1,5-Benzodiazepine derivatives as potential antimicrobial agents: design, synthesis, biological evaluation, and structure-activity relationships. 2015

Lan-Zhi Wang, and Xiao-Qing Li, and Ying-Shuang An
College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, People's Republic of China. wanglanzhi@126.com.

36 Novel 1,5-benzodiazepine derivatives were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,5-benzodiazepines, thiophene or thiazole and ester group. The structures of the target compounds have been characterized by IR, (1)H NMR, (13)C NMR, MS and elemental analysis. The structure of 1v was further determined using X-ray single crystal diffraction. All synthesized 1,5-benzodiazepine derivatives were evaluated for their in vitro antimicrobial activity against C. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus. The bioactive assay results revealed that most of the 1,5-benzodiazepine derivatives exhibited considerable potency against all of the tested strains. In particular, compounds 1v and 1w (MIC: 2-6 μg mL(-1), MFC: 10-14 μg mL(-1)) exhibited excellent antifungal activity and were found to be 32-64 and 9-12.8 times more potent than the reference drugs against C. neoformans, respectively. Moreover, compound (MIC: 40 μg mL(-1)) displayed equipotent antibacterial activity against E. coli and S. aureus compared to the reference drugs. The most potent of the synthesized compounds 1v and 1w were further studied by evaluating their cytotoxicities, and the results showed that they had relatively low level cytotoxicity for BV2 cell. A preliminary study of the structure-activity relationship revealed that substituents in the phenyl ring and the thiophene ring had a great effect on the antimicrobial activity of these compounds. In addition, the thiazole ring at C2 may be a pharmacophore of these compounds and COOC2H5 group at C3 is the best substituent for the maintenance of antimicrobial activities at low concentrations (1.5625 μg per disc).

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D000890 Anti-Infective Agents Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection. Anti-Infective Agent,Anti-Microbial Agent,Antimicrobial Agent,Microbicide,Microbicides,Anti-Microbial Agents,Antiinfective Agents,Antimicrobial Agents,Agent, Anti-Infective,Agent, Anti-Microbial,Agent, Antimicrobial,Agents, Anti-Infective,Agents, Anti-Microbial,Agents, Antiinfective,Agents, Antimicrobial,Anti Infective Agent,Anti Infective Agents,Anti Microbial Agent,Anti Microbial Agents
D001569 Benzodiazepines A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring. Benzodiazepine,Benzodiazepine Compounds
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015725 Fluconazole Triazole antifungal agent that is used to treat oropharyngeal CANDIDIASIS and cryptococcal MENINGITIS in AIDS. Apo-Fluconazole,Béagyne,Diflucan,Fluc Hexal,FlucoLich,Flucobeta,Fluconazol AL,Fluconazol AbZ,Fluconazol Stada,Fluconazol von ct,Fluconazol-Isis,Fluconazol-ratiopharm,Flunazul,Fungata,Lavisa,Loitin,Neofomiral,Oxifungol,Solacap,Triflucan,UK-49858,Zonal,Apo Fluconazole,Fluconazol Isis,Fluconazol ratiopharm,UK 49858,UK49858
D016923 Cell Death The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. Death, Cell
D018360 Crystallography, X-Ray The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) X-Ray Crystallography,Crystallography, X Ray,Crystallography, Xray,X Ray Crystallography,Xray Crystallography,Crystallographies, X Ray,X Ray Crystallographies
D020128 Inhibitory Concentration 50 The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture. IC50,Concentration 50, Inhibitory

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