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

Abstract

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.