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Discovery of novel 7-aryl 7-deazapurine 3′-deoxy-ribofuranosyl nucleosides with potent activity against Trypanosoma cruzi
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| Abstract |
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| 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. |
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English
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| Source (journal) |
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Journal of medicinal chemistry. - Washington, D.C., 1963, currens | |
| Publication |
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Washington, D.C. : 2018
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0022-2623 [print]
1520-4804 [online]
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61:20(2018), p. 9287-9300
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000448754900020
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30234983
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| Full text (publisher's version - intranet only) |
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