Design, Synthesis And Biological Evaluation Of Various Types Of Dual (Multiple)-target Anti-Alzheimer's Agents

Alzheimer's disease (AD), the most common form of dementia, is a complex neurodegenerative disorder. Drugs approved for AD treatment are only AChE inhibitors and NMDA antagonists, both of which can only be used to alleviate the symptoms of AD. Thus, researching and developing more effective AD treatment is still one of the hotspots.Amyloid-β(Aβ), formed by the proteolytic processing ofβ-amyloid precursor protein (APP) by BACE 1, is thought to play a central role in the pathogenesis of AD. Based on the SAR of phenylpiperazine serise BACE 1 inhibitors reported in the literature, the rational drug design principle was used to design and synthesize a series of aryloxyalkylamine derivatives. Compounds 1-35 and 71 showed the most potent inhibitory activities in 33 tested compounds (1-35:IC50=18.33±2.80μM; 1-71: IC50=14.8±1.36μM).In order to find the BACE 1 inhibitor with a new scaffold structure, the pharmacophore model of BACE 1 inhibitor was built and screened the databases by the Discovery Studio software package. According to the result, three series of BACE 1 inhibitors were synthesized, and two of which showed moderate BACE 1 inhibitory activity. These two scaffold structure, which are not reported in the literature, are the potential lead compounds for the BACE 1 inhibitors.Because of the complexity and multiple etiologies of AD, Multi-Target-Directed Ligand raises as a potentially more effective strategy for AD treatment. Recent evidence indicated that excess biometals (Fe, Cu, Zn) may promote the aggregation of Aβin brain, and therefore the BACE 1 inhibitor with the ability to chelate the metals may probably generate synergy effect in reducing Aβin the brain of AD patients. Based on the previous work, a series of novel 1,3-diphenylurea derivatives were designed by hybridizing metal chelator LR-90 with BACE 1 inhibitor 1-35. Not only all eleven compounds have the BACE 1 inhibitory activity which are equivalent to 1-35, but also have the metal chelating ability. It is the first report of BACE 1 inhibitors with the ability to chelate biometals.Because of the larger water-soluble, it is hard for metal ion chelating agent to reach the target site across the blood-brain barrier. Based on the characteristics of the hydrolysis of the AChE inhibitor rivastigmine, we used prodrug design and molecular hybridization principle to design and synthesize a series of carbamate derivatives. The total fourteen compounds can inhibit the activity of AChE, and the hydrolyzates of the compounds also have the ability to chelating the metal, which may decrease the peripheral side effects.Since AChE/BACE1/H3R targets may have a synergistic effect in the treatment of AD, the database of MTDL was built by hybridizing BACE 1 inhibitor 2-134 with AChE inhibitor BYYT-25 and screened by the pharmacophore model of BACE 1 inhibitor and molecular docking model of AChE. Twentyfour compounds with high score values were synthesized and evaluated their biological activity. According to the results, all the compounds have the inhibitory activities to three targets. The most effect inhibitor 2-99 not only has the potent inhibitory activity to AChE/BACE1/H3R(H3R: IC50=280.0±98.0nM; AChE:IC50=483±5nM; BACE 1:44.79±9.44% at 20μg/mL), but also has the inverse agonist activity to H3R (IC5o=189.3±95.7nM) and good selectivity to H1R/H2R/H4R. It is the first report of MTDLs target to the AChE/BACE1/H3R.