Chelating agent inhibition of Trypanosoma cruzi epimastigotes in vitro.
Chelating agent inhibition of Trypanosoma cruzi epimastigotes in vitro.
复制标题
体外螯合剂抑制克氏锥虫上鞭毛体。
DOI：
10.1016/0162-0134(95)00027-5
复制
发表时间：
1995
影响因子：
3.9
通讯作者：
Jones,MM
中科院分区：
文献类型：
--
作者：
Rodrigues,RR;Lane,JE;Carter,CE;Bogitsh,BJ;Singh,PK;Zimmerman,LJ;Molenda,JJ;Jones,MM
许多螯合剂和它们的一些衍生物在抑制克氏锥虫（Trypanosoma cruzi）的外鞭毛体（引起恰加斯病的原生动物）的繁殖方面与苄硝唑（目前临床使用的化合物）一样有效或上级。在5 μg/mL的培养物浓度下检查所有化合物。最有效的化合物包括N，N，N′，N′-四（2-吡啶基甲基）乙二胺、N-二乙氨基硫代甲酸钠、N-二乙氨基硫代甲酸哌啶及其几种类似物、一些氮上带有两个非极性基团的其他硫代甲酸酯以及广泛用于治疗酒精中毒的N-二乙氨基硫代甲酸钠的前药二硫化四乙基秋兰姆。在螯合分子上引入另外的离子或非离子极性基团通常导致杀酪氨酸活性的损失。不显示活性的常见市售螯合剂包括d-青霉胺、内消旋-2，3-二巯基琥珀酸和三亚乙基四胺四盐酸盐。培养物的剂量-反应数据表明，这些化合物中的一些在低至0.625 μg/mL的浓度下表现出对克氏锥虫外鞭毛体的抑制。有人提出，这些化合物的作用机制是基于他们的能力，接口与必需的金属代谢在细胞内的网站的epimastigote涉及铁，铜，或锌。结果还表明，如果化合物要成功地抑制克氏锥虫的外鞭毛体，则一定程度的疏水性对于连接到文字金属键合结构的基团可能是必要的。开发特异性设计用于选择性破坏克氏锥虫的必需金属代谢的螯合剂的抗原动物药物应该提供可用于治疗恰加斯病的新一代药物。
A number of chelating agents and some of their derivatives are as effective as, or superior to, benznidazole, the compound currently in clinical use, in the suppression of the reproduction of epimastigotes of Trypanosoma cruzi, the protozoa that causes Chagas' disease. All compounds were examined at a culture concentration of 5 μg/mL. The most effective compounds included N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine, sodium diethylamine-N-carbodithioate, piperidine-N-carbodithioate and several of its analogs, a number of other carbodithioates with two nonpolar groups on the nitrogen, and tetraethylthiuram disulfide, a prodrug of sodium diethylamine-N-carbodithioate and widely used in the treatment of alcoholism. The introduction of additional ionic or nonionic polar groups on the chelating molecule generally results in a loss of tyrpanocidal activity. Common commercially available chelating agents which exhibited no activity included d-penicillamine, meso-2,3-dimercaptosuccinic acid, and triethylenetetramine tetrahydrochloride. Dose-response data on the culture indicated that some of these compounds exhibited inhibition of Trypanosoma cruzi epimastigotes at concentrations as low as 0.625 μg/mL. It is proposed that the mechanism of action of these compounds is based on their ability to interface with the essential metal metabolism at intracellular sites of the epimastigote involving iron, copper, or zinc. The results also indicate that a certain degree of hydrophobicity may be necessary for the groups attached to the literal metal-bonding structure if the compounds are to successfully inhibit the epimastigotes of Trypanosoma cruzi. The development of antiprotozoal drugs which are chelating agents specifically designed to selectively disrupt the essential metal metabolism of Trypanosoma cruzi should furnish a new generation of drugs which can be used in the treatment of Chagas' disease.