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

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

  • J Med Chem. 2017 Feb 23;60(4):1509-1522. doi: 10.1021/acs.jmedchem.6b01740.
Francisco José Fueyo González 1,  Godwin U Ebiloma 2 3,  Carolina Izquierdo García 1,  Victor Bruggeman 1,  José María Sánchez Villamañán 1,  Anne Donachie 2,  Emmanuel Oluwadare Balogun 4 5,  Daniel Ken Inaoka 4 6,  Tomoo Shiba 7,  Shigeharu Harada 7,  Kiyoshi Kita 4 6,  Harry P de Koning 2,  Christophe Dardonville 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 2 Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8TA, United Kingdom.
  • 3 Department of Biochemistry, Kogi State University , Anyigba 1008, Nigeria.
  • 4 Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo , Tokyo 113-0033, Japan.
  • 5 Department of Biochemistry, Ahmadu Bello University , Zaria 2222, Nigeria.
  • 6 School of Tropical Medicine and Global Health, Nagasaki University , Nagasaki, 852-8523, Japan.
  • 7 Department of Applied Biology, Kyoto Institute of Technology , Kyoto 606-8585, Japan.
PMID: 28112515 DOI: 10.1021/acs.jmedchem.6b01740
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.

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