Blank Brian R, Gut Jiri, Rosenthal Philip J, Renslo Adam R
Department of Pharmaceutical Chemistry and ‡Department of Medicine, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
J Med Chem. 2017 Jul 27;60(14):6400-6407. doi: 10.1021/acs.jmedchem.7b00699. Epub 2017 Jul 10.
We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. Conformational analysis suggested that trans-3″-substituted trioxolanes would exhibit Fe(II) reactivity and antiparasitic activity similar to that achieved with canonical cis-4″ substitution. The chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria model. As predicted, the trans-3″ analogues exhibited in vitro antiplasmodial activity remarkably similar to that of their cis-4″ comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3″ analogues (e.g., 12i) outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials.
我们描述了对具有与蒿甲醚区域异构体取代模式的抗疟1,2,4 - 三氧杂环戊烷的首次系统研究。构象分析表明，反式-3″-取代的三氧杂环戊烷将表现出与典型顺式-4″取代所达到的类似的Fe(II)反应性和抗寄生虫活性。手性3″类似物被制备为单一立体异构体，并与其4″同系物一起针对培养的疟原虫和在鼠疟模型中进行评估。如所预测的，反式-3″类似物表现出与它们的顺式-4″对照物非常相似的体外抗疟原虫活性。相比之下，对于一些同系物对，伯氏疟原虫小鼠模型中的疗效差异很大。新型3″类似物中最好的（例如12i）优于蒿甲醚本身，单次口服给药后可使小鼠治愈。总体而言，这项研究为调节Fe(II)反应性以及1,2,4 - 三氧杂环戊烷抗疟药的药代动力学和药效学性质提出了新途径。
