Design,Synthesis And Evaluation Of Novel Carbamate Derivatives For The Treatment Of Alzheimer’s Disease

Alzheimer’s disease（AD）is a chronic neurodegenerative disease in the elderly,which can lead to progressive dementia syndrome.Currently,clinical drugs for the treatment of Alzheimer’s disease include donepezil,carbalatine,galantamine,huperzine A,N-methyl-D-aspartic acid receptor antagonists,compound preparations,GV-971 and Aβ-monoclonal antibody.These treatments do not materially ameliorate,prevent or cure the disease,which would have serious social and economic implications for an aging society.Therefore,it is urgent to study new drugs to treat AD.Currently,single-target drugs are not effective in stopping the progression of the disease.In view of the complex pathogenesis of AD,multi-target strategy is considered to be the most effective treatment for AD.The advantage of multi-target design strategy is to design a single drug with multiple actions,which can not only bind two or more pharmacophore in a single molecule,but also selectively bind the corresponding target to reduce adverse reactions.Quinoline derivatives are important bioactive nitrogenous heterocyclic compounds.They exist widely in nature and have multiple pharmacological activities such as anti-inflammatory and antioxidant.Recent study showed that acetophenone derivatives are highly selective MAO-B inhibitors,so acetophenone was designed as the backbone for developing multifunctional drugs.Rivastigmine is a drug for the treatment of AD and is a bischolinesterase inhibitor that inhibits Ach E and Bu Ch E well and improves cholinergic levels.It is highly selective for the blood-brain barrier,thereby improving symptoms in AD patients.Rivastigmine also produces a s APPα,which prevents the development of AD.Therefore,the design introduces the pharmacophore---carbamate fragments of rivastigmine in the hope of obtaining better efficacy.Based on the multi-target design strategy,with quinoline with multiple biological activities and acetophenone with MAO-B inhibitor as lead compounds,rivastigmine pharmacophores with dicholinesterase inhibitors were introduced into the molecule,and new carbamate derivatives were obtained through MTDLs,hoping to obtain a multifunctional new drug that can treat AD.In this paper,17 quinoline-carbamate derivatives and 25 acetophenone-carbamate derivatives were designed and synthesized,and their structures were characterized by ¹H NMR,¹³C NMR,HR-ESI-MS and HPLC.The inhibitory activities of quinolin-carbamate derivatives against ACh E and Bu Ch E were determined by the modified Ellman’s method.Herein,a series of novel quinoline-O-carbamate derivatives was rationally designed for treating AD by fusing quinoline and rivastigmine.The synthesized target compounds were synthesized and evaluated by ACh E/Bu Ch E inhibition and anti-inflammatory property.The in vitro biogical activities revealed that compound 3f was a reversible dual ee ACh E/eq Bu Ch E inhibitor with IC₅₀ values of 1.3μM and 0.81μM,respectively.Compound 3f also showed good anti-inflammatory property by declining the production of inflammatory mediators IL-6,IL-1βand NO.In addition,compound 3f presented significant neuroprotective effect on Aβ_25-35-induced PC12 cell injury.Moreover,compound 3f possessed favorable stabilties in artificial gastrointestinal fluids,liver microsomes in vitro and plasma.Furthermore,compound 3f significantly improved dyskinesia and reaction capacity of Al Cl₃-induced zebrafish AD model by increasing the level of ACh.Therefore,compound 3f was a promising multifunctional agent for the treatment of AD,deserving for further investigation.In summary,25 novel 2-acetylphenol-rivastigmine hybrids were rationally designed as multifunctional agents for the treatment of AD through MTDLs strategy.The target compounds were synthesized and evaluated by ACh E/Bu Ch E inhibition,antioxidant activity,MAO-A/MAO-B inhibition,metal chelation,neuroprotective effect and BBB permeability in vitro.The results in vitro displayed that compounds 6c and 6j were significant ACh E inhibitors with IC₅₀ values of 8.7μM and 11.4μM,respectively.Compound 6c and 6j also showed good antioxidant activity with ORAC value of 1.2 eq and 1.0 eq,respectively.Moreover,compounds 6c and 6j showed potent MAO-B inhibitory activity with IC₅₀ values of 2.9μM and 10.5μM,respectively.In addition,compounds 6c and 6j were selective metal chelators.Furthermore,compound 6c demonstrated significant neuroprotective effect on H₂O₂-induced PC12 cells injury.More importantly,compound 6c demonstrated favourable drug-like property and good blood brain barrier permeability in vitro.Therefore,compound6c was a promising multifunctional agent for treating AD,deserving further investigation.