title: Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity.
abstract: Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.
authors: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors: Irene
authors: I
authors: Sola
authors: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors: Sílvia
authors: S
authors: Castellà
authors: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors: Elisabet
authors: E
authors: Viayna
authors: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors: Carles
authors: C
authors: Galdeano
authors: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
authors: Martin C
authors: MC
authors: Taylor
authors: Bradford School of Pharmacy, University of Bradford, West Yorkshire BD7 1 DP, United Kingdom; Department of Pharmaceutics, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors: Stephen Y
authors: SY
authors: Gbedema
authors: Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: Belén
authors: B
authors: Pérez
authors: Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain.
authors: M Victòria
authors: MV
authors: Clos
authors: Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors: Deuan C
authors: DC
authors: Jones
authors: Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors: Alan H
authors: AH
authors: Fairlamb
authors: Bradford School of Pharmacy, University of Bradford, West Yorkshire BD7 1 DP, United Kingdom.
authors: Colin W
authors: CW
authors: Wright
authors: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
authors: John M
authors: JM
authors: Kelly
authors: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain. Electronic address: dmunoztorrero@ub.edu.
authors: Diego
authors: D
authors: Muñoz-Torrero
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D006420:Hemeproteins; D014344:Trypanocidal Agents; C020753:hemozoin; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; C001920:4-aminoquinoline
keywords: Antimalarial agents; Brain permeability; Inhibitors of β-haematin formation; Molecular hybridization; Trypanocidal agents; Trypanothione reductase inhibitors