title: Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity.
abstract: 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 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.
authors.affiliation: 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.forename: Ornella
authors.initials: O
authors.lastname: Di Pietro
authors.affiliation: Barcelona Science Park, Baldiri Reixac, 10-12, E-08028, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Vicente-García
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Taylor
authors.affiliation: Laboratori de Parasitologia, Departament de Microbiologia i Parasitologia Sanitàries, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Berenguer
authors.affiliation: 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.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.affiliation: 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.forename: Anna
authors.initials: A
authors.lastname: Lanzoni
authors.affiliation: 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.forename: Irene
authors.initials: I
authors.lastname: Sola
authors.affiliation: Barcelona Science Park, Baldiri Reixac, 10-12, E-08028, Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Sayago
authors.affiliation: Laboratori de Parasitologia, Departament de Microbiologia i Parasitologia Sanitàries, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Riera
authors.affiliation: Laboratori de Parasitologia, Departament de Microbiologia i Parasitologia Sanitàries, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Fisa
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Barcelona, Spain.
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Barcelona, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
authors.forename: John M
authors.initials: JM
authors.lastname: Kelly
authors.affiliation: Barcelona Science Park, Baldiri Reixac, 10-12, E-08028, Barcelona, Spain; Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Lavilla
authors.affiliation: 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.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004593:Electrophorus; D018314:Leishmania infantum / Q000187:drug effects*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D002800:Cholinesterase Inhibitors; D011804:Quinolines; D000110:Acetylcholinesterase
keywords: Benzo[h][1,6]naphthyridines; Brain permeability; Leishmanicidal agents; Povarov reaction; Pyrano[3,2-c]quinolines; Trypanocidal agents