title: 1,5-Benzodiazepine derivatives as potential antimicrobial agents: design, synthesis, biological evaluation, and structure-activity relationships.
abstract: 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).
authors: College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, People's Republic of China. wanglanzhi@126.com.
authors: Lan-Zhi
authors: LZ
authors: Wang
authors: Xiao-Qing
authors: XQ
authors: Li
authors: Ying-Shuang
authors: YS
authors: An
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D015725:Fluconazole / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D001569:Benzodiazepines; D015725:Fluconazole