Revisiting Pyrazolo[3,4‑d]pyrimidine Nucleosides as Anti-Trypanosoma cruzi and Antileishmanial Agents

Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of de novo purine s...

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Published inJournal of medicinal chemistry Vol. 64; no. 7; pp. 4206 - 4238
Main Authors Bouton, Jakob, Ferreira de Almeida Fiuza, Ludmila, Cardoso Santos, Camila, Mazzarella, Maria Angela, Soeiro, Maria de Nazaré Correia, Maes, Louis, Karalic, Izet, Caljon, Guy, Van Calenbergh, Serge
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 08.04.2021
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
CHRONIC PHASE
IN-VITRO
HEART-TRANSPLANTATION
PYRAZOLOPYRIMIDINE NUCLEOSIDES
BIOLOGICAL-ACTIVITY
CHAGAS-DISEASE
INOSINE ANALOGS
PURINE ANALOGS
LEISHMANIA-DONOVANI
AMERICAN LEISHMANIA
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Summary:Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of de novo purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3′-position led to analogues with potent anti-Trypanosoma brucei and anti-Trypanosoma cruzi activities. In this work, we report the design and synthesis of pyrazolo­[3,4-d]­pyrimidine nucleosides with 3′- and 7-modifications and assess their potential as anti-Trypanosoma cruzi and antileishmanial agents. One compound was selected for in vivo evaluation in an acute Chagas disease mouse model.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00135