title: Antileishmanial effect of new indeno-1,5-naphthyridines, selective inhibitors of Leishmania infantum type IB DNA topoisomerase.
abstract: Visceral leishmaniasis is a neglected disease of poor and developing countries. The current therapeutic approach is based on pentavalent antimonial (SbV) drugs and amphotericin B, both nephrotoxic and parenterally administered drugs. Therefore, there is a real need of new antileishmanial drugs. Eukaryotic type I DNA topoisomerases (TopIB) have been identified as druggable targets against leishmaniasis. These enzymes are involved in solving topological problems generated during replication, transcription and recombination of DNA. Leishmanial TopIB is a unique heterodimeric protein structurally different than that found in the mammalian host, thus making it an interesting target for drug discovery. Tetrahydro indeno-1,5-naphthyridines 5 and indeno[1,5]naphthyridines 6 were synthesized. The inhibition of Leishmania and human TopIB of these polycyclic heterocycles were studied and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum were evaluated. In this regard, it is noteworthy that some of the prepared heterocycles, as compounds 6b, 6i and 5 h, showed selective inhibition of LtopIB while no inhibition of hTopIB was observed at evaluated conditions. In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Tetrahydro indeno-1,5-naphthyridines 5e and 5h showed good antileishmanial activity (IC50values of 0.67 ± 0.06 and 0.54 ± 0.17 μM) with similar activity than the standard drug amphotericin B (0.32 ± 0.05 μM) and even tetrahydro indeno-1,5-naphthyridine 5h showed higher (SI) towards L. Infantum amastigotes. Likewise, in the family of indeno-[1,5]-naphthyridines 6, compound 6b showed good antileishmanial activity (IC50value 0.74 ± 0.08 μM) and higher selective index (SI) towards L. Infantum amastigotes than amphotericin B.
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Tejería
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Pérez-Pertejo
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Reguera
authors.affiliation: Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Balaña-Fouce
authors.affiliation: Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Alonso
authors.affiliation: Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fuertes
authors.affiliation: Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: María
authors.initials: M
authors.lastname: González
authors.affiliation: Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Rubiales
authors.affiliation: Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center), Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain. Electronic address: francisco.palacios@ehu.eus.
authors.forename: Francisco
authors.initials: F
authors.lastname: Palacios
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects* / Q000201:enzymology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000977:Antiparasitic Agents; D009287:Naphthyridines; D059004:Topoisomerase I Inhibitors; C000612780:indeno(1,5)naphthyridine; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: DNA-topoisomerase; Indeno-naphthyridines; Leishmania