Conjugates of 2,4-dihydroxybenzoate and salicylhydroxamate and lipocations display potent antiparasite effects by efficiently targeting the Trypanosoma brucei and Trypanosoma congolense mitochondrion

Fueyo González, F. J. et al. (2017) Conjugates of 2,4-dihydroxybenzoate and salicylhydroxamate and lipocations display potent antiparasite effects by efficiently targeting the Trypanosoma brucei and Trypanosoma congolense mitochondrion. Journal of Medicinal Chemistry, 60(4), pp. 1509-1522. (doi:10.1021/acs.jmedchem.6b01740) (PMID:28112515)

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Abstract

We investigated a chemical strategy to boost the trypanocidal activity of 2,4-dihydroxybenzoic acid (2,4-DHBA)- and salicylhydroxamic acid (SHAM)-based trypanocides with triphenylphosphonium and quinolinium lipophilic cations (LC). Three series of LC conjugates were synthesized that were active in the submicromolar (5a–d and 10d–f) to low nanomolar (6a–f) range against wild-type and multidrug resistant strains of African trypanosomes (Trypanosoma brucei brucei and T. congolense). This represented an improvement in trypanocidal potency of at least 200-fold, and up to >10 000-fold, compared with that of non-LC-coupled parent compounds 2,4-DHBA and SHAM. Selectivity over human cells was >500 and reached >23 000 for 6e. Mechanistic studies showed that 6e did not inhibit the cell cycle but affected parasite respiration in a dose-dependent manner. Inhibition of trypanosome alternative oxidase and the mitochondrial membrane potential was also studied for selected compounds. We conclude that effective mitochondrial targeting greatly potentiated the activity of these series of compounds.

Item Type:Articles
Additional Information:This work was funded by the Spanish Ministerio de Economia y Competitividad (SAF2015-66690-R). G.U.E. was supported by a TET-fund studentship from the government of Nigeria and by a Mac Robertson Travel Scholarship from the College of Medical, Veterinary and Life Sciences of the University of Glasgow.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Donachie, Ms Anne Marie and De Koning, Professor Harry
Authors: Fueyo González, F. J., Ebiloma, G. U., Izquierdo García, C., Bruggeman, V., Sánchez Villamañán, J. M., Donachie, A., Balogun, E. O., Inaoka, D. K., Shiba, T., Harada, S., Kita, K., de Koning, H. P., and Dardonville, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN:0022-2623
ISSN (Online):1520-4804
Published Online:23 January 2017
Copyright Holders:Copyright © 2017 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 60(4): 1509-1522
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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