Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi
Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi
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DOI：
10.1021/jm030549j
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发表时间：
2004-06-03
影响因子：
7.3
通讯作者：
Chibale, K
中科院分区：
文献类型：
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作者：
Greenbaum, DC;Mackey, Z;Chibale, K
我们合成了一个硫代氨基脲类化合物文库，并对三种寄生半胱氨酸蛋白酶cruzain、falcipain-2和rhodesain进行了筛选，并分别对这三种蛋白酶的寄生源克氏锥虫、恶性疟原虫和布鲁氏锥虫进行了筛选。筛选发现了对酶和寄生虫有效的化合物，但也发现了一些化合物，尽管缺乏对蛋白酶的活性，但它们是杀寄生虫的。几种化合物对所有被试寄生虫都有效。这些有希望的先导化合物在小鼠中进行了一般毒性测试，只有一种先导化合物在62小时后产生了可观察到的毒性。我们的研究结果表明，硫代氨基脲代表了通过抑制半胱氨酸蛋白酶和其他新靶点杀死几种原生动物寄生虫的有效先导药物。
We have synthesized a library of thiosemicarbazones and screened them against three parasitic cysteine proteases, cruzain, falcipain-2, and rhodesain, and against the respective parasite sources of these three proteases, Trypanosoma cruzi, Plasmodium falciparum, and Trypanosoma brucei. The screens identified compounds that were effective against the enzymes and the parasites but also some compounds that were parasiticidal despite a lack of activity against the proteases. Several compounds were effective in killing all tested parasites. These promising lead compounds were tested for general toxicity in mice, and only one produced observable toxicity after 62 h. Our results suggest that thiosemicarbazones represent validated drug leads that kill several species of protozoan parasites through the inhibition of cysteine proteases as well as other novel targets.