Synthesis,Antimicrobial Activity And Structure-activity Relationship Of Diester Substituted1,5-benzodiazepine Compounds

1,5-benzodiazepines are a class of biologically active molecules containing nitrogen heterocycles,Which possess unique physiological and pharmacological activities.Studies have shown that it possess anticonvulsant,antidepressant,treatment of insomnia,anxiolysis,calm and so on.In recent years,many studies have reported that 1,5-benzodiazepine widely used as anti-viral infection,inhibition of bacteria and fungi and so on.Therefore,the research on synthesis method and biological activity of 1,5-benzodiazepine has become one of the hotspots in drug synthesis.Our group has been devoted to the synthesis of 1,5-benzodiazepine compounds and the research of antibacterial activity.Series of novel structure 1,5-benzodiazepine were synthesized,and some compounds were found to have excellent antimicrobial activity that contain a ester group on the nitrogen heterocycle.Some studies have shown that the ester group is a active groups and the introduction of ester groups can effectively improve the antibacterial activity of the compound.In order to find the leading compounds of1,5-benzodiazepines with higher antibacterial activity,we designed and synthesized two novel series of 1,5-benzodiazepines with ester groups,investigated their antibacterial activity and structure-activity relationship.The main contents of this paper are as follows.1.Synthesis of 2-substituted aryl-4-propanoate-1,5-benzodiazepine derivatives with a cyclic ester chain structure introduced on the C-4 position of nitrogen heterocycle: The new amine structure of 2-substituted aryl-4-propanoate-1,5-benzodiazepine derivatives were synthesized though aldol condensation,nucleophilic addition and cyclization,where the ethyl levulinate,para-substituted benzaldehyde and substituted o-phenylenediamine were used as the raw material.The structures of all the compounds were confirmed by 1H NMR,IR,MS and elemental analysis.2.Synthesis and antibacterial activity of 2,3-diester-4-alkyl-1,5-benzodiazepines of diester-based structure: 30 kinds of novel 1,5-benzodiazepines with diester groups were synthesized using o-phenylenediamine or substituted ortho-phenylenediamine,dicarbonyl ester compound and ethyl glyoxylate as raw materials.All of the compounds werecharacterized by 1H NMR,13 C NMR,IR,MS and elemental analysis confirmed to be structurally correct.The possible reaction mechanism was proposed.The synthesis of2,3-diester-4-alkyl-1,5-benzodiazepines have been evaluated for their antifungal activity(C.neoformans,C.neoformans clinical isolates and C.albicans)and antibacterial activity(E.coli and S.aureus)by a filter paper method.The results showed that most of the compounds has high antibacterial activity,especially the inhibition zone diameter of compound IVu against C.neoformans clinical isolates was 29.70 mm.The value of MIC of compound IVu were found more potent than the reference drugs fluconazole against C.neoformans and C.neoformans clinical isolates.Therefore,the compound IVu can be considered lead compounds for drug development.3.From the qualitative point of view,the structure-activity relationship of different groups and antibacterial activity of the compounds was analyzed.And from the quantitative point of view,the structure-activity relationship was discussed by the DFT method on B3LYP/6-31 G level which obtain the related structural parameters.And a possible correlation QSAR(quantitative relationship between structure and antimicrobial activity)equation is established and validated.The structure-activity relationship can provide a theoretical basis for the prediction of the discovery of more active compounds.