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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\u2013hydrazone derivatives (1a\u20131e) 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 IC\u2085\u2080 values ranging from 8.66 to 13.9\u00a0\u00b5M, highlighting their strong neuroactive profiles. Notably, compound 1b emerged as the most effective AChE inhibitor (IC\u2085\u2080\u2009=\u20098.66\u00a0\u00b5M), 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\n                    <jats:italic>Acinetobacter baumannii<\/jats:italic>\n                    and\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    , with MIC values of 32\u00a0\u00b5g\/mL and 64\u00a0\u00b5g\/mL, respectively. Importantly, all derivatives (1a\u20131e) exhibited dose-dependent antibiofilm activity, achieving up to 83.4% biofilm disruption in\n                    <jats:italic>Acinetobacter baumannii<\/jats:italic>\n                    and 72.8% in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    at 1024\u00a0\u00b5g\/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\u2013hydrazone platform, establishes a clear structure\u2013activity relationship, and highlights its potential as a multifunctional therapeutic strategy against both neurodegenerative disorders and MDR bacterial infections.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05002-8","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T05:01:37Z","timestamp":1768885297000},"page":"9189-9201","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel triphenylphosphonium-hydrazone salts: integrated experimental and computational insights into AChE inhibition and resistance-overcoming antimicrobial and antibiofilm potential"],"prefix":"10.1007","volume":"399","author":[{"given":"Metin","family":"Y\u0131ld\u0131r\u0131m","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakan","family":"\u00dcnver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adem","family":"Necip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00fcsra","family":"Hord","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Ersatir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"5002_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2022.e10625","author":"A Akta\u015f","year":"2022","unstructured":"Akta\u015f A, Yakal\u0131 G, Demir Y, G\u00fcl\u00e7in \u0130, Ayg\u00fcn M, G\u00f6k Y (2022) The palladium-based complexes bearing 1, 3-dibenzylbenzimidazolium with morpholine, triphenylphosphine, and pyridine derivate ligands: synthesis, characterization, structure and enzyme inhibitions. 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