title: Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity.
abstract: Searching for prospective vanadium-based drugs for the treatment of Chagas disease, a new series of heteroleptic [V(IV)O(L-2H)(NN)] compounds was developed by including the lipophilic 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) NN ligand and seven tridentate salicylaldehyde semicarbazone derivatives (L1-L7). The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligand is bidentate bound through both nitrogen donor atoms in an axial-equatorial mode. The EPR and (51)V-NMR spectra of aerated solutions at room temperature indicate that the compounds are stable to hydrolysis and that no significant oxidation of V(IV) to V(V) takes place at least in 24h. The complexes are more active in vitro against Trypanosoma cruzi, the parasite responsible for Chagas disease, than the reference drug Nifurtimox and most of them are more active than previously reported [V(IV)O(L-2H)(NN)] complexes of other NN co-ligands. Selectivity towards the parasite was analyzed using J-774 murine macrophages as mammalian cell model. Due to both, high activity and high selectivity, L2, L4, L5 and L7 complexes could be considered new hits for further drug development. Lipophilicity probably plays a relevant role in the bioactivity of the new compounds. The [V(IV)O(L-2H)(NN)] compounds were designed aiming DNA as potential molecular target. Therefore, the novel L1-L7 tmp complexes were screened by computational modeling, comparing their DNA-binding features with those of previously reported [V(IV)O(L-2H)(NN)] compounds with different NN co-ligands. Whereas all the complexes interact well with DNA, with binding modes and strength tuned in different extents by the NN and semicarbazone co-ligands, molecular docking suggests that the observed anti-T. cruzi activity cannot be explained upon DNA intercalation as the sole mechanism of action.
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Scalese
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Julio
authors.initials: J
authors.lastname: Benítez
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rostán
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Correia
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Lara
authors.initials: L
authors.lastname: Bradford
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Marisol
authors.initials: M
authors.lastname: Vieites
authors.affiliation: Laboratorio de Química Teórica y Computacional, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400, Uruguay.
authors.forename: Lucía
authors.initials: L
authors.lastname: Minini
authors.affiliation: Laboratorio de Química Teórica y Computacional, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400, Uruguay.
authors.forename: Alicia
authors.initials: A
authors.lastname: Merlino
authors.affiliation: Laboratorio de Química Teórica y Computacional, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400, Uruguay.
authors.forename: E Laura
authors.initials: EL
authors.lastname: Coitiño
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Estefania
authors.initials: E
authors.lastname: Birriel
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Javier
authors.initials: J
authors.lastname: Varela
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: João Costa
authors.initials: JC
authors.lastname: Pessoa
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay. Electronic address: dgambino@fq.edu.uy.
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D016054:DNA, Protozoan / Q000737:chemistry; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D062105:Molecular Docking Simulation; D012664:Semicarbazones / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D017968:Vanadium Compounds / Q000737:chemistry*
chemical_list: D000447:Aldehydes; D000981:Antiprotozoal Agents; D056831:Coordination Complexes; D016054:DNA, Protozoan; D007364:Intercalating Agents; D012664:Semicarbazones; D017968:Vanadium Compounds; C013243:salicylaldehyde
keywords: DNA interaction; Oxidovanadium(IV) complexes; Salicylaldehyde semicarbazones; Tetramethylphenanthroline; Trypanosoma cruzi