Design, synthesis and biological evaluation of thiazolyl-halogenated pyrroles or pyrazoles as novel antibacterial and antibiofilm agents

  • Eur J Med Chem. 2024 Feb 15:268:116221. doi: 10.1016/j.ejmech.2024.116221.
Yuanchen Zhong  1 ,  Huan Liu  2 ,  Feifei Chen  2 ,  Qian He  3 ,  Xiaofei Zhang  4 ,  Lefu Lan  5 ,  Chunhao Yang  6
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Department of Chemistry, Shanghai University, Shanghai 200444, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: [email protected].
  • 5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
PMID: 38382392 DOI: 10.1016/j.ejmech.2024.116221
Abstract

The formation of biofilm is one of the important factors for bacteria to develop drug-resistant. A series of halogenated-pyrroles or pyrazoles containing thiazole groups as Antibacterial agents were designed and synthesized to target biofilms. Among them, compound 8c showed Antibacterial activity against various Gram-positive bacteria, particularly against vancomycin-resistant Enterococcus faecalis (MIC ≤0.125 μg/mL). Additionally, this compound significantly inhibited biofilm formation of Staphylococcus aureus and Pseudomonas aeruginosa at sub-MIC doses. Furthermore, compound 8c exhibited significantly lower mammalian cell toxicity compared to pyrrolomycin C and its hepatic microsomal metabolic stability in various species was also evaluated. Further experiment on the Infection model of Galleria mellonella proved that the compound was effective in vivo.

Keywords
Anti-biofilm; Antibacterial agents; Drug-resistant bacteria; Pyrrolomycin analogues; Thiazole.
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