Evaluation of the antiprotozoan properties of 5'-norcarbocyclic pyrimidine nucleosides

Alzahrani, K. J., Matyugina, E. S., Khandazhinskaya, A. L., Kochetkov, S. N., Seley-Radtke, K. L. and de Koning, H. P. (2017) Evaluation of the antiprotozoan properties of 5'-norcarbocyclic pyrimidine nucleosides. Bioorganic and Medicinal Chemistry Letters, 27(14), pp. 3081-3086. (doi:10.1016/j.bmcl.2017.05.052) (PMID:28571825)

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Abstract

Carbocyclic nucleoside analogues have a distinguished history as anti-infectious agents, including key antiviral agents. Toxicity was initially a concern but this was reduced by the introduction of 5'-nor variants. Here, we report the result of our preliminary screening of a series of 5'-norcarbocyclic uridine analogues against protozoan parasites, specifically the major pathogens Leishmania mexicana and Trypanosoma brucei. The series displayed antiparasite activity in the low to mid-micromolar range and establishes a preliminary structure-activity relationship, with the 4',N(3)-di-(3,5-dimethylbenzoyl)-substituted analogues showing the most prominent activity. Utilizing an array of specially adapted cell lines, it was established that this series of analogues likely act through a common target. Moreover, the strong correlation between the trypanocidal and anti-leishmanial activities indicates that this mechanism is likely shared between the two species. EC50 values were unaffected by the disabling of pyrimidine biosynthesis in T. brucei, showing that these uridine analogues do not act directly on the enzymes of pyrimidine nucleotide metabolism. The lack of cross-resistance with 5-fluorouracil, also establishes that the carbocyclic analogues are not imported through the known uracil transporters, thus offering forth new insights for this class of nucleosides. The lack of cross-resistance with current trypanocides makes this compound class interesting for further exploration.

Item Type:Articles
Additional Information:K.J.A. is funded through a PhD studentship from Taif University, Taif, Saudi Arabia. Chemical synthesis and physico-chemical characterization of compounds (E.S.M, A.L.K and S.N.K) were supported by Russian Science Foundation Project № 14-50-00060.
Keywords:Carbocyclic nucleoside, leishmania, pyrimidine, Trypanosoma brucei, uracil.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Alzahrani, Khalid Jamaan and De Koning, Professor Harry
Authors: Alzahrani, K. J., Matyugina, E. S., Khandazhinskaya, A. L., Kochetkov, S. N., Seley-Radtke, K. L., and de Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Bioorganic and Medicinal Chemistry Letters
Publisher:Elsevier
ISSN:0960-894X
ISSN (Online):1464-3405
Published Online:17 May 2017
Copyright Holders:Copyright © 2017 Elsevier Ltd.
First Published:First published in Bioorganic and Medicinal Chemistry Letters 27(14): 3081-3086
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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