Structure-Activity Relationship Exploration of 3'-Deoxy-7-deazapurine Nucleoside Analogues as Anti-Trypanosoma brucei Agents.,ACS Infectious Diseases

当前位置： X-MOL 学术 › ACS Infect. Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Structure-Activity Relationship Exploration of 3'-Deoxy-7-deazapurine Nucleoside Analogues as Anti-Trypanosoma brucei Agents.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-06-22 , DOI: 10.1021/acsinfecdis.0c00105
Fabian Hulpia ₁ , Gustavo D Campagnaro ₂ , Khalid J Alzahrani _{2,

3} , Ibrahim A Alfayez ₂ , Marzuq A Ungogo _{2,

4} , Dorien Mabille ₅ , Louis Maes ₅ , Harry P de Koning ₂ , Guy Caljon ₅ , Serge Van Calenbergh ₁

Affiliation

Human African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei parasites. These protists are unable to produce the purine ring, making them vulnerable to the effects of purine nucleoside analogues. Starting from 3′-deoxytubercidin (5), a lead compound with activity against central-nervous-stage human African trypanosomiasis, we investigate the structure–activity relationships of the purine and ribofuranose rings. The purine ring tolerated only modifications at C7, while from the many alterations of the 3′-deoxyribofuranosyl moiety only the arabino analogue 48 showed pronounced antitrypanosomal activity. Profiling of the most potent analogues against resistant T. brucei strains (resistant to pentamidine, diminazene, and isometamidium) showed reduced dependence on uptake mediated by the P2 aminopurine transporter relative to 5. The introduction of a 7-substituent confers up to 10-fold increased affinity for the P1 nucleoside transporter while generally retaining high affinity for P2. Four of the most promising analogues were found to be metabolically stable, earmarking them as suitable backup analogues for lead 5.

中文翻译：

3'-脱氧-7-脱氮嘌呤核苷类似物作为布鲁氏锥虫的构效关系研究。

人类非洲锥虫病是一种由布鲁氏锥虫寄生虫引起的被忽视的热带病。这些原生生物不能产生嘌呤环，使其容易受到嘌呤核苷类似物的影响。从3'-deoxytubercidin（5）（一种对中枢神经阶段人类非洲锥虫病具有活性的先导化合物）开始，我们研究了嘌呤和呋喃核糖环的结构-活性关系。嘌呤环仅耐受C7处的修饰，而从3'-脱氧核糖呋喃糖基部分的许多改变中，只有阿拉伯类似物48显示出显着的抗锥虫活性。分析最有效的抗布鲁氏杆菌的类似物株（耐喷他脒，diminazene和isometamidium）显示减少了对摄取P2氨基嘌呤相对于转运蛋白介导的依赖5。7位取代基的引入使对P1核苷转运蛋白的亲和力提高了10倍，而通常保持对P2的高亲和力。发现四个最有前途的类似物在代谢上稳定，将它们指定为铅5的合适后备类似物。

更新日期：2020-08-14

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11