|
Title
|
|
|
|
Discovery of novel 7-aryl 7-deazapurine 3′-deoxy-ribofuranosyl nucleosides with potent activity against Trypanosoma cruzi
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Chagas disease is the leading cause of cardiac-related mortality in Latin American countries where it is endemic. Trypanosoma cruzi, the disease-causing pathogen, is unable to synthesize purines de novo, necessitating salvage of preformed host purines. Therefore, purine and purine-nucleoside analogues might constitute an attractive source for identifying antitrypanosomal hits. In this study, structural elements of two purine-nucleoside analogues (i.e., cordycepin and a recently discovered 7-substituted 7-deazaadenosine) led to the identification of novel nucleoside analogues with potent in vitro activity. The structureactivity relationships of substituents at C-7 were investigated, ultimately leading to the selection of compound 5, with a C-7 para-chlorophenyl group, for in vivo evaluation. This derivative showed complete suppression of T. cruzi Y-strain blood parasitemia when orally administered twice daily for 5 days at 25 mg/kg and was able to protect infected mice from parasite-induced mortality. However, sterile cure by immunosuppression could not be demonstrated. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
| |
|
Publication
|
|
|
|
Washington, D.C.
:
2018
| |
|
ISSN
|
|
|
|
0022-2623
[print]
1520-4804
[online]
| |
|
Volume/pages
|
|
|
|
61
:20
(2018)
, p. 9287-9300
| |
|
ISI
|
|
|
|
000448754900020
| |
|
Pubmed ID
|
|
|
|
30234983
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|
Full text (publisher's version - intranet only)
|
|
|
|
| |
|