Studies On The Synthesis And AChE Inhibitory Activity Of Flavonoids Mannich Base Derivatives

Flavonoids which are widely found in nature, are an important class of naturalproducts, and have important medicinal activities, such as anti-cancer, antitumor,antibacterial, antiviral activity, anti-cardiovascular disease, enzyme inhibitory activity,anti-free radical anti-oxidation activity and so on. Diosmetin and acacetin arecommon natural flavonoids with anti-cancer, anti-tumor, immune regulation,anti-fatigue and other biological activities. In order to further study the biologicalactivities of these natural flavonoids and explore their structure-activity relationshipsand meet the needs of drug development, the thesis attempted to facile synthesized aseries of flavones, flavonols and flavones Mannich base derivatives from hesperidin,naringin and phloroglucinol.1、7,3′-O-dimethyl diosmetin1and3′-O-dimethyl diosmetin2were synthesizedfrom hesperidin, through glycoside hydrolysis under acidic conditions, I2/Pydehydrogenation, selective methylation. A series of new flavonoids Mannich basederivatives4~12were synthesized from7,3′-O-dimethyl diosmetin and3′-O-dimethyldiosmetin, with formaldehyde and secondary amine under acidic conditions modifiedby Mannich reaction.2、 Acacetin3was synthesized from naringin, through I2/Py dehydrogenation,selective methylation, glycoside hydrolysis. A series of new Mannich base derivatives13~18were synthesized from acacetin, formaldehyde and secondary amine underacidic conditions in Mannich reaction, And the ammonia methyl was introducing inthe parent structure.3、Phloroglucinol as raw material, through F-C acylation, benzyloxy reaction,condensation of aldehydes and ketones, chalcone oxidative cyclization,Baker-Venkatarama rearrangement reaction, DMDO oxidation reaction, H2-Pd/Creduction reaction step in the synthesis of natural products kaempferol.4、 The synthesized Mannich base derivatives were evaluated foracetylcholinesterase (AChE) inhibition activity using the modified Ellman andmethod mesylate neostigmine as positive control. The results indicate that thecompounds4,5,6,7,9,15,17,18have a good acetylcholinesterase (AChE)inhibiting activity, the compound5(IC50=0.54μmol L-1) demonstrated strongeracetylcholinesterase inhibitory activity than the positive control drug Neoeserine methyl sulfate (IC50=1.38μmol L-1), the compound6(IC50=1.39μmol L-1) wassimilar to that of Neoeserine methyl sulfate.Fifteen unreported flavonoids Mannich base derivatives and two flavonolcompounds were synthesized. The structures of all synthesized compounds have beenconfirmed by more than one of the1H NMR,13C NMR and MS.