Design, Synthesis And Evaluation Of4-dimethylamine Flavonoid Derivatives

Flavonoids are natural compounds widely distributed in nature, which are a class of polyphenoliccompounds. And flavonoids are secondary metabolites produced by plants through photosynthesis, andhave various biological activities, such as antioxidant, anti-tumor, anti-radiation, anti-inflammatory,hypoglycemic effect, anti-bacterial anti-viral, anti-osteoporosis, anti-cardiovascular disease effect andimmune regulation. Thus, flavonoids have been widely used in medicine, health products. Since flavonoidsshowed multiple physiological activity, causing the research interest of researchers. So far, a lot ofsynthesis methods of flavonoids have been reported, providing more flexibility for subsequent research.But its biological activity performance is not satisfactory. Therefore, modification of the flavonoids andoptimized for the biological activity of the compound preferably has an important significance.Alzheimer’s disease is also called senile dementia, is a neurodegenerative disease that characterized byprogressive memory and cognitive dysfunction. Cholinergic hypothesis thought that, the leading cause ofAD’s is droping of cholinergic nerve function. Acetylcholine (ACh) widely present in the brain. And it is animportant neurotransmitter in the central nervous system, plays an important role in learning and memory.With the development of AD disease, cholinergic neurons appears irreparable damage, resulting insignificant reduction of choline neurotransmitter in the hippocampus and cerebral cortex of patients.Reduction of choline neurotransmitter leads to decreased synthesis of ACh in the brain, so that AChreceptors sensitive reduced levels of ACh and decrease, causing the patient to reduce the cognitive abilityand memory. ACh is still hydrolysised by acetylcholinesterase (AChE), leading to the contents of AChlower and lower. This will lead to a vicious cycle. Many experiments and clinical trials have been proven that preventing acetylcholinesterase to hydrolysis ACh can alleviate dementia processes. According to thehypothesis, a series of flavonoids were designed and synthesized, hoping to find a better cholinesteraseinhibitor and to research their structure-activity relationships, for the compounds’ design and activityresearch provide evidence in the next step.N, N-dimethyl-flavone derivatives have strong affinity for Aβ, and which comprising N,N-dimethyl-aromatic ring have a good resistance to oxidation. So we choose N, N-dimethyl flavone asnucleus. According to the crystal structure of cholinesterase, we used amino group with different chainlength to connect to the flavonoid nucleus terminal, in order to simultaneously act on the two active siteof cholinesterase, enhance inhibitory activity. Meanwhile, we hope to retain the nucleus’ antioxidantcapacity and its affinity for Aβ.We designed and synthesised eighteen novel flavonoids as potential multi-target anti-AD drugs, andtested their inhibition activities of two cholinesterases. Final we discussed their structure-activityrelationships. We study these compounds’ binding mode with AChE and BChE by enzyme inhibitionkinetics and molecular docking method. And for some compounds,we test the vitro inhibition of Aβself-aggregation experiments, anti-oxidation experiments and cytotoxicity test. The results showed that thesynthetic flavonoids showed good cholinesterase inhibitory activity. IC50values were close to thenanomolar level. And compounds having better BChE inhibitory activity. When compounds having thesame chain length and the substituent is diethylamine and pyrrole, these compounds have better activity ofAChE. AChE inhibition kinetics and molecular docking experiments showed that5j is typically mixedinhibition indicates that such derivatives simultaneously interact with he catalytic active site (CAS) and theperipheral anionic site of AChE. The results of A42self-aggregation inhibition test show that the testedcompounds can prevent A42self-aggregation, the best compound is5r, and inhibition rate was48.13%, and similarity to curcumin which is the reference compounds (51%). Anti-oxidation experiments andcytotoxic experiments show that5o has strong antioxidant capacity, the measured compounds’ ORAC valuerange from1.5to2.6; most compounds have vary degrees suppression on HepG2cells and normal livercells QSG-7701, and concentration-dependent.In summary, the compound5o is performance in all aspects, can be used as a reference designcompounds in the next step. It also describes that these flavonoids have increased activity and the purposeof multi-target effects, so these compounds have developed into a multi-targeted drugs to treat ADapplication prospects.