Anti-trypanosomal activity of doubly modified salinomycin derivatives
Anti-trypanosomal activity of doubly modified salinomycin derivatives
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DOI：
10.1016/j.ejmech.2019.03.061
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发表时间：
2019-07-01
影响因子：
6.7
通讯作者：
Huczynski, Adam
中科院分区：
文献类型：
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作者：
Antoszczak, Michal;Steverding, Dietmar;Huczynski, Adam
作为一组生物活性化合物，聚醚抗生素（离子载体）表现出广泛的有趣的药理学特性，从抗菌到抗癌活性。越来越多的证据表明，包括盐霉素 (SAL) 在内的离子载体及其半合成类似物是开发抗寄生虫病药物的有希望的候选者。我们之前的研究表明，SAL 的 Cl 羧酸酯部分的酯化和酰胺化提供了对布氏锥虫（导致非洲锥虫病的原生动物寄生虫）具有有效活性的化合物。在本文中，我们介绍了 SAL 的 Cl 酯、酰胺和异羟肟酸缀合物、其 C20-氧代和炔丙胺类似物以及新型 Cl/C20 双重修饰衍生物的合成途径、晶体结构和抗锥虫活性。使用布氏锥虫和人骨髓 HL-60 细胞的血流形式评估杀锥虫和细胞毒性活性，结果表明，单一修饰的 C20-oxo 和炔丙胺前体分子 10 和 16 是最具抗锥虫性和选择性的化合物，其 50% 生长抑制 (GI(50)) 值为 0.037 和 0.035 μM，选择性指数为 252 和 0.035 μM。分别为300。 SAL 的水杨基异羟肟酸缀合物（化合物 9）以及苯甲基异羟肟酸和水杨基异羟肟酸缀合物 10（化合物 11 和 12）也显示出良好的杀锥虫活性，GI（50）值在 0.032 至 0.035 μM 之间，但选择性较差。研究结果证实，SAL 的修饰可以产生具有改善的杀锥虫活性的衍生物，这可能是进一步抗锥虫药物开发的有趣的先导化合物。 (C) 2019 Elsevier Masson SAS。版权所有。
As a group of biologically active compounds, polyether antibiotics (ionophores) show a broad spectrum of interesting pharmacological properties, ranging from anti-bacterial to anti-cancer activities. There is increasing evidence that ionophores, including salinomycin (SAL), and their semi-synthetic analogues are promising candidates for the development of drugs against parasitic diseases. Our previous studies have shown that esterification and amidation of the Cl carboxylate moiety of SAL provides compounds with potent activity against Trypanosoma brucei, protozoan parasites responsible for African trypanosomiasis. In this paper, we present the synthetic pathways, crystal structures and anti-trypanosomal activity of Cl esters, amides and hydroxamic acid conjugates of SAL, its C20-oxo and propargylamine analogues as well novel Cl/C20 doubly modified derivatives. Evaluation of the trypanocidal and cytotoxic activity using bloodstream forms of T. brucei and human myeloid HL-60 cells revealed that the single modified C20-oxo and propargylamine precursor molecules 10 and 16 were the most anti-trypanosomal and selective compounds with 50% growth inhibition (GI(50)) values of 0.037 and 0.035 mu M, and selectivity indices of 252 and 300, respectively. Also the salicylhydroxamic acid conjugate of SAL (compound 9) as well as benzhydroxamic acid and salicylhydroxamic acid conjugates of 10 (compounds 11 and 12) showed promising trypanocidal activities with GI(50) values between 0.032 and 0.035 mu M but less favorable selectivities. The findings confirm that modification of SAL can result in derivatives with improved trypanocidal activity that might be interesting lead compounds for further anti-trypanosomal drug development. (C) 2019 Elsevier Masson SAS. All rights reserved.