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Abstract <p><b>Objective:</b> Alzheimer’s disease (AD) and microbial infections represent critical global health challenges, particularly within aging populations. Owing to their structural versatility and multi-target pharmacophores, Schiff bases serve as privileged scaffolds for the design of dual-acting therapeutic agents targeting both AD progression and infectious pathogens. <b>Methods:</b> In this study, a novel series of seven Schiff base derivatives (<b>PSD1–PSD7</b>) was synthesized and evaluated for their cholinesterase inhibitory potency and antibacterial efficacy. Antibacterial activity against Gram-positive and Gram-negative strains was quantified <i>via</i> zone of inhibition and minimum inhibitory concentration (MIC) assays. Inhibitory profiles against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were systematically determined. Furthermore, molecular docking and binding pocket analyses were performed on AChE (PDB ID: 1EVE), BuChE (PDB ID: 7AWH), and peptide deformylase (PDB ID: 1G2A) to elucidate the structural basis of enzyme inhibition and microbial survival disruption. <b>Results and Discussion:</b> Among the synthesized library, derivative <b>PSD2</b> emerged as the most potent candidate, displaying remarkable AChE inhibition (IC<sub>50</sub> = 2.71 µM, selectivity ratio = 10.62) that significantly outperformed the reference drug galantamine (IC<sub>50</sub> = 20.3 µM, selectivity ratio = 4.24). In antimicrobial assays, compounds <b>PSD2</b> and <b>PSD4</b> exhibited broad-spectrum efficacy with low MIC values (0.8–2.0 µmol/mL), comparable to the standard antibiotic gentamicin. Computational molecular docking corroborated these experimental findings; <b>PSD2</b> exhibited superior binding affinities within the catalytic gorges of both cholinesterases relative to galantamine, yielding docking scores of –10.7 kcal/mol for AChE and –10.1 kcal/mol for BuChE. <b>Conclusions:</b> A new series of functionally diverse Schiff base derivatives was designed, synthesized, and biologically validated. The exceptional dual cholinesterase inhibition and broad-spectrum antimicrobial profiles demonstrated by <b>PSD2</b> and <b>PSD4</b> underscore their potential as multifunctional lead architectures for disease-modifying therapeutic development.</p>

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Dual Cholinesterase Inhibition and Antimicrobial Activity of 4-Aminoantipyrine-Derived Schiff Bases for the Management of Alzheimer’s Disease and Microbial Infections

  • 期刊论文

  • 发表日期：

    2026年7月28日

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  • Prasad Sanjay Dhiwar,
  • Pronoy Kanti Das,
  • Samir Panda,
  • Prasenjit Prasad,
  • Vishal Zambre,
  • Fernando Berton Zanchi

摘要

Abstract

Objective: Alzheimer’s disease (AD) and microbial infections represent critical global health challenges, particularly within aging populations. Owing to their structural versatility and multi-target pharmacophores, Schiff bases serve as privileged scaffolds for the design of dual-acting therapeutic agents targeting both AD progression and infectious pathogens. Methods: In this study, a novel series of seven Schiff base derivatives (PSD1–PSD7) was synthesized and evaluated for their cholinesterase inhibitory potency and antibacterial efficacy. Antibacterial activity against Gram-positive and Gram-negative strains was quantified via zone of inhibition and minimum inhibitory concentration (MIC) assays. Inhibitory profiles against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were systematically determined. Furthermore, molecular docking and binding pocket analyses were performed on AChE (PDB ID: 1EVE), BuChE (PDB ID: 7AWH), and peptide deformylase (PDB ID: 1G2A) to elucidate the structural basis of enzyme inhibition and microbial survival disruption. Results and Discussion: Among the synthesized library, derivative PSD2 emerged as the most potent candidate, displaying remarkable AChE inhibition (IC50 = 2.71 µM, selectivity ratio = 10.62) that significantly outperformed the reference drug galantamine (IC50 = 20.3 µM, selectivity ratio = 4.24). In antimicrobial assays, compounds PSD2 and PSD4 exhibited broad-spectrum efficacy with low MIC values (0.8–2.0 µmol/mL), comparable to the standard antibiotic gentamicin. Computational molecular docking corroborated these experimental findings; PSD2 exhibited superior binding affinities within the catalytic gorges of both cholinesterases relative to galantamine, yielding docking scores of –10.7 kcal/mol for AChE and –10.1 kcal/mol for BuChE. Conclusions: A new series of functionally diverse Schiff base derivatives was designed, synthesized, and biologically validated. The exceptional dual cholinesterase inhibition and broad-spectrum antimicrobial profiles demonstrated by PSD2 and PSD4 underscore their potential as multifunctional lead architectures for disease-modifying therapeutic development.