Design, synthesis, and biological evaluation of plasmodium falciparum lactate dehydrogenase inhibitors
Design, synthesis, and biological evaluation of plasmodium falciparum lactate dehydrogenase inhibitors
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DOI：
10.1021/jm070336k
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发表时间：
2007-08-09
影响因子：
7.3
通讯作者：
Avery, Mitchell A.
中科院分区：
文献类型：
--
作者：
Choi, Seoung-ryoung;Pradhan, Anupam;Avery, Mitchell A.
恶性疟原虫乳酸脱氢酶（plasmodiumfalciparumlactatedehydrogenase，pfLDH）是疟原虫能量产生的关键酶，是潜在的抗疟化疗靶点。已知的是，单独的草氨酸部分（丙酮酸类似物）显示出比人LDH更高的对pfLDH的抑制，这表明其可用于开发选择性抑制剂。设计并合成了草酰胺酸衍生物。衍生物5和7表现出对pfLDH的活性，其IC 50值分别为3.13和1.75 μ M，并且分别对哺乳动物LDH具有59倍和7倍的选择性。他们也有针对恶性疟原虫苹果酸脱氢酶（pfMDH），这可能会填补pfLDH的作用时，pfLDH的活性降低微摩尔范围内的活动。因此，这些草酰胺酸衍生物的某些成员可能对pfLDH和pfMDH具有双重抑制活性。推测LDH/MDH双重抑制剂作为抗疟药物具有增强的潜力。
Plasmodium falciparum lactate dehydrogenase (pfLDH) is a key enzyme for energy generation of malarial parasites and is a potential antimalarial chemotherapeutic target. It is known that the oxamate moiety, a pyruvate analog, alone shows higher inhibition against pfLDH than human LDHs, suggesting that it can be used for the development of selective inhibitors. Oxamic acid derivatives were designed and synthesized. Derivatives 5 and 7 demonstrated activities against pfLDH with IC50 values of 3.13 and 1.75 mu M, respectively, and have 59- and 7-fold selectivity over mammalian LDH, respectively. They also have micromolar range activities against Plasmodium falciparum malate dehydrogenase (pfMDH), which may fill the role of pfLDH when the activity of pfLDH is reduced. Thus, certain members of these oxamic acid derivatives may have dual inhibitory activities against both pfLDH and pfMDH. It is presumed that dual LDH/MDH inhibitors would have enhanced potential as antimalarial drugs.