Synthesis and in vitro antibacterial activity of gemifloxacin derivatives containing a substituted benzyloxime moiety

• Published in: European journal of medicinal chemistry Vol. 55; pp. 125 - 136
• Main Authors: Feng, Lianshun, Lv, Kai, Liu, Mingliang, Wang, Shuo, Zhao, Jing, You, Xuefu, Li, Sujie, Cao, Jue, Guo, Huiyuan
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.09.2012; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Bacteria - drug effects; Biological and medical sciences; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Fluoroquinolones - chemical synthesis; Fluoroquinolones - chemistry; Fluoroquinolones - pharmacology; Gemifloxacin derivatives; Hydrophobic and Hydrophilic Interactions; Life Sciences & Biomedicine; Medical sciences; Microbial Sensitivity Tests; Miscellaneous; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Oximes - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Synthesis; Antibacterial activity; Gemifloxacin derivatives; Synthesis; FLUOROQUINOLONES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.07.010

A series of novel gemifloxacin (GMFX) derivatives containing a substituted benzyloxime moiety with remarkable improvement in lipophilicity were synthesized. The target compounds evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that most of the target compounds have considerable potency against all of the tested Gram-positive strains including MRSA and MRSE (MIC: <0.008–8 μg/mL), although they are generally less active than the references against the Gram-negative strains. In particular, compound 11l (MIC: <0.008–4 μg/mL) was found to be 8–2048 and 2–128 times more potent than levofloxacin (LVFX) and GMFX against the Gram-positive strains, respectively. Moreover, against MRSA clinical isolates, 11l (MIC90: 1 μg/mL) is 8-fold more active than GMFX, and 2-fold more active than GMFX and moxifloxacin against MRSE clinical isolates (MIC90: 4 μg/mL). [Display omitted] A series of novel gemifloxacin derivatives with remarkable improvement in lipophilicity were synthesized and compound 11l is found to be 8–2048 and 2–128 times more potent than levofloxacin and gemifloxacin against the Gram-positive strains. ► Most of the compounds showed potent activity against Gram-positive strains. ► 11l was 2–2048 times more potent than levofloxacin and GMFX. ► 11l was more active than GMFX and moxifloxacin against MRSE clinical isolates. ► Structure–activity relationships of these compounds have been discussed.