2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties
2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties
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DOI：
10.1039/c5md00062a
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发表时间：
2015-01-01
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影响因子：
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通讯作者：
O'Neill, Paul M.
中科院分区：
文献类型：
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作者：
Charoensutthivarakul, Sitthivut;Hong, W. David;O'Neill, Paul M.
2-吡啶喹诺酮类药物经5-7步制备，经先导优化，对恶性疟原虫的抗疟活性低至12 nM。与本系列之前的类似物相比，所选择的分子具有更好的溶解度，降低脱靶毒性的潜力和改善的代谢稳定性。与Pfbc(1)复合物靶点的同源性模型进行的对接研究表明，Tyr16残基在识别高活性喹诺酮类抑制剂中发挥了关键作用。
A series of 2-pyridylquinolones has been prepared in 5-7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum (Pf) has been achieved. Compared with previous analogues in this series, selected molecules have improved solubility, a reduced potential for off-target toxicity and improved metabolic stability profiles. Docking studies performed with a homology model of the Pfbc(1) complex target demonstrate a key role for the Tyr16 residues in the recognition of highly active quinolone based inhibitors.