1. Academic Validation
  2. Synthesis and evaluation of 3'-fluorinated 7-deazapurine nucleosides as antikinetoplastid agents

Synthesis and evaluation of 3'-fluorinated 7-deazapurine nucleosides as antikinetoplastid agents

  • Eur J Med Chem. 2021 Apr 15:216:113290. doi: 10.1016/j.ejmech.2021.113290.
Jakob Bouton 1 Arno Furquim d'Almeida 1 Louis Maes 2 Guy Caljon 2 Serge Van Calenbergh 3 Fabian Hulpia 1
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium.
  • 2 Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7), B-2610, Wilrijk, Belgium.
  • 3 Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium. Electronic address: serge.vancalenbergh@ugent.be.
Abstract

Kinetoplastid parasites are the causative agents of neglected tropical diseases with an unmet medical need. These parasites are unable to synthesize the purine ring de novo, and therefore rely on purine salvage to meet their purine demand. Evaluating purine nucleoside analogs is therefore an attractive strategy to identify antikinetoplastid agents. Several anti-Trypanosoma cruzi and anti-Trypanosoma brucei 7-deazapurine nucleosides were previously discovered, with the removal of the 3'-hydroxyl group resulting in a significant boost in activity. In this work we therefore decided to assess the effect of the introduction of a 3'-fluoro substituent in 7-deazapurine nucleosides on the anti-kinetoplastid activities. Hence, we synthesized two series of 3'-deoxy-3'-fluororibofuranosyl and 3'-deoxy-3'-fluoroxylofuranosyl nucleosides comprising 7-deazaadenine and -hypoxanthine Bases and assayed these for antiparasitic activity. Several analogs with potent activity against T. cruzi and T. brucei were discovered, indicating that a fluorine atom in the 3'-position is a promising modification for the discovery of antiparasitic nucleosides.

Keywords

3′-fluoronucleoside; 7-deazapurine; Kinetoplastid; Trypanosoma brucei; Trypanosoma cruzi.

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