Dienyl Sμlfonyl Fluorides As Selective BuChE Inhibitors:Structure-activity Relationship And Evaluation Of Anti-alzheimer’s Disease Activity

Alzheimer’s disease is a chronic neurodegenerative disease that is the main cause of dementia,and with the acceleration of aging,AD patients are also increasing,and more and more families are greatly affected by AD.According to the cholinergic hypothesis,AD is mainly caused by cholinergic neuron loss and progressive decline of acetylcholine（ACh）in the forebrain,so inhibition of cholinesterase becomes a better treatment for AD.To discover novel scaffolds as antidementia leads,a series ofδ-aryl-1,3-dienesulfonyl fluorides withα-halogen,α-aryl,andα-ethinyl groups were assayed for their Ch E inhibitory activity,in which compound A10 was identified as a selective Bu Ch E inhibitor(IC₅₀=0.021μM for eq BCh E and 3.62μM for h Bu Ch E).SAR of Bu Ch E inhibition revealed:（i）o->m->p-;–OCH₃>–CH₃>–Cl（–Br）forδ-aryl;（ii）α-Br>α-Cl,α-I.Compound A10 showed neuroprotective effects and good BBB penetration ability,and enzyme kinetic experiments indicated its mixed competitive inhibitory effect on Bu Ch E（Ki=29 n M）,safety of benign nerves and liver.A10 treatment almost completely restored Aβ_1-42-induced cognitive dysfunction to normal levels,and assessment of the total amount of Aβ_1-42also confirmed its anti-amyloidogenic profile.Therefore,the potential Bu Ch E inhibitor A10 is a promising and effective lead in the treatment of AD.Sulfur（VI）-Fluoride Exchange（Su FEx）is a modular next-generation click chemistry oriented towards the rapid and reliable assembly of functional molecules.Since Professor Sharpless first proposed this reaction in 2014,this reaction has been widely used in many aspects such as drug molecular synthesis,chemical biology,polymer synthesis and modification,and has shown a good application prospect.We established a high-throughput optimization process for one-step reaction on a 96-well plate based on sulfonyl fluoride Su FEx click chemistry,selected the above potential leads of dienesulfonyl fluoride and amine library for high-throughput screening of cholinesterase inhibitors.Through this method,the newly synthesized compounds do not need to be purified and directly applied to cholinesterase inhibition activity screening.Through regular summary,the modified compounds with better activity were selected for a large number of synthesis.We hope that based on this,we can accelerate the high-throughput SAR process,promote the high-throughput screening of conventional use,and contribute to better and faster discovery of new anti-AD drugs.Regarding this method,we have only conducted preliminary exploration,and the later research group will conduct more in-depth research.