Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives
Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives
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DOI：
10.1016/j.exppara.2011.01.009
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发表时间：
2011-04-01
影响因子：
2.1
通讯作者：
Deharo, Eric
中科院分区：
文献类型：
--
作者：
Estevez, Yannick;Quiliano, Miguel;Deharo, Eric
测试了吡唑和丙烯酮喹恶啉衍生物对细胞内形态的秘鲁利什曼原虫和克氏锥虫的抑制作用。这两个系列都测试了对增殖和非增殖细胞的毒性。2，6-二甲基-3-f-喹恶啉-1，4-二氧化物对黑热病原虫生长有50%的抑制作用，对增殖的肾脏细胞无影响，对THP-1细胞和小鼠巨噬细胞毒性较低。属于丙烯酮喹恶啉系列的化合物对克氏支原体具有中等活性。在这些化合物中，有两个特别令人感兴趣，(2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3，4，5-trimethoxy-phenyl)-propenone和(2E)-3-(3，4，5-trimethoxy-phenyl)-1-(3，6，7-trimethyl-quinoxalin-2-yl)-propenone.前者对增殖细胞(肿瘤和寄生虫)具有选择性活性，对小鼠腹腔巨噬细胞无活性；后者对利什曼原虫有活性，对其他受试细胞无活性。此外，在电子计算机方面的研究表明，这两个系列都遵守利平斯基的规则，它们证实了杀胰酶活性和LogP之间的线性相关性。对接研究表明，第二系列化合物可以与克氏锥虫的聚(ADP-核糖)聚合酶蛋白相互作用。(C)2011 Elsevier Inc.保留所有权利。
Pyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9 mu M, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages: the latter was active against Leishmania and inactive against the other tested cells. Furthermore, in silico studies showed that both series respected Lipinski's rules and that they confirmed a linear correlation between trypanocidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi. (C) 2011 Elsevier Inc. All rights reserved.