Carbonic anhydrase inhibitors:: Inhibition of Plasmodium falciparum carbonic anhydrase with aromatic/heterocyclic sulfonamides-in vitro and in vivo studies
Carbonic anhydrase inhibitors:: Inhibition of Plasmodium falciparum carbonic anhydrase with aromatic/heterocyclic sulfonamides-in vitro and in vivo studies
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DOI：
10.1016/j.bmcl.2008.09.030
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发表时间：
2008-10-15
影响因子：
2.7
通讯作者：
Supuran, Claudiu T.
中科院分区：
文献类型：
--
作者：
Krungkrai, Jerapan;Krungkrai, Sudaratana R.;Supuran, Claudiu T.
研究了具有多种支架结构的芳香/杂环磺胺类化合物库对疟原虫恶性疟原虫（pfCA）碳酸酐酶（CA, EC 4.2.1.1）的抑制作用。低微摩尔和亚微摩尔的体外抑制剂被检测到，而一些化合物在细胞培养中显示出体外抗恶性疟原虫活性。其中一种衍生物4-（3,4-二氯苯脲）硫脲基苯磺酰胺是体外有效的pfCA抑制剂（K-I为0.18 μ M），抑制恶性疟原虫体外生长，IC50为1 μ M，对人疟疾感染动物模型伯氏疟原虫感染小鼠也有效，其ID50为10 mg/kg（标准氯喹的ID50为5 mg/kg）。通过抑制嘧啶核苷酸生物合成的第一步，即ca介导的氨基甲酰磷酸生物合成，原生动物CAs的磺胺抑制剂可能具有开发人类疟疾新疗法的潜力。(c) 2008 Elsevier Ltd.版权所有。
A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds has been assayed for inhibition of the carbonic anhydrase (CA, EC 4.2.1.1) from the malaria parasite Plasmodium falciparum (pfCA). Low micromolar and submicromolar in vitro inhibitors were detected, whereas several compounds showed ex vivo anti- P. falciparum activity, in cell cultures. One derivative, that is, 4-(3,4-dichlorophenylureido) thioureido-benzenesulfonamide was an effective in vitro pfCA inhibitor (K-I of 0.18 mu M), inhibited the ex vivo growth of P. falciparum with an IC50 of 1 mu M, and was also effective as an antimalarial agent in mice infected with P. berghei, an animal model of human malaria infection, with an ID50 of 10 mg/kg (chloroquine as standard showed an ID50 of 5 mg/kg). By inhibiting the first step of pyrimidine nucleotide biosyntheses, that is, the CA-mediated carbamoylphosphate biosynthesis, sulfonamide inhibitors of the protozoan CAs may have potential for the development of novel therapies of human malaria. (c) 2008 Elsevier Ltd. All rights reserved.