Design And Synthesis Of α-Synuclein Fibrosis Inhibitor-like Probes And Binding Activity

Parkinson’s disease（PD）is a common disease in clinical practice today.The pathogenesis of PD is not fully understood.In recent years,many studies have shown that the aggregation and fibrillation ofα-synuclein（α-Syn）play a key role in the development of PD.Therefore,in the study of PD formation mechanism,the aggregation and fibrillation mechanism ofα-Syn is one of the current research hotspots.It has been found that an effective way for inhibitingα-Syn aggregation and fibrillation is to find a suitable molecular ligand to binding theα-Syn monomer at the lag phase,stabilizing the monomeric form ofα-Syn and maintaining its activity.1.As a potentialα-Syn aggregation inhibitor,the two series of sheet-like conjugated compounds have designed and synthesized,which possessed of different skeleton and various heteroatom in the two blocks located both ends of linker,and these compounds have goodπ-electron delocalization and high ability of hydrogen bonds formation.The structural formula is as follows:（?）2.A total of 23 new benzoxazoles and benzimidazoles conjugated pyridine analogs were synthesized.The key intermediate compound Int 1 was prepared from chloroacetonitrile and ethanol,Int 2,Int 3 was from pyridinaldehyde and acetaldehyde by aldol reaction,and Int 4 was from 1,3-dimethyl uracil.Benzoxazoles and benzimidazoles was synthesized from substituted aniline and Int 1.Finally,the target molecules were synthesized via Witting reaction.3.Evaluation of anti-aggregation activity of compounds onα-SynAll synthetic compounds were tested for their anti-aggregation activity in vitro.The results showed that the inhibition rate ofα-Syn aggregation by the compound ranged from 37.7%to 76.0%.Among them,compounds 3a,3b,3d,3j and 3o showed an inhibition rate of more than 70%.The IC₅₀0 of compound 3o was as low as 1.09μM,indicating a good activity of the compound.4.The possible binding mode of the ligand andα-Syn was calculated by AutoDock 4.2 software.The central domain polypeptide（NACore）of the NAC domain of monomerα-Syn（4RIL）and compound 3o was selected as model,the binding energy and inhibitory constant were obtained.The molecule is suggested binding in parallel to the NACore within NAC domain ofα-Syn,interfering aggregation of NAC region within differentα-Syn monomer,and further inhibiting or slowing down the formation ofα-Syn oligomer nuclei.