ANTIMALARIAL AGENTS BASED ON BIOHETEROCYCLES

基于生物杂环的抗疟剂

• 批准号: 3854816
• 负责人: L A COHEN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3854816
• 关键词: Aotus; Plasmodium falciparum; alkyl group; alkylation; aminoacid analog; antimalarial agents; chemical group; chemical structure function; chemical substitution; conformation; drug design /synthesis /production; drug screening /evaluation; enzyme substrate; ethylenediamines; fluoroaminoacid; histamine; histidine; imidazole; iodination; iodine; laboratory mouse; temperature; tissue /cell culture

The high antimalarial activity we had found for 2-fluorohistidine (2FHIS) against Plasmodium falciparum in vitro could not be extended because the compound proved too toxic to owl monkeys, despite the fact that mice tolerate up to 500 mg/kg. Therefore, we have screened a large number of other substituted histidines (which we had synthesized for the first time) for in vitro antimalarial activity: 2-iodo showed very strong and 2-azido gave moderate activity. Neither 4-X-histidines nor 2,4-di-X-histidines show any activity, while 2-iodohistamine is somewhat active. To our surprise, the 2-chloro and 2-bromo analogues are inactive. Thus, the role of the iodine atom cannot be electronic but may be just the right size to plug the erythrocyte membrane diffusion hold present in infected cells. In contrast to 2-FHIS, 2-IHIS does not significantly retard protein synthesis while retarding maturation, a result supporting the proposed mechanism of action. Although 2-IHIS proved non-toxic to monkeys, it retarded growth of parasite for only 24 h. We suspected that the compound may be a substrate for a mammalian deiodinase but, in the course of a search for such a deiodinase, found that the iodine is rapidly removed by any synthetic or natural sulfhydryl species under physiological conditions. This loss of activity would not be observed in vitro because of the very low levels of sulfhydryl compounds present in the culture medium. The finding that the deiodination need not be enzyme-mediated greatly reduces the possibility of stabilizing the drug by bulky N-alkylation of the imidazole ring or by use of the D-histidine series. Another approach, therefore, involves efforts to replace the iodine atom by metabolically stable groups of comparable size: iPr, tBu, Ph, Bz, etc. The most direct route to 2-alkylhistidines is based on a procedure we had developed to synthesize 2-perfluoroalkylhistidines - ring closure of 1,2- diacylaminoethylenes. Initial attempts to apply the same scheme for the introduction of alkyl or aryl groups did not succeed because of decomposition at the high temperatures required. We are now utilizing specific catalysts in order to facilitate these ring closures at lower temperatures.

我们发现 2-氟组氨酸 (2FHIS) 具有高抗疟活性 体外抗恶性疟原虫的效果无法扩展，因为 事实证明，该化合物对猫头鹰猴来说毒性太大，尽管老鼠 耐受量高达 500 mg/kg。 因此我们筛选了大量的 其他取代的组氨酸（我们首次合成） 体外抗疟活性：2-碘显示很强，2-叠氮显示出很强的抗疟活性 给予适度的活动。 既不是 4-X-组氨酸，也不是 2,4-二-X-组氨酸 显示出任何活性，而 2-碘组胺则具有一定的活性。 致我们的 令人惊讶的是，2-氯和2-溴类似物没有活性。 因此，角色 碘原子的大小不可能是电子的，但可能正好适合 堵塞受感染细胞中存在的红细胞膜扩散保持。 在 与 2-FHIS 相比，2-IHIS 不会显着阻碍蛋白质合成 在延缓成熟的同时，这一结果支持了所提出的机制 行动。 尽管 2-IHIS 被证明对猴子无毒，但它会延缓猴子的生长。 寄生期只有24小时。 我们怀疑该化合物可能是底物 对于哺乳动物脱碘酶，但是在寻找这样的过程中 脱碘酶，发现碘可以通过任何合成或 生理条件下的天然巯基种类。 这种损失 由于活性水平非常低，因此在体外观察不到活性 培养基中存在巯基化合物。 研究结果表明 脱碘不需要酶介导，大大降低了 通过咪唑环的大量 N-烷基化或使用来稳定药物 D-组氨酸系列。 因此，另一种方法涉及努力用以下物质取代碘原子： 大小相当的代谢稳定组：iPr、tBu、Ph、Bz 等。 获得 2-烷基组氨酸的最直接途径基于我们的程序 开发用于合成 2-全氟烷基组氨酸 - 1,2- 的闭环 二酰氨基乙烯。 最初尝试将相同的方案应用于 烷基或芳基的引入没有成功，因为 在所需的高温下分解。 我们现在正在利用 特定的催化剂，以促进这些闭环在较低的 温度。