title: Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents.
abstract: A series of novel 1,5-benzodiazepine derivatives were rationally designed and synthesized following the principle of the superposition of bioactive substructures by the combination of 1,5-benzodiazepine, pyridine (phenyl), and an ester group. The structures of the target compounds were determined by (1) H NMR, (13) C NMR, MS, IR, and elemental analysis. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi C. neoformans, C. neoformans clinical isolates (ATCC 32264), C. albicans (ATCC 10231), Gram-negative bacterium E. coli (ATCC 44752), and Gram-positive bacterium S. aureus (ATCC 25923). The results of the bioactive assay demonstrated that most of the tested compounds exhibited variable inhibitory effects on the growth of the tested microorganisms. All the active compounds showed better antifungal activity than antibacterial activity. Notably, compound 2b displayed the highest activity (MIC = 30 μg/mL) against C. neoformans and (MIC = 31 μg/mL) against C. neoformans clinical isolates. In addition, compound 2a also showed excellent activity against C. neoformans and C. neoformans clinical isolates with minimum inhibitory concentration of 35 and 36 μg/mL, respectively. Compounds 2a and 2b were further studied by evaluating their cytotoxicities, and the results showed that they have relatively low level cytotoxicity for BV2 and 293T cell. Preliminary structure-activity relationship study on three diverse sets (C-2, C-3, and C-8 positions) of 1,5-benzodiazepines was performed. The results revealed that the presence of a -CH3 group at the C-8 position had a positive effect on the inhibitory activity of these compounds. Additionally, the 2-pyridyl group at the C-2 position may be a pharmacophore and -COOC2 H5 at C-3 position is the best substituent for the maintenance of antimicrobial activities.
authors: College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.
authors: Ying-Shuang
authors: YS
authors: An
authors: College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.
authors: Zhen-Fang
authors: ZF
authors: Hao
authors: College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.
authors: Xiu-Jun
authors: XJ
authors: Zhang
authors: College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.
authors: Lan-Zhi
authors: LZ
authors: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000254:growth & development; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; C000615609:ethyl-4,8-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1,5-benzodiazepine-3-carboxylate; C000615608:ethyl-4-methyl-2-(pyridin-2-yl)-2,5-dihydro-1,5-benzodiazepine-3-carboxylate; D001569:Benzodiazepines
keywords: 1,5-benzodiazepine; antimicrobial activity; structure-activity relationship; synthesis