title: Risedronate metal complexes potentially active against Chagas disease.
abstract: In the search for new metal-based drugs for the treatment of Chagas disease, the most widespread Latin American parasitic disease, novel complexes of the bioactive ligand risedronate (Ris, (1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl)phosphonate), [M(II)(Ris)(2)]·4H(2)O, where M═Cu, Co, Mn and Ni, and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O were synthesized and characterized by using analytical measurements, thermogravimetric analyses, cyclic voltammetry and infrared and Raman spectroscopies. Crystal structures of [Cu(II)(Ris)(2)]·4H(2)O and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O were solved by single crystal X-ray diffraction methods. The complexes, as well as the free ligand, were evaluated in vitro against epimastigotes and intracellular amastigotes of the parasite Trypanosoma cruzi, causative agent of Chagas disease. Results demonstrated that the coordination of risedronate to different metal ions improved the antiproliferative effect against T. cruzi, exhibiting growth inhibition values against the intracellular amastigotes ranging the low micromolar levels. In addition, this strong activity could be related to high inhibition of farnesyl diphosphate synthase enzyme. On the other hand, protein interaction studies showed that all the complexes strongly interact with albumin thus providing a suitable means of transporting them to tissues in vivo.
authors.affiliation: DEC, Facultad de Química, Universidad de la República, Gral. Flores 2124, C. C. 1157, 11800 Montevideo, Uruguay.
authors.forename: Bruno
authors.initials: B
authors.lastname: Demoro
authors.forename: Francesco
authors.initials: F
authors.lastname: Caruso
authors.forename: Miriam
authors.initials: M
authors.lastname: Rossi
authors.forename: Diego
authors.initials: D
authors.lastname: Benítez
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Beatriz
authors.initials: B
authors.lastname: Parajón-Costa
authors.forename: Jorge
authors.initials: J
authors.lastname: Castiglioni
authors.forename: Melina
authors.initials: M
authors.lastname: Galizzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
authors.forename: Lucía
authors.initials: L
authors.lastname: Otero
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D056831:Coordination Complexes / Q000737:chemistry* / Q000627:therapeutic use*; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D051228:Geranyltranstransferase / Q000378:metabolism; D008956:Models, Chemical; D000068296:Risedronic Acid; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D014961:X-Ray Diffraction
chemical_list: D056831:Coordination Complexes; D051228:Geranyltranstransferase; D000068296:Risedronic Acid; D012968:Etidronic Acid
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