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Discovery of pyrrolo[2,3-b]pyridine (1,7-dideazapurine) nucleoside analogues as anti-Trypanosoma cruzi agents.

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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. Uncapable of synthesizing purines de novo, this… Click to show full 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. Uncapable 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 five and fifteen 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.

Keywords: pyridine dideazapurine; pyrrolo pyridine; nucleoside analogues; trypanosoma cruzi; discovery pyrrolo

Journal Title: Journal of medicinal chemistry
Year Published: 2019

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