The Research Of Synthesis, Antimicrobial Activity And SAR About 1,5-Benzodiazepines With Nitrogen-Containing Heterocyclic Group At 2-Position

1,5-Benzodiazepines and their derivatives are important nitrogen-containing heterocyclic compounds due to possess diverse physiological activities and biological properties. Benzodiazepines were first coined as the archetypal privileged substructure by Evans et al. in 1988. There are broad application prospects in the researches of new drugs. In recent years, some 1,5-benzodiazepines with high antimicrobial activity were found. Many 1,5-benzodiazepines derivatives have similar antimicrobial activity with the Nystatin and penicillin. Therefore, the research on synthesis method and biological activity of 1,5-benzodiazepines have become one of hot issues. For many years,our group has been interested in 1,5-benzodiazepine derivatives and prepared several series of 1,5-benzodiazepines. Many 1,5-benzodiazepines with excellent antimicrobial activity have been found. Among all the synthesized 1,5-benzodiazepines, 2-thiazole-3-ester-4- methyl- 1,5-benzodiazepine have the most antimicrobial activity and broad-spectrum inhibitory effect against all of the tested microorganisms. In order to obtained more 1,5-benzodiazepine derivatives with excellent antimicrobial activity, we designed and synthesized a novel series 1,5-benzodiazepine derivatives on the basis of lead compound 2- thiazole-3-ester-4- methyl- 1,5-benzodiazepine. The structures of the target compounds have been determined by 1H NMR, 13 C NMR, MS, IR and elemental analysis. All the synthesized compounds have been evaluated for their antimicrobial activities in vitro against fungi C. neoformans, C. neoformans clinical isolates(ATCC 32264), C. albicans(ATCC 10231), representative Gram-negative bacterium E. coli(ATCC 44752) and Gram-positive bacterium S. aureus(ATCC 25923). Preliminary structure-activity relationship has been studied. All the contents of this paper include four aspects as follows: 1. 16 4-methyl-2-(pyridin-2-yl)-2,5-dihydro-1,5-benzodiazepines have been synthesized in two steps. The reaction was conducted in the green solvent Et OH in the presence of PMA(H3PMo12O40) at ice-bath. Simple operation, short reaction time, high yields and environment friendly are the advantages of this method. In addition,all the synthesized compounds have been evaluated for their antimicrobial activities in vitro against C. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus. Theresults of bioactive assay showed that most of the tested compounds displayed variable inhibitory effects on the growth of the tested microorganisms. All the active compounds showed better antifungal activity than antibacterial activity. Preliminary structure-activity relationship has been studied. 2. 16 ester-4-methyl-2-(pyridin-2-yl)-2,5-dihydro-1,5-benzodiazepine-3-carboxylate derivatives have been synthesized by one-pot, three-component reaction of substituted 1,2-phenylenediamines, 2-pyridinecarboxaldehyde, and β-keto ester in the presence of a catalytic amount of silica-supported Fe Cl3(Fe Cl3-Si O2). The catalyst Fe Cl3-Si O2 was found highly active, robust, recovered and reuseable. Simple operation, short reaction time, high yield, environment friendly and the use of an inexpensive and readily available catalyst are the advantages of this method. 3. In continuation of our previous work on the researches of 1,5-benzodiazepines, we synthesized 17 1,5-benzodiazepines containing thiazole group on the basis of2-thiazole-3-ester-4- methyl-8-substituted 1,5-benzodiazepine with excellent antimicrobial activity. All the synthesized compounds have been evaluated for their antimicrobial activities in vitro against C. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus. 4. The relationship of their structures and antibacterial activities was discussed by DFT method on B3LYP/ 6-31 G level. Many datas were obtained including stereo configuration, bond lengths, bond angles, Mulliken charge, HOMO, LUMO and orbital contribution of the compounds.