Fragment-based Design,Synthesis Of Isatin Derivatives And Inhibitory Activity Against Human Monoamine Oxidase B

Parkinson’s disease(PD)is a chronic central nervous system degenerative disease,also known as "tremor palsy",which primarily affects the motor system.The patient’s symptoms generally manifest as involuntary tremors in the hands,head or mouth,muscle stiffness,slow movements,and posture balance disorders,etc.As a result,patients unable to take care of themselves.Studies have implicated that human monoamine oxidase-B(hMAO-B)can catalyze and oxidate a variety of monoamines including dopamine(DA),serotonin(5-hydroxytryptamine,5-HT).The activity of hMAO-B increased obviously with age.Meanwhile,the content of dopamine in the brain decreased significantly.Eventually led to PD.Therefore,developing highly effective,highly selective and safe hMAO-B inhibitors is essential to treat PD.Herein,we report our efforts to design and synthesis forty-eight compounds in five different but associated scaffolds,which were based on isatin,a fragment having weak activity against hMAO-B in an X-ray crystal structure(PDB ID:2XFP)by employing fragment-based and structure-based drug design strategy.All compounds were evaluated for their inhibitory activity against hMAO-A and hMAO-B.The data showed that a few compounds exhibited excellent activity and selectivity.Among them,compound A3 was 11 and 13 times more potent and 23.64 and 6.8 times more selective than the marked drugs,selegiline and safinamide.In addition,we observed that the polar 3-one carbonyl group of isatin was surrounded in a hydrophobic microenvironment.If it was converted into a suitable hydrophobic group,it may further increase its affinity against hMAO-B.Therefore,we carried out a series of modifications to this carbonyl group.However,the endeavors did not bring about improved hMAO-B inhibitors.To a certain extent,this result contradicts our understanding of the molecular interactions and molecular recognition in biological systems.