Design,Synthesis And Biological Evaluation Of Chiral Oxazine Fused Benzimidazole Derivatives

Benzimidazoles are a class of benzoheterocyclic compounds with two nitrogen atoms.The special structure and good coordination ability of benzimidazole endows the compound with various biological and physiological activities.Therefore,benzimidazoles are widely used in both the pharmaceutical and pesticide industries.Because of its great potential in antibacterial,anti-inflammatory,insecticidal,antiviral,and antitumor activity,development of novel bioactive benzimidazole derivatives have been one of the research hotspot in the medicinal field.In this paper,oxazine fused benzimidazoles and benzimidazolequinones derivatives were designed and synthesized from 1,4:3,6-dianhydro-D-fructose and substituted o-phenylenediamine.And the biological activity of the target compounds were also evaluated.The details are as follows:1.The reaction conditions were optimized for synthesis of furanoxazine fused benzimidazole derivatives starting from 1,4:3,6-dianhydro-D-fructose and o-phenylenediamine.A series of target compounds with various substitutions on aromatic ring and some compounds with modification on furan ring were prepared.2.A method has been developed for synthesis of oxazine fused benzimidazoles starting from furanoxazine fused benzimidazoles.A series of oxazine fused benzimidazole derivatives were synthesized.3.Based on the 8-methoxy substituted furooxazine fused benzimidazole,novel furanoxazine fused benzimidazolequinones derivatives were synthesized via a sequence of reactions including nitration,reduction,oxidation and substitution.4.By using MTT assay the inhibitory activity of the target compounds was evaluate on eight tumor cell lines such as human esophageal cancer cell TE1,human gastric cancer cell MGC-803 and breast cancer cell MCF-7 etc.The results showed that benzimidazolequinones derivatives and some individual benzimidazole derivatives have excellent antitumor activity.For example,the inhibitory activity of compound d6 against TE1 cell lines reached at a level of IC50 at 4.245 μM.5.Antiviral activity of the compounds was evaluated separately on respiratory syncytial virus(RSV),and hepatitis B virus(HBV).The results showed that some compounds have potent anti-RSV activity,but all have weak anti-HBV activity.In this thesis,73 compounds including 68 new compounds were synthesized.All the compounds were characterized by 1H NMR,13C NMR spectra and other necessary analytical methods.The substitution position on benzimidazole derivatives was determined by X-ray single crystal diffraction.Biological evaluation showed that some compounds are worth studying further.