2. Academic Validation
  3. Design, synthesis, and biological evaluations of substituted pyrazoles as pyrrolomycin analogues against staphylococcal biofilm

Design, synthesis, and biological evaluations of substituted pyrazoles as pyrrolomycin analogues against staphylococcal biofilm

  • Eur J Med Chem. 2022 Jun 5;236:114309. doi: 10.1016/j.ejmech.2022.114309.
Xiang Huan 1,  Yanhui Wang 2,  Xiaofeng Peng 2,  Shanshan Xie 2,  Qian He 3,  Xiaofei Zhang 4,  Lefu Lan 5,  Chunhao Yang 6
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Jiangsu, 210046, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, 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 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 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].
  • 6 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Jiangsu, 210046, China; 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: 35398730 DOI: 10.1016/j.ejmech.2022.114309
Abstract

The formation of biofilm enables Staphylococcus aureus to resist Antibiotics and causes chronic infections. Several compounds of pyrrolomycins are potent Antibacterial agents which display inhibition upon staphylococcal biofilms. We designed and synthesized two series of substituted pyrazoles as pyrrolomycin analogues. Compounds 17a, 17d and 17h displayed potent Antibacterial activity against various vancomycin-resistant Enterococcus faecalis (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), and 17d showed the most potent activity against MRSA (MIC = 0.0625 μg/mL), vancomycin-intermediate Staphylococcus aureus (VISA) (MIC = 0.0313 μg/mL). Further study indicated that compound 17h could significantly reduce the biofilm formation of MRSA and exhibited promising selectivity. In vitro liver microsomal stability was also evaluated and the results manifested that 17h was metabolically stable in human liver microsomes.

Keywords

Antibacterial agents; Gram-positive drug-resistant bacteria; Pyrrolomycin analogues; Staphylococcal biofilm; Substituted pyrazoles.

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