Malaria parasite carbonic anhydrase: inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential
Malaria parasite carbonic anhydrase: inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential
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DOI：
10.1016/s2221-1691(11)60034-8
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发表时间：
2011-06-01
影响因子：
1.7
通讯作者：
Krungkrai, Jerapan
中科院分区：
文献类型：
--
作者：
Krungkrai, Sudaratana R.;Krungkrai, Jerapan
恶性疟原虫是大多数危及生命的人类疟疾病例的罪魁祸首，每年导致150万至270万人死亡。抗药性疟疾寄生虫在全球的出现，需要确定和表征新的药物靶标及其潜在的抑制剂。我们确定了碳酸酐酶（CA）基因在恶性疟原虫。pfCA基因编码α-碳酸酐酶，一种Zn 2 +-金属酶，具有与人类宿主CA酶不同的催化性质。PfCA酶的氨基酸序列与类似的原生动物和人类酶不同。一个图书馆的芳香族/杂环磺胺类药物具有很大的多样性的支架被发现是非常好的抑制剂疟疾酶在中低微摩尔和亚微摩尔抑制。取代芳族-脲基-或芳族-甲亚胺片段的分子的基团的结构和母体磺酰胺的长度是磺酰胺的抑制性质的关键参数。一种衍生物，即4-（3，4-二氯苯脲基）硫脲基苯磺酰胺（化合物to）是体外最有效的恶性疟原虫CA抑制剂，也是体外抑制恶性疟原虫生长最有效的抗疟化合物。化合物10在感染伯氏疟原虫（Plasmodium berghei）的小鼠中也是有效的体内抗疟剂，所述伯氏疟原虫是用于人类疟疾感染的药物测试的动物模型。因此，可以得出结论，针对寄生虫CA的磺胺类抑制剂可能具有开发抗人类疟疾的新疗法的潜力。
Plasmodium falciparum is responsible for the majority of life threatening cases of human malaria, causing 1.5-2.7 million annual deaths. The global emergence of drug-resistant malaria parasites necessitates identification and characterization of novel drug targets and their potential inhibitors. We identified the carbonic anhydrase (CA) genes in Plasmodium falciparum. The pfCA gene encodes an alpha -carbonic anhydrase, a Zn2+-metalloenzme, possessing catalytic properties distinct from that of the human host CA enzyme. The amino acid sequence of the PfCA enzyme is different from the analogous protozoan and human enzymes. A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions. The structure of the groups substituting the aromatic-ureido- or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides. One derivative, that is, 4-(3,4-dichlorophenylureido)thioureido-benzenesulfonamide (compound to) was the most effective in vitro Plasmodium falciparum CA inhibitor, and was also the most effective antimalarial compound on the in vitro Plasmodium falciparum growth inhibition. The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei, an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.