Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion
| Autor: | Kiyoshi Kita, Emmanuel Oluwadare Balogun, Francisco José Fueyo González, Daniel Ken Inaoka, Harry P. de Koning, Victor Bruggeman, Godwin U. Ebiloma, Shigeharu Harada, Tomoo Shiba, Anne M. Donachie, José María Sánchez Villamañán, Christophe Dardonville, Carolina Izquierdo García |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Alternative oxidase Trypanosoma congolense Trypanosoma brucei brucei Mitochondrion Trypanosoma brucei Cell Line 03 medical and health sciences chemistry.chemical_compound Salicylamides Drug Discovery Hydroxybenzoates Humans Potency Membrane Potential Mitochondrial biology Cell cycle biology.organism_classification Trypanocidal Agents Salicylhydroxamic acid Mitochondria Multiple drug resistance Trypanosomiasis African 030104 developmental biology chemistry Biochemistry Trypanosoma Molecular Medicine |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1520-4804 0022-2623 2015-6669 |
| Popis: | 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. The logistical collaboration of Drs. Jagerovic, Goya, and Herranz is gratefully acknowledged. 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 |
| Databáze: | OpenAIRE |
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