Synthesis and evaluation of a collection of purine-like C-nucleosides as antikinetoplastid agents.

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. Image 1 • A collection of purine-like C -nucleosides comprising five different heterocyclic nucleobase surrogates was synthesized. • Modifications tailored towards antikinetoplastid activity were introduced. • Promising hits for Trypanosoma brucei , Trypanosoma cruzi and Leishmania infantum were discovered. • The nature of the heterocyclic nucleobase surrogate had a profound influence on the selectivity profile of the compounds. [ABSTRACT FROM AUTHOR]