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Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 Feb 23; Vol. 60 (4), pp. 1509-1522. Date of Electronic Publication: 2017 Feb 09. - Publication Year :
- 2017
-
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.
- Subjects :
- Cell Line
Drug Discovery
Humans
Hydroxybenzoates chemistry
Membrane Potential, Mitochondrial drug effects
Mitochondria drug effects
Salicylamides chemistry
Trypanocidal Agents chemistry
Trypanosoma brucei brucei metabolism
Trypanosoma congolense metabolism
Trypanosomiasis, African drug therapy
Hydroxybenzoates pharmacology
Salicylamides pharmacology
Trypanocidal Agents pharmacology
Trypanosoma brucei brucei drug effects
Trypanosoma congolense drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28112515
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01740