Design,Synthesis And Anti-AD Activity Evaluation Of Multi-Target HDAC-AChE Inhibitors

Alzheimer’s disease(AD)is currently the most common chronic degenerative disease of the central nervous system.Once sick,the patient’s disease will gradually worsen over time.The typical clinical manifestations are progressive memory decline and cognitive impairment.Intracerebral lesions of patients are usually manifested as senile plaques(SP)formed by the deposition of extracellular Aβ amyloid protein,and nerves formed by abnormally entangled intracellular hyperphosphorylated Tau protein.Neurofibrillar tangle(NFTs)and a large number of neurons are lost.So far,due to the complexity of the pathogenesis of AD,its specific pathogenesis is still unclear,but with the deepening of AD research,a variety of theories have been produced.The classic theories are:cholinergic loss theory,main amyloid cascade theory,Tau protein hyperphosphorylated theory,metal ion abnormality theory,oxidative stress theory,mitochondrial damage theory,neuroinflammation theory.Among them,the theory of cholinergic loss is the one with the longest development.The FDA approved the marketing of anti-AD drugs(donepezil,tacrine,galantamine,rivastigmine,memantine)among the first four inhibitor are cholinesterase inhibitors.However,when all these drugs on the market exert their anti-AD treatment effects,they can only improve the symptoms of patients and delay the course of the disease,but they cannot reverse the condition and completely cure the disease.More and more studies have shown that for the treatment of complex diseases like AD,multi-target drug design strategies are an important and effective strategy.In recent years,many studies have shown that HDAC(histone deacetylase)is closely related to the formation of long-term memory and the production of cognition.Therefore,HDAC has become a popular target for the development of anti-AD drugs.The pharmacophore model of HDAC inhibitors consists of three parts.1)Zinc ion chelating group ZBG,which is used to chelate the zinc ion at the bottom of the catalytic active center of histone deacetylase.2)Cap structure,this partial structure is used to occupy the hydrophobic surface of the active center of histone deacetylase,usually a hydrophobic structure such as various aromatic groups.3)Linker structure,which is used to connect the Cap structure and the ZBG part,which firmly occupies the tubular hydrophobic region of the enzyme active pocket when it interacts with the target enzyme.This topic is based on the HDAC pharmacophore model,selects the benzylpiperidine part of the AChE inhibitor donepezil structure that can bind to the catalytic active site of AChE as the Cap part,and uses different lengths of aliphatic or aromatic chains as the Linker.Oxamic acid or o-phenylenediamine as ZBG,designed and synthesized two series of 31 novel HDAC-AChE multi-target compounds.Preliminary anti-AD activity evaluation of HDAC-AChE multi-target anti-AD derivatives.Evaluation indicators include HD AC and ChE inhibitory activity,ABST free radical scavenging activity,metal ion chelating ability,inhibitory activity of Aβ142 accumulation,and depolymerization of Aβ1-42 activity and PC12 cell protective activity against H2O2 damage.The results showed that most of the compounds showed good HDAC inhibitory activity,but the compound has weak inhibitory activity on cholinesterase.Among them,the compounds d5 and d10 showed a more balanced inhibitory activity in the two enzymes(d5:AChEIC50=6.8900 μM,HDACIC50=0.1713μM,d 10:AChEIC50=3.2193 μM,HDACIC50=0.4526 μM).Some compounds were selected to further evaluate ABST free radical scavenging ability and metal ion chelating ability.Most of the tested compounds showed free radical scavenging ability equivalent to the positive drug Trolox.In the metal Cu2+ chelation experiment,compound d5-d10,d15,and d31 have significantly better copper ion chelating activity than donepezil.Among them,the inhibition rates of compounds d5,d7,d8,d9,d10,and d15 are 38.97%,39.03%,41.07%,36.65%,30.67%and 37.29%,respectively.This shows that the designed compound has the potential to target the excess of AD free radicals and the imbalance of metal homeostasis.Further experiments on Aβ1-42 of some compounds showed that both d5 and d10 showed mild inhibition and depolymerization of Aβ1-42 self-inducing aggregate activity.In addition,these two compounds also showed significant inhibition of Cu2+-induced Aβ1-142 aggregation activity(inhibition rate d5:33.8%,d10:34.2%).Next,in evaluating the protective activity of the compounds against H2O2 damage to PC 12 cells,the compounds d5 and d10 showed better neuroprotective effects than donepezil and SAHA.