a Programa de Pós-Graduação em Farmácia, Universidade Federal da Bahia , Salvador , BA , Brazil.
b Programa de Pós-Graduação em Biotecnologia, Universidade Estadual de Feira de Santana , Feira de Santana , BA , Brazil.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1439-1450. doi: 10.1080/14756366.2019.1651311.
Leishmaniasis is a tropical disease found in more than 90 countries. The drugs available to treat this disease have nonspecific action and high toxicity. In order to develop novel therapeutic alternatives to fight this ailment, pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHF-TS) have been targeted, once is auxotrophic for folates. Although PTR1 and DHFR-TS from other protozoan parasites have been studied, their homologs in have been poorly characterized. Hence, this work describes the optimal conditions to express the recombinant PTR1 and DHFR-TS enzymes, as well as balanced assay conditions for screening. Last but not the least, we show that 2,4 diaminopyrimidine derivatives are low-micromolar competitive inhibitors of both enzymes (PTR1 Ki = 1.50-2.30 µM and DHFR Ki = 0.28-3.00 µM) with poor selectivity index. On the other hand, compound (2,4-diaminoquinazoline derivative) is a selective PTR1 inhibitor (Ki = 0.47 µM, selectivity index = 20).
利什曼病是一种在 90 多个国家发现的热带病。可用于治疗这种疾病的药物具有非特异性作用和高毒性。为了开发治疗这种疾病的新的治疗方法，已经针对蝶呤还原酶 1（PTR1）和二氢叶酸还原酶-胸苷酸合成酶（DHF-TS）进行了研究，因为 是叶酸的营养缺陷型。尽管已经研究了来自其他原生动物寄生虫的 PTR1 和 DHFR-TS，但它们在 的同源物的特征描述较差。因此，本工作描述了表达重组 PTR1 和 DHFR-TS 酶的最佳条件，以及筛选的平衡测定条件。最后但并非最不重要的是，我们表明 2,4-二氨基嘧啶衍生物是这两种酶的低微摩尔竞争性抑制剂（PTR1 Ki=1.50-2.30 µM 和 DHFR Ki=0.28-3.00 µM），选择性指数较差。另一方面，化合物 （2,4-二氨基喹唑啉衍生物）是一种选择性 PTR1 抑制剂（Ki=0.47 µM，选择性指数=20）。
