Ruthenium complexes endowed with potent anti-Trypanosoma cruzi activity: Synthesis, biological characterization and structure-activity relationships.
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.
Donnici
Claudio Luis
CL
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
Araújo
Maria Helena
MH
Oliveira
Henrique S
HS
Moreira
Diogo Rodrigo Magalhães
DR
Pereira
Valéria R Alves
VR
de Assis Souza
Marina
M
de Castro
Maria Carolina Accioly Brelaz
MC
Leite
Ana Cristina Lima
AC
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
D006835:Hydrazones; D017975:Ruthenium Compounds; D013844:Thiazoles; D014344:Trypanocidal Agents; D004247:DNA