Design,Synthesis And Evaluation Of Novel Naringenin Derivatives As Multifunctional Agents For The Treatment Of Alzheimer’s Disease

Alzheimer’s disease（AD）is a devastating and progressive neurodegenerative disease that leads to cognitive impairment,eventually leading to dementia and death.Currently available drugs for the treatment of AD can only temporarily improve the clinical symptoms,but cannot effectively slow or prevent the progression of the disease.There are many and complex pathogenic factors of AD,leading to the lack of therapeutic drugs for AD.Given that AD is a complex disease with multi-factor pathological nature,the traditional single-target drugs cannot effectively solve the problem of AD.It has been found that multi-target drug design can effectively avoid its high toxicity and selectivity,and can act on a single small molecule compound with multiple targets at the same time to amplify its efficacy.Therefore,the"multi-target directed ligand"strategy has become the most promising direction for AD drug development.Studies have shown that naringenin has antioxidant,anti-inflammatory activity and neuroprotective effects,which is a promising candidate drug for anti-AD.However,the polyhydroxy structure of naringenin limits its clinical application as an anti-AD drug,and its oral bioavailability is only 15%.A series of multi-targeted naringenin derivatives were designed to improve their anti-AD activity.In vitro bioactivity results of naringenin-O-alkylamine derivatives indicated compound5f had good antioxidant activity（ORAC=2.3 eq）and hu ACh E inhibitory activity(IC₅₀=0.91μmol/L)in vitro.Kinetic studies and propidium iodide displacement experiments showed that compound 5f could bind both CAS and PAS of hu ACh E.5f inhibited self-induced aggregation of Aβ_1⁴2 with an inhibition rate of 62.1%.It also significantly inhibited the aggregation of hu ACh E-Aβ_1⁴0,and the inhibition rate was 51.7%.In addition,compounds 5f were selective metal chelation agents and remarkably inhibited Cu²⁺-induced Aβ_1⁴2aggregation with 73.5%inhibition rate,respectively.Furthermore,compounds 5f presented good BBB permeability in vitro,good neuroprotective effects and anti-inflammatory property.The further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed good hepatoprotective effect by its antioxidant activity.Therefore,compound 5f was a potential multifunctional candidate for the treatment of AD,deserving the further investigation.Based on the naringenin-O-alkylamine derivatives,we introduced the pharmacometer-carbamate fragments of rivarastine through the MTDLs strategy,thus rationally designing a series of naringenin-donepezil-rivarastine derivatives as multifunctional drugs for the treatment of AD.Compound 11b exhibited a selective ee ACh E inhibitory activity(IC₅₀=0.27μM,SI=0.14)and a good antioxidant activity（ORAC=1.2 eq）.Compound 11b is also a selective metal chelator.In addition,compound 11b showed good stability not only in artificial gastrointestinal fluids but also in the liver microsomes.Further bioactivity evaluation is ongoing Taken together,compound 11b is a promising candidate for anti-AD and deserves further investigation.In this study,33 intermediates and 42 target compounds were synthesized,including 8synthetic intermediates and 22 target compounds in naringenin-O-alkylamine derivatives,25synthetic intermediates and 20 target compounds in naringenin-donepezil-rivastigmine derivatives,and 8 synthetic intermediates and 22 target compounds in naringenin-O-alkylamine derivatives.All the structures were characterized by ¹H NMR,and some were characterized by ¹³C NMR and HR-ESI-MS.