title: Conjugates of 2,4-Dihydroxybenzoate and Salicylhydroxamate and Lipocations Display Potent Antiparasite Effects by Efficiently Targeting the Trypanosoma brucei and Trypanosoma congolense Mitochondrion.
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.
authors.affiliation: Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Fueyo González
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8TA, United Kingdom.|Department of Biochemistry, Kogi State University , Anyigba 1008, Nigeria.
authors.forename: Godwin U
authors.initials: GU
authors.lastname: Ebiloma
authors.affiliation: Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Izquierdo García
authors.affiliation: Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Bruggeman
authors.affiliation: Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Sánchez Villamañán
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8TA, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Donachie
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo , Tokyo 113-0033, Japan.|Department of Biochemistry, Ahmadu Bello University , Zaria 2222, Nigeria.
authors.forename: Emmanuel Oluwadare
authors.initials: EO
authors.lastname: Balogun
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo , Tokyo 113-0033, Japan.|School of Tropical Medicine and Global Health, Nagasaki University , Nagasaki, 852-8523, Japan.
authors.forename: Daniel Ken
authors.initials: DK
authors.lastname: Inaoka
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology , Kyoto 606-8585, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Shiba
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology , Kyoto 606-8585, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Harada
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo , Tokyo 113-0033, Japan.|School of Tropical Medicine and Global Health, Nagasaki University , Nagasaki, 852-8523, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8TA, United Kingdom.
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.affiliation: Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Christophe
authors.identifier: 0000-0001-5395-1932
authors.initials: C
authors.lastname: Dardonville
mesh_terms: D002460:Cell Line; D055808:Drug Discovery; D006801:Humans; D062385:Hydroxybenzoates / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D012457:Salicylamides / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism; D014348:Trypanosoma congolense / Q000187:drug effects* / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D062385:Hydroxybenzoates; D012457:Salicylamides; D014344:Trypanocidal Agents; C005703:salicylhydroxamic acid; C017704:beta-resorcylic acid