Novel biaryloxazolidinone derivatives with broad-spectrum antibacterial activity, favorable drug-like profiles and in vivo efficacy against linezolid-resistant Staphylococcusaureus

• Published in: European journal of medicinal chemistry Vol. 273; p. 116493
• Main Authors: Duan, Meibo, Qiu, Chuang, Huang, Xinyu, Sun, Lei, He, Xinzi, Wang, Zechen, Yue, Hao, Wang, Kun, Qi, Yinliang, Peng, Shan, Shi, Xuan, Xi, Zhiguo, Tong, Minghui, Ding, Xiudong, Hou, Yunlei, Zhao, Yanfang
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.07.2024
• Subjects: Antibacterial activity; Biaryloxazolidinone; Drug-resistant bacteria; Druglikeness; Structure-activity relationships; Antibacterial activity; Druglikeness; Drug-resistant bacteria; Structure-activity relationships; Biaryloxazolidinone
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116493

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 μg/mL), MSSA (MIC = 0.125 μg/mL), MRSA (MIC = 0.06 μg/mL), LRSA (MIC = 0.125 μg/mL) and LREFa (MIC = 0.5 μg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0−t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection. [Display omitted] •26 biaryloxazolidinone analogues were designed and synthesized.•Compound 8b showed potent antibacterial activity against MDR Gram-positive bacteria.•Compound 8b showed excellent PK and safety profiles.•Compound 8b showed potent in vivo efficacy in a mouse model of LRSA systemic infection.