The Research On Synthesis And Antibacterial Activity Of1,5-benzodiazepines With Ester Groups And The Five-membered Heterocyclic Ring

This paper aims to synthesize a series of1,5-benzodiazepines which with potentiallybiologically active, then test their in vitro antibacterial activities, study the structure-activityrelationships, and develop a kind of new nitrogen-containing heterocyclic compounds withhigh antibacterial activity. First30kinds of novel2-aromatic heterocyclic-3-ester-4-methyl-8-substituted1,5-benzodiazepines were designed and synthesized by traditional two-stepmethod. The structures of all the products were characterised by1H NMR, IR, MS, elementalanalysis and single crystal diffraction. And their in vitro antimicrobial activities against fungi(C. neoformans and C. neoformans clinical isolates, C. albicans), representative Gramnegative bacteria (E. coli) and Gram positive bacteria (S. aureus) were examined. And studythe structure-activity relationships from the micro and macroscopic perspective respectively.In addition, this paper also used one-step, three-component synthesized14species2-aromaticheterocyclic-3-ester-4-methyl-7-substituted1,5-benzodiazepine. This method not only hasmild reaction conditions, simple operation, high efficiency and high product yield but alsomore important is environment-friendly. The following is the main content of the thesis:1. Screening of synthetic route and optimization of reaction conditions: This paperrelates to three starting compounds, they are o-phenylenediamine or substitutedo-phenylenediamine, ethyl acetoacetate and thiophene aldehyde, substituted thiophenealdehyde or thiazole aldehyde respectively. Designed three synthetic routes from which tochoose the optimal synthetic route and then experimental conditions were optimized. Thepossible reaction mechanism is proposed.2. Two-step:30kinds of novel2-aromatic heterocyclic-3-ester-4-methyl-8-substituted1,5-benzodiazepines were designed and synthesized by two-step method.3. One-pot: One-pot, three-component synthesis of14kinds of novel2-aromaticheterocyclic-3-ester-4-methyl-7-substituted1,5-benzodiazepines.4. Characterization: The structures of all the products were characterised by1H NMR, IR,MS, elemental analysis and so on.5. Antimicrobial Test: All the30kinds of2-aromatic heterocyclic-3-ester-4-methyl-8 -substituted1,5-benzodiazepines were evaluated for their in vitro antibacterial activity againstC. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus using diskdiffusion methods at200μg/disc concentration, the antibacterial results comparison withstandard drug fluconazole and ciprofloxacin. And then a more comprehensive study of thestructure-activity relationship shows that a thiazole group may be a pharmacophore of thiskind of compounds, it can increase biological activity and a broad spectrum of thesecompounds; Carbethoxy helps the compound maintain its antimicrobial activity at lowconcentrations; A substituent on the benzene ring will reduce the biological activity byincrease the volume of the compound; An electron-donating group (CH3) on the thienyl groupcan contribute to the selectivity against C. albicans specifically, but an electron-withdrawinggroup (Br) on the thienyl group can lead the compound has no antibacterial activity. The valueof MIC、MIC80、MFC were found more potent than Fluconazole about IVq and IVr against C.neoformans and clinical strain. IVq with an MIC value of40μg/mL against both S. aureusand E. coli, demonstrates equipotent antibacterial activity to the standard drug Ciprofloxacin.So compounds IVr and IVq can be considered lead compounds for drug development.6. DFT Method: The structure-activity relationships were discussed by DFT method onB3LYP/6-31G level. That can obtain the datas about bond lengths, bond angles, Mullikencharge, HOMO, LUMO and orbital contribution of the compounds. These are necessary tostudy of structure-activity relationship from the micro perspective. The results showed thatplanar configuration will decrease the antibacterial activity of this kind of compound, butdistorted structure can increase their antimicrobial capacity and broad-spectrum; Compoundshave more positively charged on C10and higher electron density on N7and N11can showhigher antibacterial activity; N11and C10show smaller contribution value for LUMO, N7andC9show larger contribution value for LUMO compounds display better antibacterial activity.