2. Academic Validation
  3. Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates

Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates

  • Eur J Med Chem. 2024 Feb 5:265:116107. doi: 10.1016/j.ejmech.2023.116107.
Jing Zhang 1,  Yi-Min Tan 1,  Shu-Rui Li 1,  Narsaiah Battini 1,  Shao-Lin Zhang 2,  Jian-Mei Lin 3,  Cheng-He Zhou 4
Affiliations

Affiliations

  • 1 Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
  • 2 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, China. Electronic address: zhangsl@cqu.edu.cn.
  • 3 Department of Infections, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China. Electronic address: linjianmei@med.uestc.edu.cn.
  • 4 Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China. Electronic address: zhouch@swu.edu.cn.
PMID: 38171147 DOI: 10.1016/j.ejmech.2023.116107
Abstract

Unique benzopyridone cyanoacetates (BCs) as new type of promising broad-spectrum Antibacterial candidates were discovered with large potential to combat the lethal multidrug-resistant Bacterial infections. Many prepared BCs showed broad Antibacterial spectrum with low MIC values against the tested strains. Some highly active BCs exhibited rapid sterilization capacity, low resistant trend and good predictive pharmacokinetic properties. Furthermore, the highly active sodium BCs (NaBCs) displayed low hemolysis and cytotoxicity, and especially octyl NaBC 5g also showed in vivo potent anti-infective potential and appreciable pharmacokinetic profiles. A series of preliminary mechanistic explorations indicated that these active BCs could effectively eliminate Bacterial biofilm and destroy membrane integrity, thus resulting in the leakage of Bacterial cytoplasm. Moreover, their unique structures might further bind to intracellular DNA, DNA gyrase and Topoisomerase IV through various direct noncovalent interactions to hinder Bacterial reproduction. Meanwhile, the active BCs also induced Bacterial oxidative stress and metabolic disturbance, thereby accelerating bacterial Apoptosis. These results provided a bright hope for benzopyridone cyanoacetates as potential novel multitargeting broad-spectrum Antibacterial candidates to conquer drug resistance.

Keywords

Antibacterial; Cyanoacetate; Quinolone; Resistance.

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