Design, Synthesis And Activity Evaluation Of Dual Target Inhibitors Of AD

Alzheimer's disease (AD) is a degenerative disease of the central nervous system, the pathology hallmarks of which are senile plaques (SP) and neurofibrillary tangles (NFT). The evidences have been identified multiple mechanisms of the disease, so it is impossible to slow down or cure AD in the way of traditional drug design of"one-target,one-disease". Focusing on the complex mechanisms of AD, this paper chose AchE and BACE-1 as the objects of study: AchE, which can catalyze the hydrolysis of acetylcholine, plays the key role in the nerve conduction. And BACE-1 is the rate-limiting enzyme in the formation of Aβ42, which can assemble in the brain into the senile plaques, which lead to the apoptosis of neuron. The design, synthesis of the AchE and BACE-1 inhibitors by CADD and the evaluation activity for the inhibitors provide theoretical support and experimental basis for the new anti-AD drugs'design and the structure optimization.This paper's content include as follows:1. Design of the small molecular anti-AD compounds with dual target inhibition activityFist, this paper designed substituted phenyl piperazion as the mother structure by the pharmacophore model of AchE inhibitors which had been constructed; Second, the pharmacophore model of BACE-1inhibitors, which has reliable predictive ability, was established by CADD; Last, through docking the selected structures with BACE-1 inhibitors pharmacophore model and structure optimization, this paper designed the target compounds.2. Synthesis and identification of the target compoundsThis paper synthesized six target compounds by microwave irradiation and routine method, which were all characterized by UV, 1H-NMR and 13C-NMR. 3. Biological activity screeningActivity of AchE inhibition was assayed by the classic means of Ellman. Compound 1 and 4 showed potent inhibition activity. And compound 4 reached 50% in the inhibition activity at the concentration of 10μM, which is a little lower than tacrrine at the same concentration.Assay for protection of SH-SY5Y cells damaged by H2O2 or CoCl2 showed that compound 4 has potent protection for SH-SY5Y cells damaged by H2O2, and all the compounds has moderately or highly protection for SH-SY5Y cells damaged by CoCl2.4. The pharmacophore model checkingComparing the data of biological activity with the predictive values of the pharmacophore models of the inhibitors, the reliability and forecast ability of the pharmacophore models were verified.5. ConclusionThis paper established pharmacophore models of AchE inhibitors and BACE-1 inhibitors by CADD. On the basis of pharmacophore models, six compounds with mother structure of phenyl piperazine and thiazole were designed, which have the potent dual target inhibition activity. Meanwhile this paper assayed the bioactivity of compounds by taking in vitro experiments including enzyme and SH-SY5Y cells.The innovative points of thispaper show as follows:Pharmacophore model of BACE-1 inhibitors were established which has good predictive ability, and six compounds of dual target inhibiton activity were designed.All the six compounds showed good protection of SH-SY5Y cells damaged by CoCl2.