Quiliano Miguel, Pabón Adriana, Ramirez-Calderon Gustavo, Barea Carlos, Deharo Eric, Galiano Silvia, Aldana Ignacio
Universidad de Navarra, Institute of Tropical Health (ISTUN), Campus Universitario, 31008 Pamplona, Spain; Universidad de Navarra, Facultad de Farmacia y Nutrición, Department of Organic and Pharmaceutical Chemistry, Campus Universitario, 31008 Pamplona, Spain.
Malaria Group, Universidad de Antioquía, Medellín 1226, Colombia.
Bioorg Med Chem Lett. 2017 Apr 15;27(8):1820-1825. doi: 10.1016/j.bmcl.2017.02.049. Epub 2017 Feb 21.
We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC=1.40μM, FCR-3 IC=2.56μM) and 19 (3D7 IC=0.24μM, FCR-3 IC=2.8μM) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC-values>241μM) and most selective (SI>86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system.
我们报告了15种肼/酰肼喹喔啉1,4 - 二氧化物衍生物针对恶性疟原虫3D7氯喹敏感株和FCR - 3多药耐药株以及婴儿利什曼原虫（无菌无鞭毛体）的设计（基于计算机辅助的ADMET标准）、合成、细胞毒性研究（HepG - 2细胞）和生物学评价。其中14种衍生物是新型喹喔啉1,4 - 二氧化物衍生物。化合物18（3D7 IC = 1.40μM，FCR - 3 IC = 2.56μM）和19（3D7 IC = 0.24μM，FCR - 3 IC = 2.8μM）被确定为对恶性疟原虫活性最高的化合物，它们的细胞毒性最小（CC值> 241μM）且选择性最高（SI> 86）。所测试的化合物中没有一种对婴儿利什曼原虫有活性。此外，还研究了肼和酰肼结构在喹喔啉1,4 - 二氧化物体系中的功能作用。
