Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA.
Department of Chemistry, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA.
Molecules. 2018 Jul 4;23(7):1626. doi: 10.3390/molecules23071626.
() is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure⁻activity relationship (SAR) study of the thiophene molecule . Overall, eight thiophene derivatives of were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule showed the highest in vitro activity against promastigotes (EC 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of on promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of derivatives allowed the identification of the novel molecule , which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells.
() 是一种引起皮肤利什曼病的原生动物寄生虫。目前约有 1200 万人感染，年发病率为 130 万例。本研究旨在合成一系列新型噻吩衍生物，并评估其寄生活性和潜在作用机制 (MOA)。我们对噻吩分子进行了构效关系 (SAR) 研究。总的来说，通过硅胶柱层析法合成并纯化了 8 种噻吩衍生物。在这 8 种类似物中，分子 对 亲代虫的体外活性最高（EC 0.09 ± 0.02 μM），在仅 0.63 μM 时对细胞内无鞭毛体的增殖抑制率高于 75%，且选择指数良好。此外， 对 亲代虫的作用与活性氧 (ROS) 的产生有关，计算机对接研究表明， 可能在抑制硫醇还原酶方面发挥作用。总之，噻吩衍生物的综合 SAR 研究和体外评价确定了新型分子 ，该分子表现出强大的体外抗利什曼活性，导致 ROS 产生导致细胞死亡，对哺乳动物细胞没有明显的细胞毒性。
