Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas, PO Box 6154, 13083-970, Campinas, SP, Brazil.
Laboratory of Medicinal and Computational Chemistry, Institute of Physics of Sao Carlos, University of Sao Paulo, Avenida Joao Dagnone, 1100, 13563-120, Sao Carlos, SP, Brazil.
Eur J Med Chem. 2020 Sep 1;201:112418. doi: 10.1016/j.ejmech.2020.112418. Epub 2020 May 16.
A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC values of 3.89, 2.38, 2.50 and 2.85 μM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC values of 6.20, 2.20, 2.30 and 2.20 μM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.
一系列高活性的杂合体被发现是新型抗寄生虫药物。两个杂环支架（1,2,4-噁二唑和 3-羟基-2-氧代吲哚）被连接起来，得到的化合物显示出对两种原生动物寄生虫（克氏锥虫和婴儿利什曼原虫）的细胞内无鞭毛体的体外活性。使用 HFF-1 成纤维细胞和 HepG2 肝细胞评估它们的细胞毒性。化合物 5b、5d、8h 和 8o 对 L. infantum 表现出选择性（IC 值分别为 3.89、2.38、2.50 和 2.85 μM）。化合物 4c、4q、8a 和 8k 对 T. cruzi 最有效，IC 值分别为 6.20、2.20、2.30 和 2.20 μM。此外，最有效的抗 T. cruzi 化合物表现出与苯并硝唑相当或更高的体外疗效。这些易于合成的分子代表了用于设计强力和选择性克氏锥虫病和利什曼病药物发现的先导化合物的新型化学型。
