C6-O-alkylated 7-deazainosine nucleoside analogues: Discovery of potent and selective anti-sleeping sickness agents.
Eur J Med Chem
; 188: 112018, 2020 Feb 15.
Article
in En
| MEDLINE
| ID: mdl-31931339
ABSTRACT
African trypanosomiasis, a deadly infectious disease caused by the protozoan Trypanosoma brucei spp., is spread to new hosts by bites of infected tsetse flies. Currently approved therapies all have their specific drawbacks, prompting a search for novel therapeutic agents. T. brucei lacks the enzymes necessary to forge the purine ring from amino acid precursors, rendering them dependent on the uptake and interconversion of host purines. This dependency renders analogues of purines and corresponding nucleosides an interesting source of potential anti-T. brucei agents. In this study, we synthesized and evaluated a series of 7-substituted 7-deazainosine derivatives and found that 6-O-alkylated analogues in particular showed highly promising in vitro activity with EC50 values in the mid-nanomolar range. SAR investigation of the O-alkyl chain showed that antitrypanosomal activity increased, and also cytotoxicity, with alkyl chain length, at least in the linear alkyl chain series. However, this could be attenuated by introducing a terminal branch point, resulting in the highly potent and selective analogues, 36, 37 and 38. No resistance related to transporter-mediated uptake could be identified, earmarking several of these analogues for further in vivo follow-up studies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Trypanocidal Agents
/
Trypanosoma brucei brucei
/
Drug Discovery
/
Inosine
/
Nucleosides
Type of study:
Observational_studies
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2020
Document type:
Article
Affiliation country:
Belgium