title: Oxidovanadium(IV) and dioxidovanadium(V) complexes of tridentate salicylaldehyde semicarbazones: searching for prospective antitrypanosomal agents.
abstract: As a contribution to the identification of the relevant species for biological activity and the understanding of structure-activity relationships of [V(IV)O(L-2H)(NN)] antitrypanosomal complexes (NN is a bidentate polypyridyl DNA intercalator; L is a tridentate salicylaldehyde semicarbazone derivative), new [V(V)O2(L-2H)] complexes and [V(IV)O(L-2H)(NN)] complexes including bipy or dppz (dipyrido[3,2-a: 2',3'-c]phenazine) co-ligands are prepared and characterized in the solid state and in solution. Their activity is evaluated on Trypanosoma cruzi. The lipophilicity, as structural descriptor related to bioactivity, of the whole [V(IV)O(L-2H)(NN)] series is determined. Furthermore, the antiproliferative effect of those new compounds showing activity against T. cruzi is evaluated on the genetically related parasite T. brucei with the aim to develop broad spectrum agents. The new [V(IV)O(L-2H)(dppz)] complexes are about ten to fifteen times more toxic to T. cruzi than the bipy analogues and show quite good in vitro activity on T. brucei brucei. They are shown to interact with DNA, suggesting that this biomolecule may be the parasite target. The stability of the V(IV)O-complexes in solution is accessed by several techniques. Globally the data suggest that the relevant species for biological activity are the [V(IV)O(L-2H)(NN)] compounds, their order of activity being dependent on the NN nature, but not much on the substitution on the salicylaldehyde semicarbazone moiety. A parabolic relationship between biological response and lipophilicity (determined as RM=log [(1/Rf)-1] by a TLC method) is obtained. From this correlation an optimum RM value, close to 1.44, was found, which may be used as design guide for future development of antitrypanosomal compounds.
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, UDELAR, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Mariana
authors.initials: M
authors.lastname: Fernández
authors.forename: Lorena
authors.initials: L
authors.lastname: Becco
authors.forename: Isabel
authors.initials: I
authors.lastname: Correia
authors.forename: Julio
authors.initials: J
authors.lastname: Benítez
authors.forename: Oscar E
authors.initials: OE
authors.lastname: Piro
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Echeverria
authors.forename: Andrea
authors.initials: A
authors.lastname: Medeiros
authors.forename: Marcelo
authors.initials: M
authors.lastname: Comini
authors.forename: María Laura
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.forename: Joao Costa
authors.initials: JC
authors.lastname: Pessoa
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garat
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D000818:Animals; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects; D014639:Vanadium / Q000737:chemistry / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; D014344:Trypanocidal Agents; D014639:Vanadium
keywords: 2,2′-bipyridine; Antitrypanosomal; Dioxidovanadium(V) complexes; Oxidovanadium(IV) complexes; Salicylaldehyde semicarbazones; dipyrido[3,2-a: 2′,3′-c]phenazine