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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death
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Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death

机译：效力和合成有效的抗锥虫瘤Cruzi代理新的噻唑衍生物，诱导凋亡寄生虫死亡

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Chagas disease, caused by the kinetoplastid protozoan parasite Trypanosoma cruzi, remains a relevant cause of illness and premature death and it is estimated that 6 million to 7 million people are infected worldwide. Although chemotherapy options are limited presenting serious problems, such as low efficacy and high toxicity. T. cruzi is susceptible to thiazoles, making this class of compounds appealing for drug development. Previously, thiazoles resulted in an increase in anti-T. cruzi activity in comparison to thiosemicarbazones. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new thiazoles derivatives (3a-m and 4a-m), designed from molecular hybridization associated with nonclassical bioisosterism. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity, in comparison to the corresponding thiosemicarbazones. In most cases, electron-withdrawing substituents, such as bromine, 3,4-dichloro and nitro groups, greatly increased antiparasitic activity. Specifically, new thiazoles were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting macrophages viability. These compounds were also evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these molecules induce apoptosis. In conclusion, except for compounds 3h and 3k, all thiazoles derivatives evaluated exhibited higher cytotoxic activity against the trypomastigote forms than the reference medicament benznidazole, without affecting macrophages viability. Compounds 4d and 4k were highlights, CC50 = 1.2 e 1.6 mu M, respectively. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates. (C) 2017 Elsevier Masson SAS. All rights reserved.
机译：由Kinetoplastid原生动物寄生虫胰蛋白酶瘤瘤瘤瘤瘤患者遗骸，仍然是疾病和过早死亡的相关原因，估计全世界600万人至700万人受到影响。虽然化疗选择有限呈现严重的问题，如低疗效和高毒性。 T.Cruzi易患噻唑，使这类化合物对药物发育有吸引力。以前，噻唑导致抗T增加。与硫代蓟虫人相比，Cruzi活性。在这里，我们报告了结构规划，合成和抗T.克鲁齐评价新的噻唑衍生物（3A-M和4A-M），由与非核化生物肌肤相关相关的分子杂交。通过改变附着在苯基和噻唑环上的取代基，观察到取代基以保留，增强或大大增加其抗-t。与相应的硫代蓟虫相比，Cruzi活性。在大多数情况下，吸附取代基，例如溴，3,4-二氯和硝基，大大增加的抗遗传性活性。具体而言，鉴定了新的噻唑抑制偏移增殖并且对胰蛋白酶的毒性有毒，而不影响巨噬细胞活力。还评估这些化合物对克鲁松进行评估。然而，未观察到对该酶的抑制，表明化合物通过另一种机制工作。此外，检测T.Cruzi细胞死亡表明这些分子诱导细胞凋亡。总之，除了化合物3H和3K之外，评估的所有噻唑衍生物对胰蛋白酶苯并唑来说表现出对胰蛋白酶苯并唑的较高的细胞毒性活性，而不会影响巨噬细胞活力。化合物4D和4K分别亮点，CC50 = 1.2 e1.6μm。机械地，这些化合物不抑制裂扰，但是通过凋亡过程诱导克鲁齐细胞死亡，被认为是开发新的抗粘性药物候选者的良好起点。 （c）2017年Elsevier Masson SAS。版权所有。

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