Synthesis And Biological Activities Evaluation Of3-Butyl-1(3H)-isobenzofuranone Derivatives

Objective To develop3-n-Butylphthalide(NBP) derivatives with anti-platelet activity orantioxidant activity by modificated NBP with aspirin, salicylic acid, acetyl ferulic acidand edaravone.MethodsPart one: Design and syntheses of target compoundsUsing NBP as a leading compound, we designed and synthesized11new targetcompounds.3-Butyl-6-amino-1(3H)-isobenzofuranone and3-butyl-6-hydrazinyl-1(3H)-isobenzofuranone were achieved from2-formyl benzoic acid by grignard reaction, nitration,reduction, diazotization and reduction. I1-I3were obtained by the acylation of3-butyl-6-amino-1(3H)-isobenzofuranone with aspirin, salicylic acid and acetyl ferulicacid respectively. II1-II8were obtained from3-butyl-6-amino-1(3H)-isobenzofuranonewith β-dicarbontl compounds by condensation. Spectral analysis (IR,1H-NMR,13C-NMR） were used to identifie the structures of all the synthesized compounds.Part two: Preliminary biological activities evaluation of target compounds(1) Anti-platelet aggregation assay：The inhibition of platelet aggregation of thecompounds was tested by microplate-reader-nephelometry method in vitro．The positivecontrol drugs are aspirin and NBP.(2) Hydroxyl radical scavenging assay：The scavenging hydroxyl radical activitywas evaluated by using the H2O2-Fe2+hydroxyl radica’s detection system with VitaminC and edaravone as positive control drugs.ResultsThree compounds I1-I3were got by coupled reactions between NBP and aspirin,salicylic acid and acetyl ferulic acid. In view of the chemical structure of NBP andedaravone, eight compounds were synthesized which the pharmaophores of the twodrugs were incorporated into one molecule. All the synthesized compounds have notbeen reported in literature, and their chemical structures were confirmed by IR,1H-NMRand13C-NMR．Part two: Preliminary biological activities evaluation of target compounds: evaluation of anti-platelet activities and scavenging hydroxyl radical activities of targetcompounds(1) evaluation of anti-platelet activities of target compoundsAccording to the results, compound I3((E)-4-(3-((1-butyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)amino)-3-oxoprop-1-en-1-yl)-2-methoxyphenyl acetate) andII6(1-(1-butyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(4-methoxyphenyl)-1H-pyrazol-5(4H)-one) showed higher inhibitory activity against rabbit platelet aggregation inducedby ADP in vitro than thats of aspirin and NBP, with the inhibition rates of45.37%,43.46%,39.12%and33.40%at100μmol/L，respectively．Especially，compound I3displayed excellent activity,better than that of NBP(p<0.05).(2) evaluation of scavenging hydroxyl radical activities of target compoundsAccording to the results, compound II4(1-(1-butyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-3-isopropyl-1H-pyrazol-5(4H)-one) and II5(1-(1-butyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-3-phenyl-1H-pyrazo-5(4H)-one) have more activitives(p<0.05) than thats of the positive control edaravone， with the hydroxyl radicalscavenging activity rates of55.68±2.23%,56.27±2.28%and34.81±2.50%at2mmol/L，respectively．Conclusion The results of preliminary biological activities evaluation show thatthe activities of the compound I3, II4, II5and II6need further research.