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Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents.
Chem Biol Drug Des. 2016 07; 88(1):110-21.CB

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+Show Affiliations

College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, 050024, China.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26850700

Citation

An, Ying-Shuang, et al. "Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents." Chemical Biology & Drug Design, vol. 88, no. 1, 2016, pp. 110-21.
An YS, Hao ZF, Zhang XJ, et al. Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents. Chem Biol Drug Des. 2016;88(1):110-21.
An, Y. S., Hao, Z. F., Zhang, X. J., & Wang, L. Z. (2016). Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents. Chemical Biology & Drug Design, 88(1), 110-21. https://doi.org/10.1111/cbdd.12739
An YS, et al. Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents. Chem Biol Drug Des. 2016;88(1):110-21. PubMed PMID: 26850700.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents. AU - An,Ying-Shuang, AU - Hao,Zhen-Fang, AU - Zhang,Xiu-Jun, AU - Wang,Lan-Zhi, Y1 - 2016/03/06/ PY - 2015/09/20/received PY - 2016/01/22/revised PY - 2016/01/26/accepted PY - 2016/2/7/entrez PY - 2016/2/7/pubmed PY - 2017/3/14/medline KW - 1,5-benzodiazepine KW - antimicrobial activity KW - structure-activity relationship KW - synthesis SP - 110 EP - 21 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 88 IS - 1 N2 - 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. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/26850700/Efficient_Synthesis_and_Biological_Evaluation_of_a_Novel_Series_of_15_Benzodiazepine_Derivatives_as_Potential_Antimicrobial_Agents_ L2 - https://doi.org/10.1111/cbdd.12739 DB - PRIME DP - Unbound Medicine ER -