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ID: ALA4382200
Journal: J Med Chem
Title: Discovery of Novel 7-Aryl 7-Deazapurine 3'-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi.
Authors: Hulpia F, Van Hecke K, França da Silva C, da Gama Jaen Batista D, Maes L, Caljon G, de Nazaré C Soeiro M, Van Calenbergh S.
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 structure-activity 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.
CiteXplore: 30234983