6-Methyl-7-deazapurine nucleoside analogues as broad-spectrum antikinetoplastid agents

• Main Authors: Cai Lin, Fabian Hulpia, Izet Karalic, Laurens De Schepper, Louis Maes, Guy Caljon, Serge Van Calenbergh
• Format: Article
• Language: English
• Published: Elsevier 2021-12-01
• Series: International Journal for Parasitology: Drugs and Drug Resistance
• Subjects: Nucleosides; Antikinetoplastid agents; Trypanosoma cruzi; Leishmania infantum; Trypanosoma brucei
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211320721000373

Kinetoplastid parasites are the causative agents of Chagas disease (CD), leishmaniasis and human African trypanosomiasis (HAT). Despite a sustained decrease in the number of HAT cases, more efforts are needed to discover safe and effective therapies against CD and leishmaniasis. Kinetoplastid parasites lack the capability to biosynthesize purines de novo and thus critically depend on uptake and processing of purines from host cells. As such, modified purine nucleoside analogues may act as broad-spectrum antikinetoplastid agents. This study assessed the in vitro activity profile of 7-modified 6-methyl tubercidin derivatives against Trypanosoma cruzi, Leishmania infantum, Trypanosoma brucei brucei and T. b. rhodesiense, and led to the identification of analogues that display activity against all these species, such as 7-ethyl (13) and 7-chloro (7) analogues. These selected analogues also proved sufficiently stable in liver microsomes to warrant in vivo follow-up evaluation.