2. Academic Validation
  3. Design, synthesis, and discovery of cinnamoyl amide derivatives as potent NagZ inhibitors with antibacterial activity

Design, synthesis, and discovery of cinnamoyl amide derivatives as potent NagZ inhibitors with antibacterial activity

  • Eur J Med Chem. 2025 Jul 5:291:117622. doi: 10.1016/j.ejmech.2025.117622.
Jian Fu 1,  Qingqing Wang 2,  Huixiao Fu 3,  Dan Wang 2,  Aurélie Mayard 4,  Weidong Pan 5,  Stéphane P Vincent 6
Affiliations

Affiliations

  • 1 College of Pharmacy, Guizhou University of Traditional Chinese Medicine/National Engineering Technology Research Center for Miao Medicine/Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guiyang, 550025, China; Department of Chemistry, University of Namur, NARILIS (Namur Research Institute for Life Sciences), Rue de Bruxelles 61, 5000, Namur, Belgium.
  • 2 College of Pharmacy, Guizhou University of Traditional Chinese Medicine/National Engineering Technology Research Center for Miao Medicine/Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guiyang, 550025, China.
  • 3 The First People's Hospital of Guiyang, Guiyang, 550002, China.
  • 4 Research Unit in Biology of Microorganisms (URBM), NARILIS (Namur Research Institute for Life Sciences), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium.
  • 5 School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: wdpan@163.com.
  • 6 Department of Chemistry, University of Namur, NARILIS (Namur Research Institute for Life Sciences), Rue de Bruxelles 61, 5000, Namur, Belgium. Electronic address: stephane.vincent@unamur.be.
PMID: 40249971 DOI: 10.1016/j.ejmech.2025.117622
Abstract

β-N-acetylglucosaminidase (NagZ) plays an important role in the Bacterial cell wall biosynthetic pathway. Inhibiting its activity could potentially impede Bacterial growth. We report a study on the design and synthesis of cinnamoyl amides derived from rosmarinic acid (RA), and their enzymatic, Antibacterial activity against NagZ and Pseudomonas aeruginosa respectively. In vitro enzyme activity determination showed that the best synthetic RA analogues displayed higher inhibitory activity than that of parent RA, in the same range than the most potent NagZ inhibitors reported so far. Remarkably, compounds 11h and Br-6 displayed interesting binding affinity values with Ki=3.3 ± 0.5 and 3.5 ± 1.0 μM, respectively. Docking simulations evidenced significant binding interactions of cinnamoyl amide derivatives with the active site of NagZ. Moreover, kinetic evaluations indicated these compounds displayed competitive behavior. Additionally, MICs of 11h and Br-6 combined with two β-Lactam Antibiotics (imipenem and ceftazidime) were evaluated against P. aeruginosa by microdilution checkerboard assay, establishing that Antibacterial agents show synergistic effects. In vivo Antibacterial efficacy assay using a full-thickness skin defect model with P. aeruginosa Infection confirmed these observations.

Keywords

Antibacterial activity; Cinnamoyl amide derivatives; Combination therapy; NagZ; Pseudomonas aeruginosa; β-lactamase.

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