期刊
ACS INFECTIOUS DISEASES
卷 6, 期 8, 页码 2045-2056出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.0c00105
关键词
Trypanosoma brucei; purine nucleoside; nucleoside transporter
资金
- FWO-Flanders
- Science Without Borders (CNPq, Brazil) [206385/2014-5]
- Taif University
- Saudi Ministry of Health
- Petroleum Technology Development Fund of Nigeria
- University of Antwerp [TT-ZAPBOF 33049]
- FWO [G013118N]
- Hercules Foundation [AUGE/17/22 Pharm-NMR]
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.
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