posted on 2021-03-30, 20:04authored byJakob Bouton, Ludmila Ferreira de Almeida Fiuza, Camila Cardoso Santos, Maria Angela Mazzarella, Maria de Nazaré Correia Soeiro, Louis Maes, Izet Karalic, Guy Caljon, Serge Van Calenbergh
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.