Structure–activity relationship exploration of 3′-deoxy-7-deazapurine nucleoside analogues as anti-Trypanosoma brucei agents
Hulpia, F., Campagnaro, G. D., Alzahrani, K. J., Alfayez, I. A., Ungogo, M. A., Mabille, D., Maes, L., de Koning, H. P. , Caljon, G. and Van Calenbergh, S. (2020) Structure–activity relationship exploration of 3′-deoxy-7-deazapurine nucleoside analogues as anti-Trypanosoma brucei agents. ACS Infectious Diseases, 6(8), pp. 2045-2056. (doi: 10.1021/acsinfecdis.0c00105) (PMID:32568511)
Human African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei parasites. These protists are unable to produce the purine ring, making them vulnerable to the effects of purine nucleoside analogues. Starting from 3′-deoxytubercidin (5), a lead compound with activity against central-nervous-stage human African trypanosomiasis, we investigate the structure–activity relationships of the purine and ribofuranose rings. The purine ring tolerated only modifications at C7, while from the many alterations of the 3′-deoxyribofuranosyl moiety only the arabino analogue 48 showed pronounced antitrypanosomal activity. Profiling of the most potent analogues against resistant T. brucei strains (resistant to pentamidine, diminazene, and isometamidium) showed reduced dependence on uptake mediated by the P2 aminopurine transporter relative to 5. The introduction of a 7-substituent confers up to 10-fold increased affinity for the P1 nucleoside transporter while generally retaining high affinity for P2. Four of the most promising analogues were found to be metabolically stable, earmarking them as suitable backup analogues for lead 5.
F.H. thanks the FWO-Flanders for a Ph.D. scholarship, and G.D.C. thanks Science Without Borders for his Ph.D. scholarship (206385/2014-5, CNPq, Brazil). K.J.A. thanks Taif University for financial support for a research visit to the University of Glasgow. I.A.A. was supported by a Ph.D. studentship from the Saudi Ministry of Health and M.A.U. by a scholarship from the Petroleum Technology Development Fund of Nigeria. G.C. was supported by a research fund of the University of Antwerp (TT-ZAPBOF 33049). The present work was funded by the FWO (G.C., L.M., S.V.C.; Project G013118N). S.V.C. thanks the Hercules Foundation (Project AUGE/17/22 "Pharm-NMR").
Alzahrani, Khalid Jamaan and ALFAYEZ, IBRAHIM ABDULLAH M and Ungogo, Mr Marzuq and Campagnaro, Gustavo and De Koning, Professor Harry
Hulpia, F., Campagnaro, G. D., Alzahrani, K. J., Alfayez, I. A., Ungogo, M. A., Mabille, D., Maes, L., de Koning, H. P., Caljon, G., and Van Calenbergh, S.
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
ACS Infectious Diseases
Copyright © 2020 American Chemical Society
First published in ACS Infectious Diseases 6(8): 2045-2056
Reproduced in accordance with the publisher copyright policy