Estudo do perfil farmacológico de bases de Schiff e de suas interações com metais

• Ano de defesa: 2013
• Autor(a) principal: Rafael Pinto Vieira
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; UFMG
• Palavras-chave em Português: Bases de Schiff; dor; Doença de Alzheimer; inflamação; Química inorgânica; Alzheimer, Doença de; Complexos metálicos; Atividade antifúngica; Schiff, Bases de; Dor; Agentes antibacterianos; Zinco; Inflamação
• Link de acesso: http://hdl.handle.net/1843/SFSA-95ZU8J

The present work involved the preparation and a study on the physicochemical properties and pharmacological activities of semicarbazones, thiosemicarbazones, hydrazonesand their metal complexes. Since benzaldehyde semicarbazone (BS) presents anti-inflammatory and antinociceptive properties, including activities on central pain conditions, the analogues 2-, 3- and 4-hydroxybenzaldehyde semicarbazones (2-, 3- and 4-OHBS) were prepared in the present work. A study correlating NMR spectra, crystallography data and theoretical calculations of theconformational isomers energies and physicochemical properties of BS, 2-OHBS, 3-OHBS and 4-OHBS was performed. According to the results, 2-OHBS was the compound presenting the highest susceptibility to nucleophilic attack and subsequent hydrolysis. Besides, theoretical andexperimental octanol-water partition coefficients are in accordance to higher hydrophobicity of BS and 2-OHBS in comparison with 3-OHBS and 4-OHBS. The antinociceptive and anti-inflammatory properties of 2-OHBS, 3-OHBS and 4- OHBS were evaluated in animal models using BS as positive control. Among the three isomers, only 2-OHBS presented statistically different antinociceptive effect in comparison to BS inZymosan, formaldehyde and carrageenan-induced paw edema models. 2-OHBS inhibited exclusively the second phase of formaldehyde protocol, being characterized as an inhibitor of peripheral mechanisms of pain and inflammation. In contrast, BS acts on both, neurogenic(first) and inflammatory (second) phases of the formalin model.In order to correlate the biological activities of BS and 2-OHBS to their susceptibilities to hydrolysis and physicochemical properties, the immediate product of hydrolysis, semicarbazide, was evaluated in the formaldehyde and carrageenan-induced paw edema models.Semicarbazide is a well-known inhibitor of VAP-1, an enzyme strictly related to inflammatory processes. Results suggested that the peripheral activity of arilsemicarbazones, mainly in acute pain models, would be related to partial hydrolysis of the compounds, releasing semicarbazidein vivo. Besides, semicarbazide didnt present activity in neurogenic phase of the formaldehyde model, indicating that the activity of BS in first phase could be due to a particular mechanism, non-related to its hydrolysis. In a second step, the kinetics of hydrolysis of BS and 2-OHBS were evaluated in simulated gastric fluid in order to correlate their kinetic and thermodynamics (theoretical calculations) properties. Furthermore, the kinetics of hydrolysis of BS in its inclusion compoundwith .-cyclodextrin (BS.CD) and of BS mixed .CD were investigated in order to evaluate the influence of .CD on the semicarbazones pharmacokinetics. It was observed that the initial rateof hydrolysis of 2-OHBS was about 4-fold higher than that BS, confirming the tendency previously established by theoretical calculations. Thus, results suggest that 2-OHBS would be more susceptible to hydrolysis in comparison do BS, both kinetically and thermodynamically.The initial rate of hydrolysis of BS, BS.CD or a mixture of BS with .CD were statistically equivalent. Complexes of zinc(II) and gallium(III) with 2-OHBS were synthesized and evaluated as antifungal agents. Compounds were evaluated for their antifungal activities against Candida andTrychophyton rubrum strains and clinical isolates. The complex [Zn(2OBS)AcO] did not show significant activity. Besides, results for [Ga2(2OBS)3] suggested that the antifungal activity of the compound would be related to the metal itself. The antifungal activity of gallium nitrate decreased against four strains and clinical isolates of Trychophyton rubrum in the presence of increasing concentrations of iron nitrate suggesting that the mechanism of antifungal action ofgalium(III) could be related to replacement of iron(III) by galium(III) or to the disruption of iron-related redox processes in biological media. Results showed for the very first time the antifungal activity of galium(III) against Trychophyton rubrum. Since copper(II) and zinc(II) can be related to the aggregation process of amyloid. (A.) peptide in the brain of Alzheimers disease (AD) patients, the pentadentade chelators 2,6diacetylpyridine bis(thiosemicarbazone) (DAPT), 2,6-diacetylpyridine bis(semicarbazone) (DAPS) and 2,6-diacetylpyridine bis(hydrazone) (DAPH) were prepared and evaluated in in vitro models of AD. DAPT and DAPH were insoluble in the turbidity test conditions, suggesting structural modifications of these compounds would be necessary in order to increase their solubility in aqueous medium. Results of the anti-aggregation assay using A.1-40 in the presence of metals showed that DAPS is able to inhibit peptides aggregation in turbidity testconditions. Transmission electron microscopy (TEM) images confirmed the results obtained in the turbidity test. These results showed the potential of bis(thiosemicarbazones), bis(semicarbazones) and bis(hidrazones) as promising chelating agents for AD therapy.The present work is an important contribution to the study of the role of Schiffs bases in Medicinal Chemistry, since these compounds proved to be potentially useful for the treatment of pain, inflammation, and Alzheimers disease.