Cátedra de Química, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela.
Laboratorio de Ingeniería Genética, Instituto de Biomedicina, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela.
Arch Pharm (Weinheim). 2019 May;352(5):e1800281. doi: 10.1002/ardp.201800281. Epub 2019 Apr 17.
Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4-aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC values ranging from 3.84 to 10 μM. A structure-activity relationship analysis gave evidence that a piperidine or a morpholine attached as N-alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC ranging from 69 to >250 μM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony-resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism-of-action studies and molecular docking simulations were performed for the most active 4-aminoquinoline.
基于 4-氨基喹啉的传统抗疟药物对利什曼原虫表现出良好的抗增殖活性；然而，它们的临床应用目前受到限制。为了寻找新的 4-氨基喹啉来对抗美洲皮肤利什曼病，我们对一系列去羟异喹啉和异替布喹啉对两种利什曼原虫（如巴西利什曼原虫和墨西哥利什曼原虫）进行了全面的体外评估。首先，研究了喹啉对巴西利什曼原虫和墨西哥利什曼原虫的前鞭毛体形式的增殖活性，发现其中 5 种具有良好的抗利什曼原虫活性，其微摩尔 IC 值范围为 3.84 至 10 μM。构效关系分析表明，哌啶或吗啉作为 N-烷基氨基末端取代基以及在异替布喹啉核心的苯胺环上附加额外的苯基环的存在构成了产生最活性衍生物的重要药效团，其抗利什曼原虫活性远远优于参考药物葡萄糖酸锑。所有化合物对人真皮成纤维细胞的毒性相对较低，CC 值范围为 69 至 >250 μM。与参考药物相比，五种最活性化合物对巴西利什曼原虫的细胞内无鞭毛体形式表现出中度至良好的抗利什曼原虫活性。特别是化合物 2j 被鉴定为对耐锑巴西利什曼原虫无鞭毛体最有效的药物，具有可接受的生物学反应和选择性，成为进一步体内抗利什曼病评价的有前途的候选药物。对最活性的 4-氨基喹啉进行了多种作用机制研究和分子对接模拟。
