RESUMO
The only therapeutic drugs for combating dementia disease are acetylcholine esterase inhibitors (AChEI). However, the use of tacrine, the first AChEI to be launched as an Alzheimer's disease (AD) drug, has been limited by serious side effects. Therefore, efforts to search for more potent and selective inhibitors of AChE still remain highly significant in the therapeutic treatment of AD. In this work we modified the cyclohexyl ring of velnacrine, a less toxic analogue of tacrine, by synthesizing a series of thiopyranoquinolines in which the C-3 methylene unit was replaced by a sulphur atom. The anti-AChE data show that the activity was maintained with the bioisosteric substitution carried out. The introduction of a chlorine atom at different positions of the aromatic ring resulted in an array of different activities. In an attempt to understand the different behaviours displayed by the chlorine-substituted derivatives, a molecular docking study was performed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/síntese química , Tacrina/análogos & derivados , Tacrina/farmacologia , Administração Oral , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Células Sanguíneas/enzimologia , Cloro , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Enxofre , Taxa de Sobrevida , Tacrina/síntese química , Tacrina/toxicidadeRESUMO
A series of disubstituted thiazoles, functionalized with the essential 3,5-dihydroxy-6-heptenoic or heptanoic chain, were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. All the synthesized compounds 46-61 showed a moderate inhibitory potency.