Velnacrine thiaanalogues as potential agents for treating Alzheimer's disease

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 ser ious side effects. Therefore, efforts to search for more potent and selecti ve inhibitors of AChE still remain highly significant in the therapeutic tr eatment of AD. In this work we modified the cyclohexyl ring of velnacrine, a less toxic analogue of tacrine, by synthesizing a series of thiopyranoqui nolines 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 activitie s. In an attempt to understand the different behaviours displayed by the ch lorine-substituted derivatives, a molecular docking study was performed. (C ) 2001 Elsevier Science Ltd. All rights reserved.