Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity

Ornella Di Pietro, Esther Vicente-Garciá, Martin C. Taylor, Diana Berenguer, Elisabet Viayna, Anna Lanzoni, Irene Sola, Helena Sayago, Cristina Riera, Roser Fisa, M. Victòria Clos, Belén Pérez, John M. Kelly, Rodolfo Lavilla, Diego Munõz-Torrero

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46 Citations (Scopus)


© 2015 The Authors. 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 2e4-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 mM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.
Original languageEnglish
Pages (from-to)120-137
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 13 Nov 2015


  • Benzo[h][1,6]naphthyridines
  • Brain permeability
  • Leishmanicidal agents
  • Povarov reaction
  • Pyrano[3,2-c]quinolines
  • Trypanocidal agents


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