C6–O-alkylated 7-deazainosine nucleoside analogues: Discovery of potent and selective anti-sleeping sickness agents

Hulpia, F., Bouton, J., Campagnaro, G. D., Alfayez, I. A., Mabille, D., Maes, L., de Koning, H. P. , Caljon, G. and Van Calenbergh, S. (2020) C6–O-alkylated 7-deazainosine nucleoside analogues: Discovery of potent and selective anti-sleeping sickness agents. European Journal of Medicinal Chemistry, 188, 112018. (doi: 10.1016/j.ejmech.2019.112018) (PMID: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.

• Item Type: Articles
• Additional Information: F.H. thanks the FWO-Flanders for a PhD-scholarship. G.D.C. also thanks Science Without Borders for his scholarship (206385/2014-5, CNPq, Brazil). I.A.A. is grateful to the Saudi Ministry of Health for a PhD studentship. G.C. is supported by a research fund of the University of Antwerp (TT-ZAPBOF 33049). The present work has been funded by the FWO-Flanders (GC, LM, SVC; project number G013118N).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: ALFAYEZ, IBRAHIM ABDULLAH M and Campagnaro, Gustavo and De Koning, Professor Harry
• Authors: Hulpia, F., Bouton, J., Campagnaro, G. D., Alfayez, I. A., Mabille, D., Maes, L., de Koning, H. P., Caljon, G., and Van Calenbergh, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: European Journal of Medicinal Chemistry
• Publisher: Elsevier
• ISSN: 0223-5234
• ISSN (Online): 1768-325
• Published Online: 03 January 2020
• Copyright Holders: Copyright © 2020 Elsevier Masson SAS
• First Published: First published in European Journal of Medicinal Chemistry 188:112018
• Publisher Policy: Reproduced in accordance with the publisher copyright policy