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Title: Multicomponent-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity
Author: Di Pietro, O.
Vicente García, Esther
Taylor, Martin C.
Berenguer, Diana
Viayna, Elisabet
Lanzoni, Anna
Sola, Irene
Sayago, Helena
Riera Lizandra, Ma. Cristina
Fisa Saladrigas, Roser
Clos Guillén, M. Victòria
Pérez Fernández, Belén
Kelly, John M.
Lavilla Grífols, Rodolfo
Muñoz-Torrero López-Ibarra, Diego
Keywords: Disseny de medicaments
Síntesi orgànica
Barrera hematoencefàlica
Compostos heterocíclics
Medicina tropical
Drug design
Organic synthesis
Blood-brain barrier
Heterocyclic compounds
Tropical medicine
Issue Date: 13-Nov-2015
Publisher: Elsevier Masson SAS
Abstract: Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, T. 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 L. 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 IC50 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 (IC50 > 30 µM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.
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It is part of: European Journal of Medicinal Chemistry, 2015, vol. 105, p. 120-137
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ISSN: 0223-5234
Appears in Collections:Articles publicats en revistes (Biologia, Sanitat i Medi Ambient)
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

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