Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071, León, Spain.
Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain.
Eur J Med Chem. 2019 Jan 15;162:18-31. doi: 10.1016/j.ejmech.2018.10.065. Epub 2018 Oct 31.
Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L. infantum amastigotes to amphotericin B. Special interest shows tetrahydroquinolylphosphine sulfide 5a with an EC value (0.61 ± 0.18 μM) similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and selective index (SI = 56.87). In addition, compound 4c shows remarkable inhibition on Leishmania topoisomerase IB. Parallel theoretical study of stereoelectronic properties, application of docking-based virtual screening methods, along with molecular electrostatic potential and predictive druggability analyses are also reported.
杂环化合物，如磷取代苯胺、醛和苯乙烯之间的多组分环加成反应生成的杂合四氢喹啉和喹啉衍生物，已经被制备出来。这些化合物的抗利什曼原虫活性已经在利什曼原虫的前鞭毛体和巨噬细胞内无鞭毛体上进行了评估。功能化的四氢喹啉 4a、5a、6b 和喹啉 8b 具有良好的抗利什曼原虫活性，与标准药物两性霉素 B 相似，对利什曼原虫无鞭毛体的选择性指数（SI 在 43 到 57 之间）接近两性霉素 B。四氢喹啉基膦硫醚 5a 特别引人注目，其 EC 值（0.61±0.18μM）与标准药物两性霉素 B（0.32±0.05μM）相似，选择性指数（SI=56.87）。此外，化合物 4c 对利什曼原虫拓扑异构酶 IB 显示出显著的抑制作用。还报道了立体电子性质的平行理论研究、基于对接的虚拟筛选方法的应用、分子静电势和可预测药物性质分析。
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