Design,Synthesis And Biological Activity Evaluation Of Novel Benzimidazole And Benzimidazoledione Derivatives

Benzimidazole is a heterocyclic compound containing two nitrogen atoms,which is the basic skeletons of many drugs.Benzimidazole derivatives have a wide variety of biological activities such as antitumor,anti-parasites,antipeptic ulcer,antibacterial,antifungal,anti-tubercular,antiviral,antihypertensive etc.Benzoquinone is the core of many drugs,and its derivatives possess a variety of biological activities such as antitumor,antibacterial and anti-inflammatory etc.The synthesis of novel benzimidazole and quinone derivatives is an effective way to discover new drugs.As an important class of natural chiral compounds,sugar plays a vital role in pharmaceutical field.In this paper,different substituted o-phenylenediamines reacted with 1,4:3,6-dianhydro-D-fructose to yield chiral furanoxazine fused benzimidazoles.By modifying the furan ring,we synthesized a series of 3-substituted furanoxazine fused benzimidazole derivatives.On the basis of the synthesis of furanoxazine fused benzimidazoles,furanoxazine fused benzimidazole-7,10-dione amino substituted derivatives and oxazine fused benzimidazole-6,9-dione amino substituted derivatives were obtained via further structural modification.The activity studies in vitro of all compounds showed that some benzimidazole derivatives have antiviral activity,and most of benzimidazoledione derivatives have antitumor activity.1.Different substituted o-phenylenediamines and 1,4:3,6-dianhydro-D-fructose yielded furanoxazine fused benzimidazoles via condensation reactions.The sulfonylation reaction,substitution reaction and click reaction were used to introduce3-sulfonate,3-azide and 3-（1,2,3-triazole）in sequence to synthesize a series of 3-substituted furanoxazine fused benzimidazole derivatives.The SAR study of the target compounds on anti-RSV activity by the MTT method showed that C-3 of furanoxazine fused benzimidazole derivatives is a potentially sensitive site for anti-RSV activity.2.3,6-Dimethoxy-o-phenylenediamine was used as the starting material to yield furanoxazine fused benzimidazole-7,10-dione via condensation and oxidation reactions.By following introduction of different amino groups,a series of furanoxazine fused benzimidazole-7,10-dione amino substituted derivatives were obtained.The SRB staining method was used to evaluate the antitumor activities of compounds against human gastric cancer cells（MGC-803）,human breast cancer cells（MCF-7）,human esophageal cancer cells（EC109）and human cervical cancer cells（Hela）in vitro.The results showed that the aniline-substituted derivatives have good antitumor activity,while the aliphatic amine-substituted derivatives have not obvious antitumor activity.3.On the basis of furanoxazine fused benzimidazole derivatives,the furan ring was opened by LAH to yield oxazine fused benzimidazole,which was then converted into oxazine fused benzimidazole-6,9-dione by oxidation.By following introduction of different amino groups,a series of oxazine fused benzimidazole-6,9-dione amino substituted derivatives were obtained.The activity evaluation of the target compounds against four human cancer cell lines showed that the aniline-substituted derivatives have good antitumor activity,which are not better than their counterpart furanoxazine fused benzimidazole-7,10-dione amino substituted derivatives.In this paper,106 compounds including 104 new compounds were synthesized.All compounds were confirmed by ¹H NMR and ¹³C NMR.According to the results of biological activity in vitro,compounds I-01a and II-17b can be used for further biological mechanism research.