Bases de Schiff com potenciais aplicações no tratamento da doença de Alzheimer e de osteoporose

Abstract

In the present work we studied new Schiff bases derivatives as prototypes of drug candidates for the treatment of Alzheimer's disease and osteoporosis. The following compounds were obtained: 8-hydroxyquinoline-2-semicarbazone (8-HQS), 8-hydroxyquinoline-2-thiosemicarbazone (8-HQT) and 8-hydroxyquinoline-2-acetyl hydrazone (8-HQH). The physicochemical studies demonstrated that the compounds are stable and neutral at physiological pH. Complexes [Cu(8-QH)2]; [Cu(8-QS)2]; [Cu(8-QTD)]; [Zn(8-HQH)2]·5/2H2O;[Zn2(8-HQS)3]·1/2H2O and [Zn(8-HQT)(OAc-)]·1/2H2O were also synthesized. Additionally, a study of metal-ligand interaction in solution at physiological pH was conducted. The activities of the Schiff bases in in vitro models of Alzheimer's disease (AD) were evaluated. 8-HQT was not soluble under the test conditions. The ability of the compounds toinhibit A peptide aggregation induced by Cu(II) and Zn(II) was evaluated by the turbidity test, transmission electron microscopy (TEM) and fluorescence assays. In the turbidity test 8-HQH and 8-HQS showed inhibitory activity of the A1-40 peptide aggregation induced by the metalions. TEM images showed that 8-HQH presented higher capacity than 8-HQS to inhibit A1-40 peptide aggregation. In the fluorescence test, 8-HQH was able to inhibit the A1-40 peptide aggregation being, however, less effective to inhibit the binding of the peptide with thioflavin Twhen compared to Congo red. 8-HQS showed poor solubility under the test conditions. Results suggested that 8-HQH is a promising prototype of drug candidate for the treatment of AD. The Schiff bases showed low cytotoxic activity, which makes them interesting as drug candidatesfor the treatment of AD. As some inhibitors of cathepsin K contain the nitrile group in their structure and act as drug candidate for the treatment of osteoporosis, the compounds 4-formylbenzonitrile semicarbazone (4-FBS), 4-acetylbenzonitrile semicarbazone (4-ABS), 4-formylbenzonitrile thiosemicarbazone (4-FBT), 4-acetylbenzonitrile thiosemicarbazone (4-ABT), 4-formylbenzonitrile acetyl hydrazone (4-FBH) and 4-acetylbenzonitrile acetyl hydrazone (4-ABH) were obtained and characterized as prototypes of cathepsin K inhibitors. The compounds were tested for their antifungal, antibacterial and antiproliferative activities and did not show significant activity in any of the tested models when compared to the positive controls. These results established a preliminary low cytotoxic profile for the compounds, making them promising candidates for further evaluation of the inhibitory activityagainst cathepsin K, an in vitro model of osteoporosis. Since Pd(II) complexes with thiosemicarbazone have antimicrobial and antitumoractivity we obtained and characterized the [Pd(4-ABT)Cl2] complex. The compound was inactive as a cytotoxic agent against leukemic cell lines and solid tumors. We also evaluate its antifungal and antibacterial activities. Although the ligand (4-ABT) was inactive against thegrowth of all microorganisms, the complex showed antimicrobial activity against Pseudomonas aeruginosa, Staphylococcus aureus and Candida glabrata. The present work is an important contribution to the study of the role of Schiff base derivatives in Medicinal Chemistry, since these compounds proved to be potentially useful for the treatment of Alzheimer's disease and osteoporosis.