Synthesis And Activities Of Arylcoumarins And Derivatives

This paper mainly explores the synthetic route of aryl coumarin and its derivatives and screened the activities related to anti-Alzheimer’s disease（AD）.Firstly,three amino-substituted arylcoumarins were designed and synthesized.On this basis,32 arylcoumarins and their derivatives were synthesized by amide condensation,direct condensation of amino group with carboxyl group and reductive amination of ketone carbonyl group included 28 new compounds.The above reactants were obtained by three reaction routes,and the reaction routes were all carried out at room temperature.These three methods are characterized by environmental friendliness,economy,low by-products and high yield.In addition,the synthesis route of 3-benzoylcoumarins were also explored,and the substituted3-benzoylcoumarin were also an important arylcoumarin derivatives,total 8 different substitutions were obtained.The 3-benzoylcoumarin included 4 new compounds,was mild in reaction conditions and simple to separate and purify.This is a way to synthesize benzyl coumarin.We performed a preliminary screening of 40 arylcoumarins and their derivatives in vitro,including acetylcholinesterase and butyrylcholinesterase inhibitory activity.Compounds 4f,4j,4m,4l,4o,5a,7b,and 7d exhibit moderate or better acetylcholinesterase inhibitory activity,and it is noteworthy that compound 4m(IC₅₀=0.091±0.011μM)has strong acetylcholine ester.The enzyme inhibitory activity was slightly weaker than the positive drug donepezil(IC₅₀=0.012±0.001μM).Most of the compounds show moderate to good inhibitory activity against butyrylcholinesterase,notably compounds 4b,4f,4i,4j,4k,4n and 7a have stronger butyrylcholinesterase inhibition.Activity,its inhibitory activity is superior to the positive drug donepezil(IC₅₀=2.665±0.015μM).It is worth noting that compounds 4f and 4j have a good dual inhibitory effect on these two cholinesterases.We found that the methoxycholine-containing compound at the 8-position of the coumarin ring inhibited acetylcholinesterase better than the hydroxyl group-containing compound at the 7-position,indicating that the methoxy group at the 8-position of coumarin is a good acetylcholine.The esterase activity inhibiting site;the benzene ring introduced by the amide condensation has a fluorine-containing group at the 3 and 4 positions and has a good inhibitory activity on butyrylcholinesterase.Considering the choice of compounds 4f,4j,4k,4l,4m,4r,5a,7b and7d,we investigated the effect of compounds on the retardation of galvanic larvae induced by aluminum trichloride.First we chose a suitable concentration of aluminum trichloride and finally selected 5 mg/L as the model concentration.Finally,we found that compounds 4f,4j and 4m have certain significance with respect to the building module,and are obviously superior to the module at a certain concentration,close to the normal group,indicating that the compound can alleviate the zebra induced by aluminum trichloride.The behavioral effects of slow movement of larvae have a certain enlightenment for simulating the retardation and dyskinesia of Alzheimer’s disease.The target compound 4m can be used as a lead compound for the development of new anti-Alzheimer’s disease drugs for the development of multi-targeted potential drugs against Alzheimer’s disease and its complications.We also screened all compounds for in vitro activity of hypoglycemic agents based on previous studies in our group,includingα-glucosidase inhibitory activity and inhibitory activity of advanced glycation end products（AGEs）.It has a certain inhibitory effect on the formation of advanced glycation end products,and some compounds have certain inhibitory activity onα-glucosidase,which provides a reference for us to screen hypoglycemic drugs in vivo.In addition,we also carried out antibacterial experiments to determine the inhibitory activity of the compounds against five strains of Bacillus subtilis,Staphylococcus aureus,Escherichia coli,Candida albicans and Aspergillus niger.Bacillus has a certain inhibitory effect,and a few compounds have certain inhibitory effects on other bacteria.These studies have shown that aryl coumarin derivatives have a wide range of activities and have good research and development value.