Optimization of biaryloxazolidinone as promising antibacterial agents against antibiotic-susceptible and antibiotic-resistant gram-positive bacteria
| Autor: | Yinliang Qi, Yifeng Yang, Yanfang Zhao, Yingxiu Li, Xiudong Ding, Mingze Qin, Lu Sun, Feng Hu, Yajing Liu, Yachuang Wu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Monoamine Oxidase Inhibitors
Cell Survival medicine.drug_class Gram-positive bacteria Antibiotics Microbial Sensitivity Tests Gram-Positive Bacteria 01 natural sciences Microbiology Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Antibiotic resistance Drug Resistance Bacterial Drug Discovery medicine Humans Monoamine Oxidase 030304 developmental biology Pharmacology 0303 health sciences Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Organic Chemistry Hep G2 Cells General Medicine biology.organism_classification Anti-Bacterial Agents Oxindoles 0104 chemical sciences chemistry Linezolid Microsome Chemical stability Antibacterial activity Bacteria |
| Zdroj: | European Journal of Medicinal Chemistry. 185:111781 |
| ISSN: | 0223-5234 |
| Popis: | We previously discovered a series of novel biaryloxazolidinone analogues bearing a hydrazone moiety with potent antibacterial activity. However, the most potent compound OB-104 exhibited undesirable chemical and metabolic instability. Herein, novel biaryloxazolidinone analogues were designed and synthesized to improve the chemical and metabolic stability. Compounds 6a-1, 6a-3, 14a-1, 14a-3 and 14a-7 showed significant antibacterial activity against the tested Gram-positive bacteria as compared to radezolid and linezolid. Further studies indicated that most of them exhibited improved water solubility and chemical stability. Compound 14a-7 had MIC values of 0.125–0.25 μg/mL against all tested Gram-positive bacteria, and showed excellent antibacterial activity against clinical isolates of antibiotic-susceptible and antibiotic-resistant bacteria. Moreover, it was stable in human liver microsome. From a safety viewpoint, it showed non-cytotoxic activity against hepatic cell and exhibited lower inhibitory activity against human MAO-A compared to linezolid. The potent antibacterial activity and all these improved drug-likeness properties and safety profile suggested that compound 14a-7 might be a promising drug candidate for further investigation. |
| Databáze: | OpenAIRE |
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