Alzheimer’s disease (AD) is a neurodegenerative disease characterized by dementia, particularly in older adults. It is a process that is increasing significantly with the aging population worldwide, has yet to be cured, and therefore challenges healthcare systems. The ability of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors to modulate neurotransmitter levels has made AChE/BChE inhibitors central therapeutic targets in drug development studies for the treatment of AD. Previous studies have demonstrated the beneficial effects of pyrimidine derivatives on cognitive functions and highlighted their high therapeutic potential against neurodegenerative diseases. Considering the pharmacological importance of AChE/BChE inhibitors and pyrimidine derivatives, this study investigated the inhibitory potential of seven different pyrimidine derivatives ( 1–7 ) on AChE and BChE using both in vitro and in silico approaches. Analysis of IC 50 values indicated that compounds 1–7 (IC 50 : 14.89–77.70 nM) exhibited strong inhibitory effect. Compound 6 (IC 50 :14.89 nM) had the strongest inhibitory effect on AChE, while it showed a much weaker inhibitory effect against BChE (IC 50 : 357 nM), corresponding to an approximately 24-fold selectivity for AChE. Molecular modeling results indicate that compounds 6 and 7 exhibit favorable interactions within the active site of the enzyme. In addition, compounds 1 and 3 , which exhibited the strongest inhibitory effects on BChE, appear to display a multiple binding profile with the active site of BChE. Correlation and regression analyses indicated that compounds 1–7 display a structure–activity relationship (SAR) consistent with strong inhibitory potency toward AChE, while showing comparatively weaker inhibition toward BChE.

2026-05-01·CHIRALITY

Design, Synthesis, and Enantioselective Cholinesterase Inhibition of Novel Chiral Anthranilic Diamide Derivatives: In Vitro and In Silico Studies

Article

作者: Demirel, Nadir ; Kılınç, Namık ; Alım, Zuhal ; Tunç, Turgay

ABSTRACT:

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes are responsible for the hydrolysis of acetylcholine and play a vital role in Alzheimer's disease ( AD ) pathology. The observation of decreased AChE activity and a significant increase in BChE activity in the advanced stages of AD makes the identification of novel inhibitors targeting both AChE and BChE enzymes crucial. In this study, novel chiral anthranilic acid‐based diamide derivatives ( 5a – 5d , 7a , and 7b ) with pure enantiomer structures were synthesized, and their inhibitory potential on AChE and BChE was comprehensively investigated. The structures of the synthesized compounds were confirmed by 1 H NMR, 13 C NMR, IR, and LC–MS analyses. In vitro cholinesterase inhibition studies showed that all compounds exhibited significant inhibitory activity against both enzymes. Specifically, compounds 7a and 7b , containing 2,6‐pyridine dicarbonyl, exhibited higher AChE and BChE inhibition compared with the reference drug tacrine, displaying IC 50 values at the nanomolar level. Enantioselective analyses showed that S ‐enantiomers were significantly more effective in AChE inhibition, while enzyme‐specific inverse stereoselective preferences emerged in BChE inhibition. Experimental findings were supported by induced coherent molecular docking (IFD), MM‐GBSA binding free energy calculations, and 250‐ns molecular dynamics simulations. In silico analyses confirmed that 7b exhibited high stability and strong interactions in the AChE active site and 7a in the BChE active pocket. Furthermore, ADME analyses revealed that the compounds possessed favorable pharmacokinetic and drug‐like properties. In conclusion, this study demonstrates that chiral anthranilic diamide derivatives are promising novel AChE/BChE inhibitor candidates that act as potent and selective cholinesterase inhibitors.

2026-02-01·Future Medicinal Chemistry

Isovanillin-derived bis-hydrazones as dual cholinesterase and carbonic anhydrase inhibitors: synthesis, enzymatic profiling, and computational insights from molecular docking and dynamics

Article

作者: Türkeş, Cüneyt ; Duran, Hatice Esra ; Lolak, Nebih ; Yapar, Gönül ; Akocak, Suleyman

AIMS:

To develop isovanillin-based bis-hydrazones as multitarget inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I/II (hCA I/II).

MATERIALS & METHODS:

Twelve bis-hydrazones (4a-4l) were synthesized in two steps and evaluated by spectrophotometric enzyme assays, Lineweaver-Burk kinetics, molecular docking, MM-GBSA, molecular dynamics simulations, and in silico ADME/Tox profiling.

RESULTS:

All compounds showed nanomolar inhibition. Compound 4d was the most potent AChE/BChE inhibitor (K_I = 10.46 and 3.56 nM), while 4a and 4j led the hCA I/II panel (K_I = 3.46 and 16.12 nM). Docking, MM-GBSA, and molecular dynamics supported dual-site cholinesterase engagement and non-zinc, peripherally anchored hCA inhibition.

CONCLUSIONS:

Isovanillin-based bis-hydrazones, particularly 4d, 4a, and 4j, represent promising multitarget leads for cholinergic and hCA-linked disorders.

100 项与 AChE/BChE inhibitors(Instituto de Química Médica) 相关的药物交易

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