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Novel biaryloxazolidinone derivatives with broad-spectrum antibacterial activity, favorable drug-like profiles and in vivo efficacy against linezolid-resistant Staphylococcusaureus.
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.
Afiliación
  • Duan M; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Qiu C; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Huang X; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Sun L; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • He X; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Wang Z; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Yue H; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Wang K; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Qi Y; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • Peng S; 3D BioOptima, 1338 Wuzhong Avenue, Suzhou, 215104, China.
  • Shi X; 3D BioOptima, 1338 Wuzhong Avenue, Suzhou, 215104, China.
  • Xi Z; 3D BioOptima, 1338 Wuzhong Avenue, Suzhou, 215104, China.
  • Tong M; 3D BioOptima, 1338 Wuzhong Avenue, Suzhou, 215104, China.
  • Ding X; Department of Clinical Laboratory, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, China.
  • Hou Y; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: houyunlei901202@163.com.
  • Zhao Y; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: yanfangzhao@126.com.
Eur J Med Chem ; 273: 116493, 2024 Jul 05.
Article en En | MEDLINE | ID: mdl-38761790
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pruebas de Sensibilidad Microbiana / Linezolid / Antibacterianos Límite: Animals / Humans / Male Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Francia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pruebas de Sensibilidad Microbiana / Linezolid / Antibacterianos Límite: Animals / Humans / Male Idioma: En Revista: Eur J Med Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Francia