Design,Synthesis And Anti-AD Activity Of Histone Deacetylase-6 Inhibitors

Alzheimer’s disease(AD)is an irreversible neurodegenerative disease with declines in cognitive function,accompanied by symptoms such as depression,anxiety and others.At present,the main cause of its pathological changes is still unclear,and the clinical effects of existing anti-AD drugs are not satisfactory.Alzheimer’s disease is one of the major health challenges around the world,and there is a need to develop more effective anti-AD drugs.HDAC6 is highly expressed in the cerebral cortex and hippocampus of AD patients,which is closely related to the tau phosphorylation,mitochondrial dysfunction,neurotransmitter transport damage,and Aβ toxicity.Selective HDAC6 inhibitors can inhibit the phosphorylation of tau protein at the cellular and animal levels,promote tau protein degradation,weaken the nerve damage caused by Aβ and improve the cognitive deficits effectively in AD animals.Therefore,HDAC6 has become one of the most concerned targets in the development of anti-AD drugs.In our previous research,we designed,synthesized and preliminarily evaluated a series of novel HDAC6 inhibitors,and discovered a potent and highly selective HDAC6 inhibitor,W5,which is characterized by the use of phenothiazide as a Cap group,and a substituted pyridine as a Linker,and hydroxamic acid as a Zn2+binding group(ZBG).W5 has unique multi-functional anti-AD activities and is the first highly selective HDAC6 inhibitor that can directly act on Aβ.Based on the structure of W5,we made structural modifications on the cap pharmacophore,linker connecting region and the Zn2+ chelating group in this study.Substituted phenothiazines and substituted tetrahydro-y-carbolines as well as memantine were used as the Cap moiety,pyridine or pyrazole as the Linker.In addition to the hydroxamic acid,a series of amides were investigated as novel ZBGs and the substituents at the amide N atom were expected to interact with the internal cavity.The inhibitory activity of the target compound on HDAC6 was tested.Most of the hydroxamic acid derivatives showed inhibitory activity against HDAC6,while the amide derivatives were not active.Among them,the hydroxamic acid derivatives S16(IC50=835 nM)and S18(IC50=102 nM)with memantine as the Cap moiety showed moderate potency against HDAC6.The hydroxamic acid derivatives S2,S10 and S11 with methylene blue or substituted tetrahydro-y-carboline as the Cap group exhibited potent inhibitory activity against HDAC6.However,the derivatives with pyrazole as the linker showed no inhibitory activity against HDAC6.Compounds S10,S11 and their hydrochlorides Y10,and Yll potently inhibited the Cu2+-induced Aβaggregation and promoted the Cu2+-Aβ aggregates disaggregation,that were comparable or superior to the positive control clioquinol(CQ).In addition,Y10 and Yll can protect PC12 cells from Aβ or Cu2+-Aβ induced cell damage.Y10 increased the level of α-tubulin acetylation in a dose-dependent manner and inhibit tau protein phosphorylation in SH-SY5Y cells.Though the amide derivative S6 showed no inhibitory activity against HDAC6,it had the tendency to increase the levels ofα-tubulin acetylation and histone H3 acetylation as well as inhibiting tau protein phosphorylation in a dose-dependent manner.Therefore,it may be meaningful for theoretical studies and practical application to further confirm the mechanism onα-tubulin and tau protein of the amide derivatives represented by S6.