Discovery of Pyrrolo[2,3‑b]pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-Trypanosoma cruzi Agents
Posted on 2019-09-20 - 18:03
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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Lin, Cai; Hulpia, Fabian; da Silva, Cristiane França; Batista, Denise da Gama Jaen; Van Hecke, Kristof; Maes, Louis; et al. (2019). Discovery of Pyrrolo[2,3‑b]pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-Trypanosoma cruzi Agents. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.9b01275