Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose.
Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose.
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DOI：
10.1021/acs.jmedchem.3c01051
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发表时间：
2023-09-28
影响因子：
7.3
通讯作者：
Kelly, John M.
中科院分区：
文献类型：
--
作者：
Racane, Livio;Pticek, Lucija;Kostrun, Sanja;Raic-Malic, Silvana;Taylor, Martin Craig;Delves, Michael;Alsford, Sam;Olmo, Francisco;Francisco, Amanda Fortes;Kelly, John M.
我们设计并合成了一系列对称的双-6-脒基苯并噻唑衍生物与脂肪族中心单元，并评估其对非洲锥虫布氏锥虫血流形式的疗效。其中，双阳离子苯并噻唑化合物（9a）表现出亚纳摩尔的体外效力，对哺乳动物细胞具有显著的选择性（> 26，000倍）。未取代的5-脒基团和环己基间隔基是杀锥虫活性的关键决定因素。在所有情况下，用20 mg kg-1的单次剂量治疗的小鼠治愈了1期锥虫病。该化合物显示出良好的体外ADME特征，但膜渗透性较低。然而，我们发现T.布氏杆菌是由内吞作用介导的，内吞作用是导致溶酶体隔离的过程。该化合物在低纳摩尔浓度下对培养的无性形式的恶性疟原虫也有活性。因此，9a具有极好的跨物种功效，并且代表具有相当大的治疗潜力的先导化合物。
We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg–1 were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential.
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DOI：
10.3390/molecules26216518
发表时间：
2021-10-28
期刊：
Molecules (Basel, Switzerland)
影响因子：
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