Design,Synthesis,Anti-AD Activity Evaluation Of Tacrine-hydroxamate Derivatives And Improved Synthesis Of Resminostat

This paper is divided into two parts:1.Design,synthesis and anti-AD activity evaluation of novel tacrine-hydroxamic acid derivatives.2.Improved synthesis of Resminostat(4SC-201).Alzheimer's disease(AD)is a neurodegenerative disease commonly found in the elderly,which is known as dementia.The typical clinical features are characterized by decreased language expression,memory and cognitive impairment accompanied with depressive symptoms.The pathophysiology of AD is complex and many physiological and biochemical abnormalities play a key role in the pathogenesis of AD,for example,the loss of cholinergic transmission,accumulation of tau protein,excessive accumulation of A? aggregates,biometal dyshomeostasis,disturbed mitochondrial transport,glutamate excitotoxicity,oxidative stress,inflammatory processes.At present,the single-target drug for the treatment of AD in clinic can only alleviate the symptoms of AD but cannot cure the disease.Therefore,multi-target anti-AD drugs become a new strategy for AD cure.In the multi-target strategy,because cholinesterase inhibitors play an important role in alleviating AD memory-related symptoms,the cholinesterase is generally retained,and then the compound will exhibit an improvement effect on other targets by SAR research.In recent years,many studies have shown that epigenetic modification plays an important role in neurodegenerative diseases,among them histone deacetylases(HDACs)play an important regulatory role in cognition-related gene expression and signal transduction in AD patients,providing a new drug target for the treatment of AD.However,different types of HDACs play different role in the cognitive function of AD,among which the importance of HDAC2 and HDAC6 has been widely studied in the occurrence and development of AD.In addition,studies have shown that both of the catalytic anionic site(CAS)and the peripheral anionic site(PAS)of cholinesterase play important roles in contributing to the occurrence and development of AD,On the one hand,it has been proved that the combination of the compound and PAS can alleviate the aggregation of A?,antioxidant and other related symptoms,therefore,it is important that compounds can simultaneously act on the CAS and PAS for the treatment of AD.On the other hand,we know that HDACs inhibitors mainly include three parts:1.Cap,located at the inlet of HDACs,is used to identify HDACs.2.Zinc ion chelating group(ZBG)3.Linker,used to connect Cap and ZBG groups.Based on the above analysis,we found that the cholinesterase inhibitors and HDACi is quite overlaps on the structure,so we select tacrine with acetylcholinesterase activity as HDACi Cap group,in addition,we expect that the hydroxamate unit will bind to the PAS of ChE and function as a zinc binding group(ZBG).Based on this concept,we designed and synthesized 28 tacrine-hydroxamate derivatives.To validate the design rationale,structure-activity relationship(SAR)were conducted based on this scaffold.We evaluated the activity against AChE,BChE,HDAC and ABTS antioxidant activity.The results showed that tacrine-hydroxamate derivatives showed good inhibitory activity against AChE,BChE,HDAC and ABTS and potential antioxidant activity.Among them,compounds A5,A10 and A12 showed potential selectivity to AChE or BChE respectively and reached a good balance with HDAC activity(AChEIC50=0.12 nM,HDACIC50=0.23 nM).Furthermore,compounds with good inhibitory activity were selected to analyze their inhibitory and disaggregation ability on A?1-42,and compounds A5,A10,A12,etc,which showed different degrees of inhibitory and disaggregation ability.The inhibition rate was 52.12%,32.66%and 38.36%,and the disaggregation rate was 56.93%,40.74%and 59.48%,respectively.In addition,the chelating ability of copper ions was similar to positive drug EDTA.2Na.The selective results of HDAC subtype showed that the compound was broad-spectrum HDACi.Through the prediction by online server,it was found that the compound had a certain BBB penetrating ability.The compound A10 with high selectivity of AChE was selected for further study,including AChE inhibition kinetics,molecular docking,and hepatotoxicity evaluation,etc.The results showed that compound A10 was a mixed enzyme inhibitor and could act on CAS and PAS of AChE simultaneously,which was consistent with our design concept.The results of hepatotoxicity tests showed that compounds A5 and A10 had little hepatotoxicity comparable to tacrine.Besides,the improved synthesis of Reminostat,an HDACi in phase ? clinical trials,was performed.In this project,we optimize the synthesis route from 8 reaction to 4 and make it meet the requirements of industrial production with low-cost,high overall rate and green chemical.In summary,this project optimized the synthesis route of Resminostat to meet the production requirements.Twenty-eight new tacrine-hydroxamate derivatives were designed,synthesized,and biologically evaluated.It is demonstrated that A10 can serve as a lead compound to develop promising candidate analogs as AD therapeutics.Meanwhile,the synergistic mechanism between AD and HDACi remains to be further studied.