Design,Synthesis And Biological Evaluation Of Multi-target Molecules As Potential Anti-alzheimer’s Disease Agents,and Study On The Synthesis Methodology Of 3-Aryl-3-hydroxy-2-oxindoles

This thesis consists of two parts.Part 1 presents the design,synthesis,and biological evaluation of muti-target molecules as potential anti-Alzheimer’s disease agents.Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by memory and cognitive impairments.Its mechanism has not been fully elucidated due to complex etiology.The complicated pathogenesis brings great trouble to new drug research and development,and there is no effective drug to slow down,prevent and reverse the development of AD.The complex pathogenesis of AD facilitates the development of multi-target drugs strategy,the synergistic effects of multiple biological activities may bring to better therapeutic effect.Based on different lead compounds and different design strategies,we developed two kinds of multi-target derivatives as potential AD therapeutic agents in this paper.The first kind is multifunctional pyrimidinylthiourea derivatives.Starting from a small molecules library(MW ≈ 200,630 compounds),screening out an acetylcholinesterase(AChE)inhibition hit compound(A1),via structural modifications,compound A8 with significant improved AChE inhibition was found.Treated A8 as lead compound to conduct strucural modifications again,and found a series of novel pyrimidinylthiourea derivatives(A16-61).Thiourea fragment endows these compounds a variety of anti-AD related biological axtivities,such as metal ions chealating and antioxidant properties.Therefore,these pyrimidinylthiourea derivatives were considered as multifunctional anti-AD agents,and multiple biological function evaluation experiments were carried out.Among them,compounds A55 and A57 exhibited potent inhibition and excellent selectivity toward AChE(A55,IC50 = 0.204 μM,SI>196;A57,IC50 = 0.067 μM,SI>196),specific metal-chelating ability,significant antioxidant effects,modulation of metal-induced Aβ aggregation,inhibition of ROS production by copper redox cycle,low cytotoxicity,and moderate neruoprotection to human neuroblastoma SH-SY5Y cells.Moreover,compound A55 displayed approriate blood-brain barrier(BBB)permeability both in vitro and in vivo,and could improve memory and cognitive function of scopolamine-induced amnesia mice.The multifunctional profiles of A55 and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzherimer’s diesase.The second kind is multi-target molecules targeting AD accompanied with depression.One of the reasons for the difficulty in treatment of AD is that nearly all patients concurrently suffer from intricate psychological and neuropsychiatric complications,among them,depression is the most frequent one,affecting up to 50%of the patients.A high throughput screening test was conducted to screen an old drug liabray(778 marketed drugs),and disclosed that antidepressant drug Vilazodone(5-HT1A receptor partial agonist,5-HT reuptake inhibitor)possessed moderate AChE inhibitory activity(IC50 = 21.3 μM).So Vilazodone has the possible to treat the cognitive impairment and depression symptom of AD.But its AChE inhibitory potency is too weak,so the urgent affair is to modify its structure to improve the anticholinergic potency,and keep the antidepressant ability at the same time.We investigated the SAR of Vilazodone,and introduced AChE pharmacophores at the activity insensitive structural area.These pharmacophores were taken from the marketed drugs,such as Tacrine,Rivastigmine,and Donepezil,thus we developed three kinds of multi-target derivatives that target the AD with depression.In the series of Vilazodon-Tacrine,we desgined and synthesized 30 derivatives(B1-30),and tested their AChE/BuChE inhibitory activities,5-HT1A agonist activities,5-HT reuptake inhibition,and evaluated the in vitro permeablity of some compounds.Compound B5 showed relatively balanced profiles between the three targets,lower HepG2 cell toxicity than Vilazodone,moderate hERG inhibition activity,and could penetrate BBB in vivo.Furthermore,an oral intake of 30 mg/kg B5·HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice,and alleviate the depressive symptom in tail suspension test.The effectivity of B5 validates the rationality of our design strategy.We can develop the multi-target molecules targeting the AD with depression by connecting the key pharmacophores of anticholinergic agents and antidepressant agents.Compound B5 can be considered as promising prototpe,and further guide the future research of multifunctional agents for AD with depression.In the series of Vilazodon-Rivastigmine,we desgined and synthesized 11 derivatives(C1-11),and tested their AChE/BuChE inhibitory activities,and 5-HT1A agonist activities.These Vilazodone-Rivastigmine derivatives inherited the 5-HT1A agonist ability of Vilazodone,and possibly possessed the antidepressant ability of Vilazodone.Due to the problem of experimental method,the values of these compounds’ AChE/BuChE inhibitory activities were far weaker than the literature values.From the present results,the BuChE inhibitory potencies of C2/C9 are stronger than Rivastigmine,this indicates that the potencies of these Vilazodone-Rivastigmine derivatives can be compared with Rivastigmine,and even stronger than Rivastigmine.Currently we are adjusting the experimental method of AChE/BuChE inhibiton,and seek to get the real active values of these derivatives.In the series of Vilazodone-Donepezil,we desgined and synthesized 52 derivatives(D1-52),and tested their AChE/BuChE inhibitory activities,5-HT1A agonist activities,5-HT reuptake inhibition,and acquired explicit SARs.We used PAMPA assay to evaluated the permeablity of some selected compounds,and screened out 12 compounds,then evaluated their effects on the brain AChE activity after oral administration,and eventurally found 4 optimal candidate compounds(D41,D42,D43,D47).These four compounds can enter the brain in animal model experiment,and inhibite the AChE activity in the brain.These 4 compounds have the potential of being central drugs,and are treated as the optimal candidates to evaluate their animal efficacy.The animal efficacy evaluation experiment is in progress.Part 2 is research on synthetic methodolgy of 3-aryl-3-hydroxy-2-oxindoles.3-aryl-3-hydroxy-2-oxindole is one of the most important natural products privileged structure,and the research of its synthetic method has significant scientific value.We developed a new kind of synthetic method,using acetyl protected 3-hydroxy-2-oxindoles as substrates,diaryliodonium salts as arylation reagents,constructing the 3-aryl-3-hydroxy-2-oxindole structure by direct arylation reaction.This is the first report on the construction of 3-aryl-3-hydroxy-2-oxindoles by direct arylation,the reaction condition is simple,mild,metal-free,and its yield is up to 82%.The scope of substrates is wide,and this method can be used to synthesize different aryl-or heterocyclic aryl-substituted 3-aryl-3-hydroxy-2-oxindoles.