Design And Synthesis Of Oxadiazole Derivatives As GSK-3β Inhibitors And Evaluation Of Their Potential As Multifunctional Anti-Alzheimer Agents

Alzheimer’s disease（AD）is a neurodegenerative disorder with multiple onsets in the elderly,main clinical feature by progressive memory loss and speech disorder.Despite intense research,the exact pathogenesis of the disease remains unknown,and there are no effective drugs completely curing for it at the present.Senile plaques outside neurons and neurofibrillary tangles（NFTs）inside neurons are the main pathological features of AD.In addition,neuroinflammation,oxidative stress,and disturbance of glucose metabolism in the brain are important factors that promote AD occurrence and development.In recent years,many signaling pathways associated with AD neuropathology have been explored as possible candidate targets for the treatment of this condition including glycogen synthase kinase-3β（GSK-3β）.Research studies indicated that hyperactivity of GSK-3βinduce the hyperphosphorylation of tau,Aβgeneration,loss of cholinergic neurons and axons and cognitive impairment,which are hallmark features of AD.Consequently,an effective measure to inhibit GSK-3βactivity may be a very attractive drug target in AD.Pleiotropic intervention has prominent advantages for complex pathomechanisms,such as Alzheimer’s disease（AD）.In this study,a series of novel 3-（4-pyridyl）-5-（4-sulfamido-phenyl）-1,2,4-oxadiazole derivatives were designed and synthesized following the multitarget-directed ligand-based strategy.All compounds were evaluated for glycogen synthase kinase 3β（GSK-3β）inhibition and antineuroinflammatory and neuroprotective activities.Given that abnormal glucose metabolism plays an important role in AD occurrence and development,the effects of all compounds on glucose consumption in Hep G2 cells was evaluated.Compounds 5e and 10b showed good dual potency in GSK-3βinhibition(IC₅₀:5e=1.52μM,10b=0.19μM)and antineuroinflammatory potency(IC₅₀:5e=0.47±0.64μM,10b=6.94±2.33μM).The effect of compound 10b on glucose consumption was higher than that of positive drug metformin.These compounds exerted a certain neuroprotective effect.Compound10b dramatically reduced Aβ-induced Tau hyperphosphorylation,thus inhibiting GSK-3βat the cellular level.Notably,compounds 5e and 10b exhibited good inhibitory effects on the formation of intracellular reactive oxygen species（ROS）.Moreover,these compounds displayed proper blood–brain barrier permeability and lacked neurotoxicity up to 50μM concentration.Finally,in vivo experiments revealed that compound 10b improved cognitive impairment in scopolamine-induced mouse models.Results indicated that compound 10b deserves further study as a multifunctional lead compound.