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Phthalazine-based quaternary ammonium salts: synthesis, biological evaluation and membrane-targeting mechanism

Wenwen Liu1, Weiling Guo2, Dong Xiao3

  • 1Department of Neurology, Weifang People's Hospital, The First Clinical Hospital of Shandong Second Medical University, Weifang, Shandong, China.

Frontiers in Microbiology
|July 6, 2026
PubMed

Insights

Novel phthalazine-derived quaternary ammonium compounds (QACs) show potent antibacterial activity against drug-resistant bacteria like MRSA. Compound 2n demonstrates broad-spectrum efficacy and a promising mechanism for combating infections.

Area of Science:

  • Medicinal Chemistry
  • Antimicrobial Agents
  • Drug Discovery

Background:

  • Antibiotic resistance, particularly from *Staphylococcus aureus* (MRSA), is a critical global health threat.
  • Quaternary ammonium compounds (QACs) offer a membrane-disruptive mechanism with reduced resistance potential compared to traditional antibiotics.

Purpose of the Study:

  • To design, synthesize, and evaluate novel phthalazine-derived QACs for antibacterial activity.
  • To identify lead compounds and elucidate their structure-activity relationships (SAR) and mechanisms of action.

Main Methods:

  • Synthesis of a series of phthalazine-derived QACs (compounds 2a-2v).
  • Antibacterial activity testing (MIC values) against various bacterial strains, including MRSA.
  • Hemolysis assays, resistance evolution studies, stability tests, and biofilm assays.
  • Mechanistic studies involving Gram staining, enzyme activity, membrane depolarization, leakage assays, SEM, DAPI/PI staining, molecular docking, and competitive displacement assays.

Main Results:

  • Compound 2n exhibited potent broad-spectrum activity against *S. aureus*, MRSA, *Streptococcus pneumoniae*, and *Klebsiella pneumoniae* (MIC = 2 μg/mL).
  • Compound 2n demonstrated rapid bactericidal effects, low cytotoxicity (HC50 > 64 μg/mL), minimal resistance development, and good stability.
  • Mechanistic studies confirmed membrane damage as the primary antibacterial action, with potential DNA binding as an auxiliary mechanism.

Conclusions:

  • Phthalazine-derived QACs represent a promising class of antibacterial agents.
  • Compound 2n shows significant potential for development as a therapeutic agent against drug-resistant bacterial infections.
Keywords:
antibacterialcell membranemechanism of actionphthalazinequaternary ammonium compounds

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