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

(2019) JOURNAL OF MEDICINAL CHEMISTRY. 62(19). p.8847-8865
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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.
Keywords
CHAGAS-DISEASE, GLYCOSYLATION, TUBERCIDIN, INFECTION, ANTITUMOR, PHASE

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Citation

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MLA
Lin, Cai, et al. “Discovery of Pyrrolo[2,3-b]Pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-Trypanosoma Cruzi Agents.” JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 19, 2019, pp. 8847–65.
APA
Lin, C., Hulpia, F., da Silva, C. F., Batista, D. da G. J., Van Hecke, K., Maes, L., … Van Calenbergh, S. (2019). Discovery of pyrrolo[2,3-b]pyridine (1,7-dideazapurine) nucleoside analogues as anti-Trypanosoma cruzi agents. JOURNAL OF MEDICINAL CHEMISTRY, 62(19), 8847–8865.
Chicago author-date
Lin, Cai, Fabian Hulpia, Cristiane França da Silva, Denise da Gama Jaén Batista, Kristof Van Hecke, Louis Maes, Guy Caljon, Maria de Nazaré Correia Soeiro, and Serge Van Calenbergh. 2019. “Discovery of Pyrrolo[2,3-b]Pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-Trypanosoma Cruzi Agents.” JOURNAL OF MEDICINAL CHEMISTRY 62 (19): 8847–65.
Chicago author-date (all authors)
Lin, Cai, Fabian Hulpia, Cristiane França da Silva, Denise da Gama Jaén Batista, Kristof Van Hecke, Louis Maes, Guy Caljon, Maria de Nazaré Correia Soeiro, and Serge Van Calenbergh. 2019. “Discovery of Pyrrolo[2,3-b]Pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-Trypanosoma Cruzi Agents.” JOURNAL OF MEDICINAL CHEMISTRY 62 (19): 8847–8865.
Vancouver
1.
Lin C, Hulpia F, da Silva CF, Batista D da GJ, Van Hecke K, Maes L, et al. Discovery of pyrrolo[2,3-b]pyridine (1,7-dideazapurine) nucleoside analogues as anti-Trypanosoma cruzi agents. JOURNAL OF MEDICINAL CHEMISTRY. 2019;62(19):8847–65.
IEEE
[1]
C. Lin et al., “Discovery of pyrrolo[2,3-b]pyridine (1,7-dideazapurine) nucleoside analogues as anti-Trypanosoma cruzi agents,” JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 19, pp. 8847–8865, 2019.
@article{8627542,
  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.},
  author       = {Lin, Cai and Hulpia, Fabian and da Silva, Cristiane França and Batista, Denise da Gama Jaén and Van Hecke, Kristof and Maes, Louis and Caljon, Guy and Soeiro, Maria de Nazaré Correia and Van Calenbergh, Serge},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keywords     = {CHAGAS-DISEASE,GLYCOSYLATION,TUBERCIDIN,INFECTION,ANTITUMOR,PHASE},
  language     = {eng},
  number       = {19},
  pages        = {8847--8865},
  title        = {Discovery of pyrrolo[2,3-b]pyridine (1,7-dideazapurine) nucleoside analogues as anti-Trypanosoma cruzi agents},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.9b01275},
  volume       = {62},
  year         = {2019},
}

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