2. Academic Validation
  3. Optimization of biaryloxazolidinone as promising antibacterial agents against antibiotic-susceptible and antibiotic-resistant gram-positive bacteria

Optimization of biaryloxazolidinone as promising antibacterial agents against antibiotic-susceptible and antibiotic-resistant gram-positive bacteria

  • Eur J Med Chem. 2020 Jan 1;185:111781. doi: 10.1016/j.ejmech.2019.111781.
Yachuang Wu 1,  Xiudong Ding 2,  Yifeng Yang 1,  Yingxiu Li 1,  Yinliang Qi 1,  Feng Hu 3,  Mingze Qin 1,  Yajing Liu 1,  Lu Sun 4,  Yanfang Zhao 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 2 Department of Clinical Laboratory, The 309th Hospital of Chinese People's Liberation Army, Beijing, 100091, China.
  • 3 School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 4 School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: lisunlu@126.com.
  • 5 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: yanfangzhao@126.com.
PMID: 31654879 DOI: 10.1016/j.ejmech.2019.111781
Abstract

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.

Keywords

Antibiotic-resistant infections; Biaryloxazolidinone; Gram-positive bacteria; Structural optimization.

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