Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion

Francisco José Fueyo González, Godwin U. Ebiloma, Carolina Izquierdo García, Victor Bruggeman, José María Sánchez Villamañán, Anne Donachie, Emmanuel Oluwadare Balogun, Daniel Ken Inaoka, Tomoo Shiba, Shigeharu Harada, Kiyoshi Kita, Harry P. De Koning, Christophe Dardonville

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1509-1522
JournalJournal of Medicinal Chemistry
Volume60
Issue number4
Early online date9 Feb 2017
DOIs
Publication statusPublished - 23 Feb 2017

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