Revisiting tubercidin against kinetoplastid parasites: Aromatic substitutions at position 7 improve activity and reduce toxicity

Hulpia, F., Campagnaro, G. D., Scortichini, M., Van Hecke, K., Maes, L., de Koning, H. P. , Caljon, G. and Van Calenbergh, S. (2019) Revisiting tubercidin against kinetoplastid parasites: Aromatic substitutions at position 7 improve activity and reduce toxicity. European Journal of Medicinal Chemistry, 164, pp. 689-705. (doi:10.1016/j.ejmech.2018.12.050)

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Abstract

The nucleoside antibiotic tubercidin displays strong activity against different target organisms, but it is notoriously toxic to mammalian cells. The effects of tubercidin against T. brucei parasites inspired us to synthesize several C7 substituted analogs for in vitro evaluation in order to find suitable hit compounds. C7 Deazaadenosines substituted with electron-poor phenyl groups were found to have micromolar activity against T. brucei in vitro. Replacement of the phenyl for a pyridine ring gave compound 13, with submicromolar potency and much-attenuated cytotoxicity compared to tubercidin. The veterinary pathogen T. congolense was equally affected by 13 in vitro. Transporter studies in T. b. brucei indicated that 13 is taken up efficiently by both the P1 and P2 adenosine transporters, making the occurrence of transporter-related resistance and cross-resistance with diamidine drugs such as diminazene aceturate and pentamidine as well as with melaminophenyl arsenicals unlikely. Evaluation of the in vitro metabolic stability of analog 13 indicated that this analog was significantly metabolized in mouse microsomal fractions, precluding further in vivo evaluation in mouse models of HAT.

Item Type:Articles
Additional Information:F.H. is indebted to the FWO-Flanders for a PhD-scholarship. G.D.C. thanks Science Without Borders for his scholarship (206385/2014-5, CNPq, Brazil). M.S. thanks the University of Camerino, International School for Advanced Studies and an Erasmus Plus fellowship for funding. KVH thanks the Hercules Foundation (project AUGE/11/029 “3D-SPACE: 3D Structural Platform Aiming for Chemical Excellence”) and the Special Research Fund (BOF) – UGent for funding. 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 (GC, LM, SVC; project number G013118N).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Campagnaro, Gustavo and De Koning, Professor Harry
Authors: Hulpia, F., Campagnaro, G. D., Scortichini, M., Van Hecke, K., Maes, L., de Koning, H. P., Caljon, G., and Van Calenbergh, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:European Journal of Medicinal Chemistry
Publisher:Elsevier
ISSN:0223-5234
ISSN (Online):1768-3254
Published Online:21 December 2018
Copyright Holders:Copyright © 2018 Elsevier Masson SAS
First Published:First published in European Journal of Medicinal Chemistry 164: 689-705
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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