2. Academic Validation
  3. Discovery of Pyrrolo[2,3- b]pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti- Trypanosoma cruzi Agents

Discovery of Pyrrolo[2,3- b]pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti- Trypanosoma cruzi Agents

  • J Med Chem. 2019 Oct 10;62(19):8847-8865. doi: 10.1021/acs.jmedchem.9b01275.
Cai Lin 1,  Fabian Hulpia 1,  Cristiane França da Silva 2,  Denise da Gama Jaen Batista 2,  Kristof Van Hecke 3,  Louis Maes 4,  Guy Caljon 4,  Maria de Nazaré C Soeiro 2,  Serge Van Calenbergh 1
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry (Campus Heymans) , Ghent University , Ottergemsesteenweg 460 , B-9000 Gent , Belgium.
  • 2 Laboratório de Biologia Celular , Instituto Oswaldo Cruz (FIOCRUZ) , Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos , 21040-360 Rio de Janeiro , Brazil.
  • 3 XStruct, Department of Chemistry , Ghent University , Krijgslaan 281 S3 , B-9000 Gent , Belgium.
  • 4 Laboratory of Microbiology, Parasitology and Hygiene , University of Antwerp , Universiteitsplein 1 (S7) , B-2610 Wilrijk , Belgium.
PMID: 31495177 DOI: 10.1021/acs.jmedchem.9b01275
Abstract

Trypanosoma cruzi is the causative pathogen of Chagas disease and the main culprit for cardiac-related mortality in Latin-America triggered by an infective agent. Incapable of synthesizing purines de novo, this Parasite depends on acquisition and processing of host-derived purines, making purine (nucleoside) analogues a potential source of antitrypanosomal agents. In this respect, hitherto 7-deazaadenosine (tubercidin) analogues attracted most attention. Here, we investigated analogues with an additional nitrogen (N1) removed. Structure-activity relationship investigation showed that C7 modification afforded analogues with potent antitrypanosomal activity. Halogens and small, linear carbon-based substituents were preferred. Compound 11 proved most potent in vitro, showed full suppression of parasitemia in a mouse model of acute Infection, and elicited 100% animal survival after oral dosing at 25 mg/kg b.i.d. for 5 and 15 days. Cyclophosphamide-induced immunosuppression led to recrudescence. Washout experiments demonstrated a lack of complete clearance of infected cell cultures, potentially explaining the in vivo results.

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