1. Academic Validation
  2. Revisiting Pyrazolo[3,4- d]pyrimidine Nucleosides as Anti- Trypanosoma cruzi and Antileishmanial Agents

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

  • J Med Chem. 2021 Apr 8;64(7):4206-4238. doi: 10.1021/acs.jmedchem.1c00135.
Jakob Bouton 1 Ludmila Ferreira de Almeida Fiuza 2 Camila Cardoso Santos 2 Maria Angela Mazzarella 3 Maria de Nazaré Correia Soeiro 2 Louis Maes 4 Izet Karalic 1 Guy Caljon 4 Serge Van Calenbergh 1
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
  • 2 Laboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365, Manguinhos, 21040-360 Rio de Janeiro, Brazil.
  • 3 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, Perugia 06100, Italy.
  • 4 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
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 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.

Figures