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<p>Neurodegenerative disorders and multidrug-resistant (MDR) bacterial infections represent two major and interconnected global health challenges. However, current therapeutic strategies are largely limited by single-target approaches, insufficient efficacy against biofilm-forming MDR pathogens, and the lack of multifunctional small molecules capable of addressing both neurodegeneration and bacterial resistance simultaneously. These limitations constitute a critical technical bottleneck in contemporary drug discovery and underscore the urgent need for innovative, dual-action therapeutic scaffolds. In this study, five novel triphenylphosphonium–hydrazone derivatives (1a–1e) were rationally designed, synthesized, and fully characterized by FT-IR, 1H/13C NMR, and HR-MS/MS analyses to overcome these challenges by integrating neuroprotective and antimicrobial functionalities within a single molecular framework. All synthesized compounds exhibited potent acetylcholinesterase (AChE) inhibitory activity, with IC₅₀ values ranging from 8.66 to 13.9&#xa0;µM, highlighting their strong neuroactive profiles. Notably, compound 1b emerged as the most effective AChE inhibitor (IC₅₀ = 8.66&#xa0;µM), underscoring its promise as a lead scaffold for the development of next-generation anti-Alzheimer agents. Beyond enzyme inhibition, the compounds demonstrated significant antibacterial efficacy against clinically relevant carbapenem-resistant pathogens. In particular, compound 1d showed the strongest activity against <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i>, with MIC values of 32&#xa0;µg/mL and 64&#xa0;µg/mL, respectively. Importantly, all derivatives (1a–1e) exhibited dose-dependent antibiofilm activity, achieving up to 83.4% biofilm disruption in <i>Acinetobacter baumannii</i> and 72.8% in <i>Escherichia coli</i> at 1024&#xa0;µg/mL, directly addressing a major resistance-associated bottleneck in antibacterial therapy. Molecular docking studies provided mechanistic validation of this multifunctional design, revealing a strong binding affinity of compound 1d toward PBP1A (PDB: 6OWS) and the AcrB efflux pump protein (PDB: 6PT1), suggesting a previously unexplored dual antibacterial mechanism involving simultaneous inhibition of cell-wall biosynthesis and efflux-mediated drug resistance. Overall, this study introduces a novel triphenylphosphonium–hydrazone platform, establishes a clear structure–activity relationship, and highlights its potential as a multifunctional therapeutic strategy against both neurodegenerative disorders and MDR bacterial infections.</p>

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Novel triphenylphosphonium-hydrazone salts: integrated experimental and computational insights into AChE inhibition and resistance-overcoming antimicrobial and antibiofilm potential

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月20日

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  • Metin Yıldırım,
  • Hakan Ünver,
  • Adem Necip,
  • Büsra Hord,
  • Mehmet Ersatir

摘要

Neurodegenerative disorders and multidrug-resistant (MDR) bacterial infections represent two major and interconnected global health challenges. However, current therapeutic strategies are largely limited by single-target approaches, insufficient efficacy against biofilm-forming MDR pathogens, and the lack of multifunctional small molecules capable of addressing both neurodegeneration and bacterial resistance simultaneously. These limitations constitute a critical technical bottleneck in contemporary drug discovery and underscore the urgent need for innovative, dual-action therapeutic scaffolds. In this study, five novel triphenylphosphonium–hydrazone derivatives (1a–1e) were rationally designed, synthesized, and fully characterized by FT-IR, 1H/13C NMR, and HR-MS/MS analyses to overcome these challenges by integrating neuroprotective and antimicrobial functionalities within a single molecular framework. All synthesized compounds exhibited potent acetylcholinesterase (AChE) inhibitory activity, with IC₅₀ values ranging from 8.66 to 13.9 µM, highlighting their strong neuroactive profiles. Notably, compound 1b emerged as the most effective AChE inhibitor (IC₅₀ = 8.66 µM), underscoring its promise as a lead scaffold for the development of next-generation anti-Alzheimer agents. Beyond enzyme inhibition, the compounds demonstrated significant antibacterial efficacy against clinically relevant carbapenem-resistant pathogens. In particular, compound 1d showed the strongest activity against Acinetobacter baumannii and Klebsiella pneumoniae, with MIC values of 32 µg/mL and 64 µg/mL, respectively. Importantly, all derivatives (1a–1e) exhibited dose-dependent antibiofilm activity, achieving up to 83.4% biofilm disruption in Acinetobacter baumannii and 72.8% in Escherichia coli at 1024 µg/mL, directly addressing a major resistance-associated bottleneck in antibacterial therapy. Molecular docking studies provided mechanistic validation of this multifunctional design, revealing a strong binding affinity of compound 1d toward PBP1A (PDB: 6OWS) and the AcrB efflux pump protein (PDB: 6PT1), suggesting a previously unexplored dual antibacterial mechanism involving simultaneous inhibition of cell-wall biosynthesis and efflux-mediated drug resistance. Overall, this study introduces a novel triphenylphosphonium–hydrazone platform, establishes a clear structure–activity relationship, and highlights its potential as a multifunctional therapeutic strategy against both neurodegenerative disorders and MDR bacterial infections.