Laboratorio de Ingeniería Genética, Instituto de Biomedicina, Facultad de Medicina, Universidad Central de Venezuela, San Luis, Caracas, Venezuela; Cátedra de Química General, Facultad de Farmacia, Universidad Central de Venezuela, Caracas 1041-A, Venezuela.
Laboratorio de Ingeniería Genética, Instituto de Biomedicina, Facultad de Medicina, Universidad Central de Venezuela, San Luis, Caracas, Venezuela.
Bioorg Chem. 2019 Mar;83:145-153. doi: 10.1016/j.bioorg.2018.10.028. Epub 2018 Oct 17.
To identify new agents for the American Cutaneous Leishmaniasis treatment, a series of 2-aryl-quinazolin-4(3H)-ones were tested against L. mexicana, L. braziliensis and L. amazonensis parasites as potential inhibitor of folic metabolism pathway. In general, the L. braziliensis and L. mexicana promastigote parasites were more sensitive to the action of the quinazolinones than L. amazonensis. The most active derivatives showed low-micromolar EC ranging from 4 to 10 μM, being 1.3 to 4 fold more potent than glucantime reference drug. A complete in vitro evaluation on intracellular amastigote, axenic amastigote and murine peritoneal macrophage were performed for the most active derivatives. The compounds 2j, 2h, 2t and 2u displayed acceptable responses against intracellular amastigote compared to reference drug, excellent antileishmanial activities against axenic amastigote (LD ranging from 1 to 4 μM) and relative low toxicities on peritoneal macrophages. To validate the efficacy of these four derivatives, an in vitro evaluation was performed against an antimony-resistant amastigote strain; identifying to 2h and 2u as promising antileishmanial leads for further pharmacokinetics and in vivo studies. Experimental mechanism assays putted in evidences that the most active compounds act as folate inhibitor. A tentative molecular docking on pteridine reductase 1 (PTR1) enzyme showed that the most active quinazolinones 2j and 2t are located in almost identical place compared with methotrexate reference into active site.
为了寻找治疗美洲利什曼病的新药物，我们测试了一系列 2-芳基-喹唑啉-4(3H)-酮，以评估它们是否能够抑制叶酸代谢途径，从而对利什曼原虫属（L. mexicana、L. braziliensis 和 L. amazonensis）寄生虫发挥作用。一般来说，L. braziliensis 和 L. mexicana 前鞭毛体寄生虫对喹唑啉酮的反应比 L. amazonensis 更为敏感。最具活性的衍生物显示出低至微摩尔的 EC 范围为 4 至 10μM，比葡萄糖胺参考药物的效力高 1.3 至 4 倍。我们对最具活性的衍生物进行了完整的细胞内无鞭毛体、体外无鞭毛体和鼠腹腔巨噬细胞的体外评估。化合物 2j、2h、2t 和 2u 与参考药物相比，对细胞内无鞭毛体具有可接受的反应，对体外无鞭毛体具有极好的抗利什曼原虫活性（LD 范围为 1 至 4μM），对腹腔巨噬细胞的毒性相对较低。为了验证这四个衍生物的疗效，我们对一株耐锑的无鞭毛体株进行了体外评估，结果表明 2h 和 2u 是具有进一步药代动力学和体内研究前景的有希望的抗利什曼原虫先导化合物。实验机制研究表明，最具活性的化合物是叶酸抑制剂。对蝶啶还原酶 1（PTR1）酶的初步分子对接表明，与参考药物甲氨蝶呤相比，最具活性的喹唑啉酮 2j 和 2t 位于活性部位几乎相同的位置。
