Multiple-Target Drug Design, Synthesis And Activity Evaluation On Alzheimer's Disease

Alzheimer's disease (AD), which is also called senile dementia, is a progressive neurodegenerative disease. It is a long term disease with complicate etiology. The neuropathologic hallmarks are neuritic (senile) plaques and neurofibrillary tangles (NFT). Neuritic plaques are extracellular deposits ofβ-amyloid protein (Aβ) and NFT are intraneuronal cytoplasmic filaments composed of Hyperphosphorylation tau.γ- secrease is a kind of key protein in the generation of Aβ, the inhibition of which can cause the decrease of Aβ. Glycogen synthase kinase-3 (GSK-3) plays an important role in tau hyperphosphorylation, the inhibition of which may restrain the NFT. The two enzymes are both important action targets, attracting a lot of scientific teams.In this experiment, we intended to design new compounds with both inhibition activity ofγ- secrease and GSK-3 which may improve the biological activity and meantime decrease the toxicity of living body.The research object matter in this paper included as follows:1. The construction of the pharmacophore model of GSK-3 inhibitors and multiple-targets drug designTwo classes of compounds with different structures and corresponding high activity were chosen as a training set. The model was built in the CATALYST system through molecular model, conformational analysis and hypothesis generation processes. The optimum model with four features (one hydrogen-bond acceptor unit, one ring aromatic unit, and two hydrophobic aromatic units) was selected. Nine new compounds were designed based on the two pharmacophore model ofγ- secrease and GSK-3. They can match the models very well and show high inhibition activity.2. Synthesis and identification of the target compoundsThe intermediate product N-substitute phenyl ethyl glycine derivatives were synthesized from aniline derivatives by the substitution reaction and then nine new compounds were obtained by acylation reaction. The compounds obtained were identified by IR, 1H-NMR, 13C-NMR which show the structures as they really were.3. Pharmacological activity test in vitro Several compounds were assessed for their ability in vitro to inhibit GSK-3βorβ- secrease. The results show that they can inhibit the GSK-3βandβ- secrease to some extent.The model were adjusted based on the results of the pharmacological activity test, and some requests about the good inhibitors were known which may do well in the future drug design.The characters and innovation points:1. The multiple targets ofγ- secrease and GSK-3 on AD were proposed for the first time which may lead to the new drug design method on AD.2. The pharmacophore model of GSK-3 was built for the first time and several compounds were designed with good inhibition activity toward GSK-3 andγ- secrease which based on the virtual screening of the two models.3. Nine new compounds were synthesized in this experiment. The activity of some of them were assessed which showed that they have GSK-3 andβ- secrease inhibition activity.