title: Ruthenium complexes endowed with potent anti-Trypanosoma cruzi activity: Synthesis, biological characterization and structure-activity relationships.
abstract: Although effective against epimastigotes (proliferative form) and of low cytotoxicity in mammals, the aryl-4-oxothiazolylhydrazones (ATZ) display only limited activity against trypomastigotes (bloodstream form) of Trypanosoma cruzi. Considering the metal complexation approach with bioactive ligands as one possible strategy for improving the biological efficacy of ATZ, a set of eight new ruthenium-ATZ complexes (RuCl(2)ATZCOD, COD is 1,5-cyclooctadiene) were prepared, chemically and biologically characterized, including in vitro assays against epimastigotes and trypomastigote forms of the parasite and also assessment of cytotoxicity in mammals. Two of these complexes presented antitrypanosomal activity at non-cytotoxic concentrations on mammalian cells and of higher potency than its metal-free ligands, while the metallic precursor [RuCl(2)COD(MeCN)(2)] showed only moderate antitrypanosomal activity. Comparative analysis between the ruthenium complexes and metal-free ligands demonstrated the usefulness of this approach, with the establishment of new SAR data. Additional pharmacological tests, including a DNA bond assay, gave rise to the proposal of a single preliminary explanation for the molecular origin of the bioactivity.
authors.affiliation: LASELORG-QUIM-Laboratório de Síntese, Eletrossíntese Orgânica e Química Medicinal, Departamento de Química, ICEX, Universidade Federal de Minas Gerais (UFMG), 31270-901, Belo Horizonte-MG, Brazil. cdonnici@terra.com.br
authors.forename: Claudio Luis
authors.initials: CL
authors.lastname: Donnici
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Araújo
authors.forename: Henrique S
authors.initials: HS
authors.lastname: Oliveira
authors.forename: Diogo Rodrigo Magalhães
authors.initials: DR
authors.lastname: Moreira
authors.forename: Valéria R Alves
authors.initials: VR
authors.lastname: Pereira
authors.forename: Marina
authors.initials: M
authors.lastname: de Assis Souza
authors.forename: Maria Carolina Accioly Brelaz
authors.initials: MC
authors.lastname: de Castro
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000378:metabolism; D017975:Ruthenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
chemical_list: D006835:Hydrazones; D017975:Ruthenium Compounds; D013844:Thiazoles; D014344:Trypanocidal Agents; D004247:DNA