Synthesis and evaluation of a collection of purine-like C-nucleosides as antikinetoplastid agents.
Eur J Med Chem
; 212: 113101, 2021 Feb 15.
Article
in En
| MEDLINE
| ID: mdl-33385837
ABSTRACT
The kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are the causative agents of neglected tropical diseases with a serious burden in several parts of the world. These parasites are incapable of synthesizing purines de novo, and therefore rely on ingenious purine salvage pathways to acquire and process purines from their host. Purine nucleoside analogs that may interfere with these pathways therefore constitute a privileged source of new antikinetoplastid agents. In this study, we synthetized a collection of C-nucleosides employing five different heterocyclic nucleobase surrogates. C-nucleosides are chemically and enzymatically stable and allow for extensive structural modification. Inspired by earlier 7-deazaadenosine nucleosides and known antileishmanial C-nucleosides, we introduced different modifications tailored towards antikinetoplastid activity. Both adenosine and inosine analogs were synthesized with the aim of discovering new antikinetoplastid hits and expanding knowledge of structure-activity relationships. Several promising hits with potent activity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum were discovered, and the nature of the nucleobase surrogate was found to have a profound influence on the selectivity profile of the compounds.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Trypanosoma brucei brucei
/
Trypanosoma cruzi
/
Leishmania infantum
/
Antiprotozoal Agents
/
Nucleosides
Language:
En
Journal:
Eur J Med Chem
Year:
2021
Document type:
Article
Affiliation country:
Belgium