Krungkrai Sudaratana R, Krungkrai Jerapan
Unit of Biochemistry, Department of Medical Science, Faculty of Science, Rangsit University, Paholyothin Rd., Patumthani 12000, Thailand.
Asian Pac J Trop Biomed. 2011 Jun;1(3):233-42. doi: 10.1016/S2221-1691(11)60034-8.
Plasmodium falciparum (P. 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 P. falciparum. The pfCA gene encodes anα-carbonic anhydrase, a Zn(2+)-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 10) was the most effective in vitro Plasmodium falciparum CA inhibitor, and was also the most effective antimalarial compound on the in vitro P. 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.
恶性疟原虫（P. falciparum）是导致大多数危及生命的人类疟疾病例的病原体，每年造成150万至270万人死亡。全球耐药疟原虫的出现使得鉴定和表征新型药物靶点及其潜在抑制剂成为必要。我们鉴定了恶性疟原虫中的碳酸酐酶（CA）基因。pfCA基因编码一种α-碳酸酐酶，一种锌（2+）金属酶，具有与人类宿主CA酶不同的催化特性。pfCA酶的氨基酸序列与类似的原生动物和人类酶不同。发现具有多种支架结构的芳香族/杂环磺酰胺文库是该疟疾酶的良好抑制剂，抑制浓度为中低微摩尔和亚微摩尔。取代分子中芳香脲基或芳香偶氮甲碱片段的基团结构以及母体磺酰胺的长度是磺酰胺抑制特性的关键参数。一种衍生物，即4-（3,4-二氯苯基脲基）硫脲基苯磺酰胺（化合物10）是体外最有效的恶性疟原虫CA抑制剂，也是体外恶性疟原虫生长抑制方面最有效的抗疟化合物。化合物10在感染伯氏疟原虫的小鼠体内也是有效的抗疟剂，伯氏疟原虫是人类疟疾感染药物测试的动物模型。因此得出结论，靶向寄生虫CA的磺酰胺抑制剂可能具有开发针对人类疟疾新疗法的潜力。
