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Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines
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NorA Efflux Pump Inhibitors: Expanding SAR Knowledge of Pyrazolo[4,3-c][1,2]benzothiazine 5,5-Dioxide Derivatives

Giada Cernicchi1, Alessandra Di Gregorio2, Tommaso Felicetti1

  • 1Department of Pharmaceutical Sciences, Università degli Studi di Perugia, Perugia, Italy.

Archiv Der Pharmazie
|May 20, 2025
PubMed

Insights

This study identifies new pyrazolobenzothiazine compounds that inhibit Staphylococcus aureus NorA efflux pumps, potentially overcoming antibiotic resistance. These inhibitors, when combined with ciprofloxacin, reduce bacterial biofilm formation.

Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Antimicrobial resistance (AMR) is a growing global health threat.
  • Microbial efflux pumps (EPs) are key mechanisms driving AMR by expelling antibiotics.
  • The Staphylococcus aureus NorA efflux pump contributes significantly to antibiotic resistance.

Purpose of the Study:

  • To discover novel molecular classes inhibiting the Staphylococcus aureus NorA efflux pump.
  • To explore the structure-activity relationship of pyrazolobenzothiazine derivatives as NorA efflux pump inhibitors (EPIs).

Main Methods:

  • Medicinal chemistry efforts involving design and synthesis of pyrazolobenzothiazine analogues.
  • Ethidium bromide efflux inhibition assays to identify NorA EPIs.
  • Synergistic assays with ciprofloxacin (CPX) against resistant bacterial strains.
  • Evaluation in NorA-overexpressing and NorA-knockout strains.

Main Results:

  • Identified three potent NorA EPIs (compounds 3, 10, and 19) from pyrazolobenzothiazine derivatives.
  • Confirmed synergy between novel EPIs and ciprofloxacin is NorA-dependent.
  • Demonstrated that combinations of NorA EPIs and ciprofloxacin reduce biofilm production in resistant strains.

Conclusions:

  • Novel pyrazolobenzothiazine derivatives show promise as NorA efflux pump inhibitors.
  • Ethidium bromide efflux assays are effective for rapid identification of NorA inhibitors.
  • Combined therapy with NorA EPIs and ciprofloxacin may offer a strategy to combat AMR and reduce biofilm formation.
Keywords:
NorAantibiotic resistance breakersciprofloxacinefflux pump inhibitorpyrazolobenzothiazine

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