Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
Department of Clinical Laboratory, The 309th Hospital of Chinese People's Liberation Army, Beijing, 100091, China.
Eur J Med Chem. 2020 Jan 1;185:111781. doi: 10.1016/j.ejmech.2019.111781. Epub 2019 Oct 14.
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.
我们之前发现了一系列具有潜在抗菌活性的新型联苯恶唑烷酮类似物，其中含有腙部分。然而，最有效的化合物 OB-104 表现出不理想的化学和代谢不稳定性。在此，设计并合成了新型联苯恶唑烷酮类似物，以提高其化学和代谢稳定性。与雷迪沙星和利奈唑胺相比，化合物 6a-1、6a-3、14a-1、14a-3 和 14a-7 对测试的革兰氏阳性菌具有显著的抗菌活性。进一步的研究表明，它们中的大多数具有改善的水溶性和化学稳定性。化合物 14a-7 对所有测试的革兰氏阳性菌的 MIC 值为 0.125-0.25μg/mL，对抗生素敏感和耐药的临床分离菌具有优异的抗菌活性。此外，它在人肝微粒体中稳定。从安全性角度来看，它对肝细胞没有细胞毒性，并且对人 MAO-A 的抑制活性低于利奈唑胺。强大的抗菌活性以及所有这些改善的药物特性和安全性特征表明，化合物 14a-7 可能是进一步研究的有前途的候选药物。
