Discovery of Novel 7-Aryl 7-Deazapurine 3'-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi

  • J Med Chem. 2018 Oct 25;61(20):9287-9300. doi: 10.1021/acs.jmedchem.8b00999.
Fabian Hulpia  1 ,  Kristof Van Hecke  2 ,  Cristiane França da Silva  3 ,  Denise da Gama Jaen Batista  3 ,  Louis Maes  4 ,  Guy Caljon  4 ,  Maria de Nazaré C Soeiro  3 ,  Serge Van Calenbergh  1
Affiliations
  • 1. Laboratory for Medicinal Chemistry (Campus Heymans) , Ghent University , Ottergemsesteenweg 460 , Gent B-9000 , Belgium.
  • 2. XStruct, Department of Chemistry , Ghent University , Krijgslaan 281 S3 , Gent B-9000 , Belgium.
  • 3. Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ) , Fundação Oswaldo Cruz , Avenida Brasil, 4365 , Manguinhos, Rio de Janeiro , RJ 21040-900 , Brazil.
  • 4. Laboratory of Microbiology, Parasitology and Hygiene , University of Antwerp , Universiteitsplein 1 (S7) , Wilrijk B-2610 , Belgium.
PMID: 30234983 DOI: 10.1021/acs.jmedchem.8b00999
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.