Design,Synthesis And Biological Evaluation Of Gardenamide A Derivatives As Anti-alzheimer's Disease Candidate

Alzheimer's disease?AD?is the most common neurodegenerative disease of the central nervous system.With the aging of the population,the number of AD patients will further increase and seriously endanger human health.However,existing drugs can only ameliorate the symptoms of patients,which fail to fulfill the needs of clinical treatment.At present,the pathogenesis of AD has not been clearly elucidated.But,it is well-accepted that AD patients have brain atrophy,nerve injury,and cognitive impairment.Therefore,it may be the effective treatment for AD by protecting neurons.As a natural compound with neuroprotective effect,Gardenamide A has the potential to be applied as a neuroprotective agent.In this paper,with genipin as starting material,18 novel Gardenamide A derivatives were designed and synthesized.All of them were confirmed by IR,¹H NMR,¹³C NMR and ESI-Ms,and the neuroprotective effect and structure-activity relationships were studied in vitro.The preliminary pharmacological results displayed that all of them exhibited the neuroprotective effects of against OGD/R-induced neurotoxicity in rat cortical neurons.Compounds 8e,8f,8h,8i,9a,9e and 9g had significant protective effects,and compounds8e,9a,9e and 9g showed more significant activities than positive references Gardenamide A and Donepezil.The neuroprotective effects of compounds 8e,9a,9e and 9g were further studied by H₂O₂-and A?_1-42-induced neurotoxicity in rat hippocampal neurons.The efficacy results showed that these compounds can significantly increase the cell survival rate.Moreover,these derivatives did not exert severe toxicity in rat cortical neurons in cytotoxicity assay,and might serve as promising lead candidates for anti-AD drug development.