Synthesis and evaluation trypanosomicidal activity of new derivatives of megazol

Helena Braga Leites, F. S. Damasceno, A. Silber, R. Mendonça, C. N. Albuquerque
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引用次数: 1

Abstract

Objective : This work aims at the synthesis of megazol analogs with antitrypanosomicidal activity. Chagas’disease is caused by Trypanosoma cruzi and is a debilitating disease that has both acute and chronic forms. Many South Americans suffer from the chronic form of Chagas’disease, and there is no treatment currently available. Methods : In the chemical part, classical techniques of heterocyclic synthesis as well as usual methods of identification were used. In the biological part the cell proliferation test was used in vitro and the IC 50. Results : We synthesized a series of derivatives of 2-(1-methyl-5-nitro-2-imidazolyl)-5-substituted-1,3,4-thiadiazoles where 1-acetyl, 1-propyl and 1-nonyl were used as the substituent (4,6,7). Derivatives without nitro group were also synthesized (3,12) along with thiosemicarbazones (8,9,10) and a 5-(5-nitro-2-furanyl)-1,3,4-thiadiazol-2-amine (11). These compounds were evaluated using an in vitro test where were measured the cell proliferation. The derivatives that obtained the best results underwent further tests, in which their IC50 was calculated. The data revealed that two compounds (4,6) were effective against the parasite (IC50= 0.354 µM; IC50= 2.13 µM) and besides that, obtained the same results as the positive control, antimycim and rotenone. All proposed structures were obtained in satisfactory yields and purities. Conclusions : In conclusion, the in vitro trypanocidal activity makes these compounds promising leads in the development of an effective therapeutic agent. However, this study must be completed by additional tests with in vitro amastigote/macrophage models or in vivo mouse models. Analyzing the amide derivatives, compounds (4) and (6) were the ones that presented the best results.
甲甲脲新衍生物的合成及杀锥虫活性评价
目的:合成具有抗锥虫活性的甲脲类似物。恰加斯病是由克氏锥虫引起的,是一种使人衰弱的疾病,有急性和慢性两种形式。许多南美人患有慢性恰加斯病,目前尚无治疗方法。方法:在化学部分,采用杂环合成的经典技术和常用的鉴定方法。生物部分采用体外细胞增殖试验和ic50法。结果:我们合成了一系列以1-乙酰基、1-丙基和1-壬基为取代基的2-(1-甲基-5-硝基-2-咪唑基)-5-取代-1,3,4-噻二唑衍生物(4,6,7)。不含硝基的衍生物也与硫代氨基脲(8,9,10)和5-(5-硝基-2-呋喃基)-1,3,4-噻二唑-2-胺(11)合成(3,12)。这些化合物是评估使用体外试验,其中测量细胞增殖。获得最佳结果的衍生物进行了进一步的测试,并计算了它们的IC50。结果表明,两种化合物(4,6)对疟原虫有较好的抑制作用(IC50= 0.354µM;IC50= 2.13µM),结果与阳性对照、抗真菌素和鱼藤酮相同。所有提出的结构都获得了令人满意的产率和纯度。结论:该化合物具有良好的体外杀锥虫活性,有望成为一种有效的治疗药物。然而,这项研究必须通过体外无尾线虫/巨噬细胞模型或体内小鼠模型的额外测试来完成。对酰胺类衍生物进行分析,化合物(4)和(6)的效果最好。
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