Synthesis And Bioactivity Of(E)-7-benzylidene-2,2-dimethyl-7,8-dihydro-2H-furo[3,2-H]Chroman-6(3H)-One

Based on the principle of combination,thirty-eight novel compounds were designed and synthesized by combining the pharmacophoric features of furo[3,2-h]chromen-6-one and ketone.Many of these compounds were investigated for their neuraminidase inhibitory activities and antitumor activities,and their structure-activity relationships were further discussed.Firstly,4-hydroxybenzaldehyde derivatives were obtained by substitution reaction using 4-hydroxybenzaldehyde as the initial raw material.Then,(E)-7-benzylidene-2,2-dimethyl-7,8-dihydro-2H-furo[3,2-h]chromen-6(3H)-ones(F)were synthesized by reacting aromatic aldehydes with 2,2-dimethyl-7,8-dihydro-2H-furo[3,2-h]chromen-6(3H)-one(D).The new compounds(F33-F35)were prepared through reduction of some target compounds containing nitro group with iron powders.Another three new compounds(F36-F38)were synthesized from compound F35 by the methylation reaction,N-acetylation reaction and methanesulfonylation reaction respectively.The synthetic compounds were characterized by 1H NMR and 13C NMR.(E)-7-(3-methoxybenzylidene)-2,2-dimethyl-7,8-dihydro-2H-furo[3,2-h]chromen-6(3 H)-one(F20)was further confirmed by X-Ray single crystal diffraction.X-Ray analysis displayed that F20 belongs to the monoclinic system,the benzene ring and the chroman-4-one ring plane are connected by C(12)=C(14),the dihedral angle is 38.4°,and confirmed an E configuration of C(12)=C(14)double bond as the center.The crystal structure was further stabled by intermolecular van der Waals force.The results of neuraminidase inhibitory activity indicated that most of the title compounds exhibited moderate to strong inhibitory activity,and had higher activity than the intermediate D.(E)-7-(4-hydroxybenzylidene)-2,2-dimethyl-7,8-dihydro-2H-furo[3,2-h]chromen-6(3H)-one(F14)showed the best activity and IC50 value was 8.16 μg/mL.The NA inhibition rates of the 12 compounds were greater than 50%at 40 μg/mL.The structure-activity relationships was analyzed,and the mode of action of compound F14 was further understood by molecular docking.The antitumor activities of the new compounds were tested against A549 and SW480 cell lines.The results showed that the inhibitory rates of the nine target compounds(F1,etc.)were more than 50%at 20 μM when SW480 had been tested.In addition,the inhibitory rate of compound F22 on SW480 cell line was 72.8%at 10μM,which showed a strong inhibitory effect.The results of A549 cell activity test showed that compounds F7 and F13 had some inhibitory effect on A549 cells and the inhibitory rates of them were 63.7%and 59.2%at 30 μM.Some compounds showed good inhibitory activity against two cancer cell lines.The inhibition rates of(E)-7-(3-chlorobenzylidene)-2,2-dimethyl-7,8-dihydro-2H-furo[3,2-h]chromen-6(3H)-one(F7)against the SW480 and A549 cell lines were 69.7%and 63.7%at 20 μM and 30 μM respectively.