| Alzheimer’s disease（AD）is the most common form of Alzheimer’s disease,also known as cerebral degeneration or Alzheimer’s disease.It is a progressive neurological degenerative disease that occurs in old age or presenile age.Rising year by year,there is no effective treatment,and it has become the fourth largest killer of the elderly after heart disease,cancer and stroke.The pathogenesis of AD is very complicated and may involve many factors such as gene defects,metabolic disorders,free radical damage,immune neuroinflammation,neuronal apoptosis,and environmental toxins.At present,a variety of pathogenesis hypotheses have been proposed,including cholinergic theory.The theory of oxidative stress.Among them,the more important is the cholinergic theory,which was proposed by Bartus et al.In 1982.This theory holds that the loss of learning and memory abilities of AD patients and Basal forebrain cholinergic neuron damage and impaired cholinergic neurotransmission in the cortex and hippocampus are closely related.Cholinesterase is involved in the process of choline metabolism.Acetylcholine transferase（Ch AT）It catalyzes choline and acetyl-Co A to produce acetycholine（ACh）and stores it in the capsule at the end of the nerve;when the neurons are depolarized,ACh is released into the synaptic cleft and reaches the other side of the gap through active diffusion binding and activating receptors to generate signal transduction.When AD pathological process occurs,a large number of cholinergic neurons in the basal layer and cerebral cortex of AD patients’brain Loss of acetylcholinesterase（ACh E）activity increased,causes decreased acetylcholine levels,leading to loss of memory and learning in patients with cognitive.Inhibition of acetylcholinesterase can inhibit the hydrolysis of acetylcholine and increase the level of ACh in the brain,thereby improving the memory and cognitive ability of patients.In addition to ACh E in mammals,butyrylcholinesterase（Bu Ch E）also exists.Studies have found that butyrylcholinesterase also participates in the metabolism of acetylcholine and plays an important role in regulating ACh levels.Therefore,in recent years,Some scholars consider Bu Ch E as a potential therapeutic target.A class of novelδ-sulfonolactone-fused pyrazole scaffolds were prepared via sulfur（VI）fluoride exchange（Su FEx）chemistry using aryl sulfonyl fluorides and pyrazolones.Enzyme screening revealed their cholinesterase inhibitory activity,among them,compounds 4a,5a and 5d were identified as highly selective submicromolar Bu Ch E inhibitors(IC50=0.20,0.46 and 0.42μM,respectively),which exhibited nontoxicity,lipophilicity and remarkable neuroprotective activity.Kinetic studies showed that Bu Ch E inhibition of compounds 5a and 5d was reversible,mixed-type and non-competitive inhibition against Bu Ch E（Ki=145 n M and 60 n M,respectively）.Compound 5d can be accommodated into h Bu Ch E viaπ-S interaction and hydrophobic interactions.The title compounds are potentially symptomatic treatment in progressive Alzheimer’s disease. |
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