Synthesis and antibacterial activity evaluation of novel biaryloxazolidinone analogues containing a hydrazone moiety as promising antibacterial agents

• Published in: European journal of medicinal chemistry Vol. 158; pp. 247 - 258
• Main Authors: Wu, Yachuang, Ding, Xiudong, Ding, Liang, Zhang, Yongsheng, Cui, Lei, Sun, Lu, Li, Wei, Wang, Di, Zhao, Yanfang
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.10.2018; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Biaryloxazolidinone; Chemistry, Medicinal; Gram-Positive Bacteria - drug effects; Gram-Positive Bacterial Infections - drug therapy; Gram-positive organisms; Hep G2 Cells; Humans; Hydrazone moiety; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - metabolism; Hydrazones - pharmacology; Life Sciences & Biomedicine; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Molecular Docking Simulation; Oxazolidinones - chemical synthesis; Oxazolidinones - chemistry; Oxazolidinones - metabolism; Oxazolidinones - pharmacology; Pharmacology & Pharmacy; Science & Technology; Gram-positive organisms; Antibacterial activity; Hydrazone moiety; Biaryloxazolidinone; DESIGN; ANTIBIOTICS; GRAM-POSITIVE INFECTIONS; RESISTANCE; STAPHYLOCOCCUS-AUREUS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.09.004

A series of linezolid analogues containing a hydrazone moiety were designed, synthesized and evaluated for their antibacterial activity. Most compounds exhibited more potent antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Compounds 9a, 9c, 9f, 9g, 10m and 10t were more potent against tested clinical isolates of MRSA, MSSA, VRE and LREF as compared to linezolid. Compound 9a exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9a showed remarkable antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.0675 mg/mL, respectively, which was 15- to 30-fold more potent than linezolid. [Display omitted] •Biaryloxazolidinone analogues containing a hydrazone moiety.•Compound 9a exhibited a MIC value of 0.0675 μg/mL against all tested bacteria.•The potency of 9a against LREF was 15–30-fold higher than that of linezolid.•9a exhibited comparable inhibitory activity with linezolid against human MAO-A.