Web of Science: 42 cites, Scopus: 46 cites, Google Scholar: cites,
Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity
Di Pietro, Ornella (Universitat de Barcelona. Institut de Biomedicina)
Vicente-García, Esther (Barcelona Science Park)
Taylor, Martin C. (Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine)
Berenguer, Diana (Universitat de Barcelona. Departament de Microbiologia i Parasitologia Sanitàries)
Viayna, Elisabet (Universitat de Barcelona. Institut de Biomedicina)
Lanzoni, Anna (Universitat de Barcelona. Institut de Biomedicina)
Sola, Irene (Universitat de Barcelona. Institut de Biomedicina)
Sayago, Helena (Barcelona Science Park)
Riera, Cristina (Universitat de Barcelona. Departament de Microbiologia i Parasitologia Sanitàries)
Fisa, Roser (Universitat de Barcelona. Departament de Microbiologia i Parasitologia Sanitàries)
Clos, M. Victoria (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Pérez, Belén (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Kelly, John M. (Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine)
Lavilla, Rodolfo (Universitat de Barcelona. Laboratori de Química Orgànica)
Muñoz-Torrero López-Ibarra, Diego (Universitat de Barcelona. Institut de Biomedicina)
Universitat Autònoma de Barcelona. Institut de Neurociències

Data: 2015
Resum: Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[ h ][1,6]naphthyridines, pyrrolo[3,2- c ]quinolines, azepino[3,2- c ]quinolines, and pyrano[3,2- c ]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC values of 1. 5 μM, 6. 1 μM and 29. 2 μM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC > 30 μM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.
Ajuts: Ministerio de Ciencia e Innovación CTQ2011-22433, CTQ2012-30930
Nota: This work was supported by Ministerio de Ciencia e Innovacion (MICINN) (CTQ2011-22433, CTQ2012-30930) and Generalitat de Catalunya (GC) (2014SGR52, 2014SGR137, 2014SGR1241). JMK acknowledges funding support from the Wellcome Trust (Grant number WT084175). Fellowships from GC to O.D.P., E.V., and I.S. are gratefully acknowledged.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: Benzo[ h ][1,6]naphthyridines ; Pyrano[3,2- c ]quinolines ; Povarov reaction ; Trypanocidal agents ; Leishmanicidal agents ; Brain permeability
Publicat a: European Journal of Medicinal Chemistry, Vol. 105 (november 2015) , p. 120-137, ISSN 1768-3254

DOI: 10.1016/j.ejmech.2015.10.007
PMID: 26479031


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