Rojas Vargas Julio Alberto, López América García, Pérez Yulier, Cos Paul, Froeyen Matheus
Chemistry Department, Exact and Natural Science Faculty, Oriente University, Santiago de Cuba, Cuba.
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium.
Parasitol Res. 2019 May;118(5):1533-1548. doi: 10.1007/s00436-019-06206-z. Epub 2019 Mar 23.
There is an urgent need to discover and develop new drugs to combat parasitic diseases as Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei), and leishmaniasis (Leishmania ssp.). These diseases are considered among the 13 most unattended diseases worldwide according to the WHO. In the present work, the synthesis of 14 arylsubstituted imidazoles and its molecular docking onto sterol 14α-demethylase (CYP51) was executed. In addition, the compounds, antiprotozoal activity against T. brucei, T. cruzi, Trypanosoma brucei rhodesiense, and Leishmania infantum was evaluated. In vitro antiparasitic results of the arylsubstituted imidazoles against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum indicated that all samples from arylsubstituted imidazole compounds presented interesting antiparasitic activity to various extent. The ligands 5a, 5c, 5e, 5f, 5g, 5i, and 5j exhibited strong activity against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum with IC values ranging from 0.86 to 10.23 μM. Most samples were cytotoxic against MRC-5 cell lines (1.12 < CC < 51.09 μM) and only ligand 5c showed a good selectivity against all tested parasites. According to the results of the molecular docking, the aromatic substituents in positions 1, 4, and 5 have mainly stabilizing hydrophobic interactions with the enzyme matrix, while the oxygen from NO, SOH, and OH groups interacts with the Fe ion of the Heme group.
迫切需要发现和开发新的药物来对抗寄生虫病，如恰加斯病（克氏锥虫）、昏睡病（布氏锥虫）和利什曼病（利什曼原虫属）。根据世界卫生组织的说法，这些疾病被认为是全球13种最被忽视的疾病之一。在本研究中，进行了14种芳基取代咪唑的合成及其与甾醇14α-脱甲基酶（CYP51）的分子对接。此外，还评估了这些化合物对布氏锥虫、克氏锥虫、罗德西亚布氏锥虫和婴儿利什曼原虫的抗原虫活性。芳基取代咪唑对布氏锥虫、克氏锥虫、罗德西亚布氏锥虫和婴儿利什曼原虫的体外抗寄生虫结果表明，芳基取代咪唑化合物的所有样品都表现出不同程度的有趣抗寄生虫活性。配体5a、5c、5e、5f、5g、5i和5j对布氏锥虫、克氏锥虫、罗德西亚布氏锥虫和婴儿利什曼原虫表现出较强的活性，IC值范围为0.86至10.23μM。大多数样品对MRC-5细胞系具有细胞毒性（1.12＜CC＜51.09μM），只有配体5c对所有测试寄生虫表现出良好的选择性。根据分子对接结果，1、4和5位的芳基取代基主要与酶基质形成稳定的疏水相互作用，而来自NO、SOH和OH基团的氧与血红素基团的Fe离子相互作用。
