Revisiting Pyrazolo[3,4-<i>d</i>]pyrimidine Nucleosides as Anti-<i>Trypanosoma cruzi</i> and Antileishmanial Agents

Abstract

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 <i>de novo</i> 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-<i>Trypanosoma</i> brucei and anti-<i>Trypanosoma cruzi</i> activities. In this work, we report the design and synthesis of pyrazolo[3,4-<i>d</i>]pyrimidine nucleosides with 3'- and 7-modifications and assess their potential as anti-<i>Trypanosoma cruzi</i> and antileishmanial agents. One compound was selected for <i>in vivo</i> evaluation in an acute Chagas disease mouse model.