mode of action of these hybrids. Compound 8d formed a stable 1 : 1 complex with hematin suggesting that these hybrids act on a heme polymerization target. The binding of most active hybrids was studied by molecular docking analysis in the active site of Pf-DHFR-TS. The top scoring compounds with low binding energy, interact in the active site of Pf-DHFR-TS in a similar way to the natural protein substrate dihydrofolate. The pharmacokinetic properties of the most active compounds were also assessed using ADMET prediction.
机译：合成了一系列新颖的4-氨基喹啉-嘧啶杂化物，并评估了它们的抗疟活性。几种化合物对恶性疟原虫的CQ敏感和CQ耐药菌株均显示出有效的抗疟活性，而对Vero细胞系无细胞毒性。当评价其体内活性时，所选择的化合物7f在伯氏疟原虫-小鼠疟疾模型中显示出对寄生虫的轻度抑制。进行了血红素结合研究，以确定这些杂种的可能作用方式。化合物8d与血红素形成稳定的1：1络合物，表明这些杂合体作用于血红素聚合目标。通过分子对接分析在Pf-DHFR-TS的活性位点研究了大多数活性杂种的结合。具有低结合能的得分最高的化合物以与天然蛋白底物二氢叶酸相似的方式在Pf-DHFR-TS的活性位点相互作用。还使用ADMET预测评估了活性最高的化合物的药代动力学特性。

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