Design,Synthesis,Bioactive Evaluation And Structure-activity Relationships Of 1,4-Benzodioxan Derivatives

Compounds containing a 1,4-benzodioxan skeleton have received significant attention in chemical,medicinal and pharmaceutical research as this structural scaffold has broad biological activities,such as antibacterial,anticancer and anti-inflammatory activities.Since its stability,low toxicity,activity diversity and unexpected activities enhancement in an organic molecule,therefore,it has become a hotspot of pharmaceutical research.In this thesis,we focus on the identification and modification of all kinds of bioactive small molecules using 1,4-benzodioxan as a basic skeleton.Means of Computer Aided Drug Design was utilized,in which,combined with Docking calculation and comparative molecular field analysis.We reported in the present work the synthesis,active screening and structure-activity relationships of five series of 1,4-benzodioxan derivatives on the basis of introducing pharmacophore skeleton,such as oxadiazole,piperazine and thiazolidinediones,72 of which were firstly reported.All of the compounds were characterized by elemental analysis,1H NMR,and MS spectra,and some compounds were characterized by 13C NMR as well.Besides,3 compounds were structurally determined by single crystal X-ray structural analysis.Many of the designed compounds have good anti-inflammatory,anticancer and antibacterial activities.The results were concluded as follows:(1)A series of seventeen novel MetAP2 inhibitors containing 1,4-benzodioxan and oxadiazole skeletons has been synthesized and tested their biological activities.Some compounds exhibited excellent activities with low toxicity,comparable to the positive control TNF-470(IC50 = 1.96 ?M for HUVEC).Compound A1 showed the best anti-proliferative activity(IC50?1.16 ?M)and inhibitory activity on MetAP2(IC50=2.08 ?M).Further apoptosis experiment showed that compound A1 could inhibit MetAP2 activity in cells and induce apoptosis.Computer simulation results showed that compound A1 not only forming a complex ligand functional group with Co2+ of protein MetAP2,but also deeping into the binding pocket to exert its function.Meanwhile,the hydrogen bonding and ?-? interactions between MetAP2 activity center and compound A1 provide a strong theoretical support for MetAP2 inhibitor studies.(2)A series of nineteen novel PLK1 inhibitors containing 1,4-benzodioxan and diacylhydrazine skeletons has been synthesized according to the introduction of diacylhydrazine skeleton.Docking simulation results exhibited that the interactions between the amino acid residues and the designed compounds were significantly improved through introduction of the diacylhydrazine backbone.Particularly,the binding energy between compound Bll(with m-methoxy substituent)and PLK1 was-37.7233 Kal/mol.This maybe because the electron-withdrawing groups can reduce the electron density of the benzene ring,making the active center larger and easier to be get in for the benzene ring.In addition,compound Bll showed the best inhibitory activities on cervical cancer cells(ICs50=0.17 ?M)and PLKI(IC50= 0.03 ?M),prior to the positive control Poloxin(IC50 = 2.31 ?M).(3)Keeping 1,4-benzodioxan and oxadiazole skeleton unchanged,a series of seventeen novel FAK inhibitors has been synthesized with piperazine ring instead of benzene ring,and tested their antitumor activities on four cancer cell lines(HepG2,Hela,SW1116 and BGC823).The results showed that most of the compounds had potential FAK inhibitory activities,and compound C13 showed the best inhibitory activity on FAK(IC50= 0.78 ?M).According to the results of active screening and structure-activity relationships,the electron-withdrawing groups can improve the electron density of FAK amino acid residues,making the compounds difficult to enter and play a role.While the ortho-substituent was wrapped by the optimal conformation compounds and the function was blocked,thereby it is beneficial for compounds to play the antitumor activities.(4)According to the combination principle,a series of twenty COX-2 inhibitors with 1,4-benzodioxan and piperazine as basic skeletons has been designed.First,using the computer-aided drug design software,eleven compounds with better activities were screened and synthesized according to the energy situation scoring.The crystal structure of compounds Dl,D3 and D7 were determined by single crystal X-ray diffraction analysis.And then tested a series of anti-inflammatory activities.According to the carrageenan-induced swelling experiments in rats foot-being,analgesic activities and ulcer experiments,compound Dll was performed the best anti-inflammatory(92%inhibition rate),and without ulcer side effect,which is a potential efficiency and low toxicity drug.In addition,the in vitro experiment showed that compound Dll was a highly selective COX-2 inhibitor.(5)A series of eighty thiazolidinedione derivatives with 1,4-benzodioxan as a basic skeleton has been designed with computer simulation technology.Seventeen compounds were chosen according to the bing energy.Then six potential drugs were selected and tested their antibacterial and FabH inhibitory activities by ADMET simulation.The experimental results showed that the activities against Gram-negative bacteria is much better than Gram-positive bacteria,and the IC50 values are generally less than 5 ?M.Activities of individual compounds is much better than the positive control Penicillin(IC50 = 6.25 ?M).The results of FabH inhibitory activities of the tested compounds were in agreement to the structure relationships of their antibacterial activities.This agreement suggested that antibacterial activities of the synthesized compounds may be derived from the inhibition of FabH enzymatic activities.The experiment results indicated that the compound E10(IC50 = 1.56 ?M for E.coli and IC50 = 0.06 ?M for FabH)was a potential FabH inhibitor.