Cognex (tacrine) / Shionogi - LARVOL DELTA

Fused Azine Derivatives Mitigate Long-Term Paracetamol-Induced Liver Fibrosis in Mice: Role of JNK1/ASK1 and Nrf2/HO-1 Signaling Pathways. (PubMed, Inflammation) - "Our newly synthesized fused azine derivative compounds (1a, 1b, 2a, and 2b) were used in this study based on our promising results achieved by our team in previous studies on tacrine derivatives...Additionally, they reduced caspase-3 and BCL2-associated X-protein (Bax) levels and promoted Nrf2 signaling pathway activation. Notably, the in-silico computer-assisted simulation docking results were consistent with the experimental measurements."

IO biomarker • Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • BAX • CASP3 • MAPK8

Design, Synthesis and Molecular Docking Studies of Some Novel Hydrazone Derivatives Based on Trimetazidine as Selective and Potent AChE Inhibitors. (PubMed, Drug Dev Res) - "The compounds were evaluated for in vitro inhibition of AChE and butyrylcholinesterase (BChE) using donepezil and tacrine as reference inhibitors, respectively. To rationalize the observed activity trends, molecular docking studies were performed, suggesting that the most active ligands adopt donepezil-like binding modes spanning the catalytic and peripheral anionic sites and are further stabilized by π-π/π-cation contacts and hydrogen-bonding interactions within the active gorge. Overall, these findings identify trimetazidine-derived hydrazide-hydrazones as a promising chemotype for the development of selective AChE inhibitors and provide a basis for further optimization and advanced biological validation."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Virtual screening and in vitro activity of potential insecticidal agents from natural products. (PubMed, Comput Biol Chem) - "In this study, a multi-stage computational screening of 407615 natural products were conducted, utilizing filters for volatility (MW < 350Da), Protein-Ligand Interaction Fingerprint (PLIF) similarity to a tacrine reference, and a commercial cost threshold of less than 8USD/g...Kinetic analysis of one novel compound, the most potent lead (Ki=88.1±3.1μM), revealed a mixed-type inhibition mechanism. These results validate the identification of affordable, reversible, and volatile natural scaffolds that serve as promising optimizable fragments for the development of sustainable biopesticides."

Journal • Preclinical

Design, synthesis, biological evaluation, and in silico studies of novel pyrrolidine based hybrids bearing indole, chromone, and benzoylthiourea pharmacophores as multitarget hCA and AChE inhibitors. (PubMed, Comput Biol Chem) - "Compound 2ad (hCA I, Ki = 35.56 ± 5.10 nM, hCA II, Ki = 31.10 ± 4.84 nM) exhibited remarkable inhibitory activity against both hCA I and hCA II, outperforming the reference acetazolamide (AZA) (hCA I, Ki = 303.45 ± 10.21 nM, hCA II, Ki = 240.15 ± 8.65 nM). Compounds 1aa and 2bd demonstrated potent AChE inhibitory activity, displaying approximately 3-fold and 4-fold higher potency than tacrine (TAC), with Ki values of 47.92 ± 8.25 nM, and 35.04 ± 7.69 nM, respectively...Furthermore, ADMET predictions indicated good oral absorption and favorable drug-likeness properties, although optimization may be required to enhance blood-brain barrier (BBB) permeability. The experimental and computational findings support the strong interaction potential of compound 2ad toward hCA II, whereas compounds 2bd and 1aa exhibit high binding affinity toward AChE, in agreement with the experimental inhibition data."

Journal • Pain

Differential Effects of Donepezil and Tacrine on Recall-Phase Exploratory Behavior in Healthy Male Wistar Rats: A Two-Trial Y-Maze Study. (PubMed, Biomolecules) - "Absolute time spent in, and entries into, the novel arm did not differ significantly among groups (p = 0.689 and p = 0.883, respectively). Overall, these findings suggest that tacrine, but not donepezil, modified recall-phase exploratory preference in healthy rats, predominantly by reducing persistence in the familiar arm."

Journal • Preclinical

Computational design and evaluation of tacrine-based carbamate derivatives as acetylcholinesterase inhibitors. (PubMed, RSC Adv) - "The binding energies and stable conformational behavior of the selected complexes were further confirmed by MM-GBSA, PCA, FEL and DCCM analyses. Overall, the results indicate that the designed derivatives could be promising candidates for AChE inhibition in Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Repurposing of an angiotensin II receptor blocker as a competitive acetylcholinesterase inhibitor targeting Alzheimer's disease: An integrated in silico and in vitro study | Poster Board #1173 (ACS-Fall 2026) - "A library of marketed compounds was screened against the AChE (PDB ID: 7XN1) active site using Tacrine (TAC) as a bound ligand...The combined computational and experimental findings support its potential for repurposing as a therapeutic agent targeting cholinergic dysfunction in AD. Keywords: Alzheimer's disease, Acetylcholinesterase, Drug repurposing, in silico, Enzyme inhibition"

Preclinical • Alzheimer's Disease • Brain Cancer • CNS Disorders • Glioma • Solid Tumor

Nutritional profile, chemical composition, and bioactivities of an underexplored edible Elatostema stewardii using UPLC-QE-orbitrap-HRMS metabolomics integrated with chemometrics. (PubMed, Food Res Int) - "The primary root exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC50 = 0.10 and 0.41 μg/mL), comparable to tacrine, along with strong antioxidant capacity comparable to l-ascorbic acid, as evidenced by DPPH (IC50 = 8.02 μg/mL), ABTS (IC50 = 10.30 μg/mL), and FRAP (0.24 μmol Fe2+/mL) assays...S-plot analysis further revealed 99 biomarkers including known bioactive compounds, such as 18α-glycyrrhetinic acid, catechin and vicenin 2. Collectively, these findings provide scientific evidence supporting the traditional dietary use of E. stewardii and highlight its potential as a promising source of functional food or nutraceutical ingredients."

Journal • Oncology • Pain

Development of novel diaryl ether-phenolic Mannich Base derivatives with potent cholinesterase inhibition and low neuronal toxicity. (PubMed, Bioorg Chem) - "Both compounds were considerably more potent than the reference inhibitors tacrine and donepezil. In addition, the synthesized compounds exhibited acceptable predicted pharmacokinetic properties, including favorable parameters related to blood-brain barrier permeability and oral absorption. These results identify phenolic Mannich base-derived hydrazones as promising lead compounds for the development of new cholinesterase inhibitors for the treatment of Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Rational Design of Multifunctional Tacrine Derivatives as Candidates for the Treatment of Alzheimer and Parkinson Diseases. (PubMed, ChemMedChem) - "Therefore, according to in silico predictions they are expected to be beneficial for AD and PD. One of the compounds investigated here is the first reported tacrine-derived compound with potential as COMT inhibitor."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Pain • Parkinson's Disease • COMT

Benzoxazolinone-Based Propionyl Thiosemicarbazides as Multi-Target-Directed Ligands for Alzheimer's Disease: Cholinesterase and MAO Inhibition, Docking, and Molecular Dynamics. (PubMed, ACS Omega) - "Several AChE potencies approached the reference donepezil, and selected BChE activities were within an order of magnitude of tacrine. In silico ADME (QikProp) indicated compliance with Lipinski's Rule of Five and Jorgensen's Rule of Three. Collectively, this scaffold is tunable from MAO-B-selective to balanced MTDL profiles suitable for further AD-relevant optimization."

Journal • Alzheimer's Disease • CNS Disorders • Oncology • Pain

Design, synthesis, biological evaluation, and in silico analysis of novel coumarin carboxamides as acetylcholinesterase and butyrylcholinesterase inhibitors and anticancer agents. (PubMed, J Comput Aided Mol Des) - "In vitro enzyme inhibition studies validated the computational results, showing that CM4 (IC50 = 19.04 ± 1.67 nM) and CM8 (IC50 = 17.73 ± 0.66 nM) exhibited significantly greater AChE inhibition than donepezil (IC50 = 27.27 ± 1.22 nM; p < 0.001), with CM3 (IC50 = 24.84 ± 1.99 nM) comparable to donepezil, while all derivatives (CM1-CM9) significantly outperformed tacrine against BChE (p < 0.001). Moreover, CM6 and CM9 inhibited colony formation in brain, breast, and colon cancer cell lines at concentrations below 5 µM. As a result, the alignment of computational and biological data highlights these coumarin-3-carboxamides as compelling lead candidates with both neuroprotective and anticancer potential for further pharmacological development."

Journal • Breast Cancer • Colon Cancer • Colorectal Cancer • Oncology • Pain • Solid Tumor

Analysis of the Efficacy of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer's Disease, Literature Review. (PubMed, Int J Mol Sci) - "Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery...Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Developmental Disorders • Pain

Engineering a nanocluster-immobilized MOF@MOF architecture-based ratiometric fluorescence bioassay for sensing neurodegenerative disease-related acetylcholinesterase and inhibitor drugs. (PubMed, Anal Methods) - "The system demonstrates the feasibility of inhibitor screening with tacrine as a model inhibitor. This work provides a simple ratiometric platform that holds promise for AChE-related clinical diagnosis and drug discovery."

Journal • CNS Disorders • Pain

Synthesis and Biological Evaluations of New 4,5-Diphenyl-Imidazole-Indole-N-Phenylacetamide Derivatives Against α-glucosidase and Acetylcholinesterase. (PubMed, Arch Pharm (Weinheim)) - "Among the thirteen derivatives, nine were more potent than the standard α-glucosidase inhibitor (acarbose), and eleven showed higher potency than the standard AChE inhibitor (tacrine). Molecular docking and dynamics simulations confirmed the stability of compound 6j within the active site of AChE. Additionally, compound 6j demonstrated no cytotoxicity at its effective dose against AChE in the normal cell line NIH-3T3, confirming its favorable safety profile at high concentrations."

Clinical • Journal • Pain

Interactions-Guided Blueprint of Acetylcholinesterase Binding: A Review on Structural and Molecular Determinants. (PubMed, Chem Biol Interact) - "To this end, this article presents a comprehensive systematic analysis of 202 AChE-ligand complexes (1993-2025) since the first breakthrough, categorizing ligands by their core scaffolds or functional groups, including decamethonium, huprine, galanthamine, quinoline, huperzine, tacrine, pyridinium, sulphonamide, and quaternary amine derivatives...All ligands are further evaluated using Lipinski's Rule of Five filters to assess drug-likeness and identify optimization strategies for improved bioavailability and pharmacokinetics. By integrating structural insights with ligand features, this article provides a comprehensive framework for the rational design and optimization of next-generation AChE modulators across neurological and toxicological conditions."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Pain

Comparative Effects of Donepezil and Tacrine on Recall-Related Exploratory Behavior in a Subacute Lipopolysaccharide-Induced Neuroinflammatory Model of Cognitive Impairment. (PubMed, Biomedicines) - " Subacute LPS administration produced a measurable recall-phase exploratory impairment in the Y-maze. Donepezil and tacrine attenuated several components of this impairment, with partially distinct dose-related behavioral profiles."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation

Effects of a Tacrine Analogue on Behavioral and Biochemical Parameters in Drosophila melanogaster. (PubMed, Chem Biodivers) - "However, 0.1875 mM THA showed higher acetylcholinesterase activity only in the thorax, suggesting cholinergic modulation in muscle. These findings suggest that THA supplementation supports neural and muscle health in this animal model and may be a potential treatment for chronic diseases."

Journal

2-Quinolinone Derivatives as Dual Cholinesterase Inhibitors: Experimental and Computational Insights. (PubMed, Med Chem) - "Overall, the findings of this study guide the development of more potent and selective inhibitors by appropriate structural modifications of the 2(1H)-quinolinone skeleton."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Design, synthesis and biological evaluation of tacrine-sulphonamide hybrids as a potent acetylcholinesterase inhibitor. (PubMed, RSC Adv) - "In vitro screening using Ellman's method confirmed potent AChE inhibition, with IC50 values in the nanomolar range. Structure-activity relationship analysis indicated that methyl-substituted piperidine derivatives significantly enhanced inhibitory potency, with compounds 6j and 6k achieving IC50 values of 7.40 nM and 11.33 nM, respectively."

Journal • Pain

Recent trends in anti-Alzheimer's potential of novel biologically active isatin analogues: synthetic strategies, structural activity relationship studies and molecular docking insights. (PubMed, Mol Divers) - "Furthermore, hybridization of isatin core with pharmacologically active moieties like triazoles, coumarins, tacrine, benzylamine, piperazine, quinoline, hydrazones and melatonin afford more promising multitarget-directed ligands with improved BBB permeability, antioxidant potential and improved neuroprotective properties...In addition, key emphasis is placed on SAR trends which is responsible for promoted potency and selectivity including electron-withdrawing substitutions, linker optimization, hydrophobic interactions and dual-site binding with catalytic as well as peripheral anionic sites of target enzymes. Integration of hybrid isatin scaffolds with complementary pharmacophore combined with advanced in silico modeling and preclinical evaluation may pave the way for next-generation multifunctional therapeutics with improved efficacy and safety in treatment of Alzheimer's disease."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation

An integrated in silico approach to identify pyridine-based AChE and BChE inhibitors for Alzheimer's disease. (PubMed, Comput Biol Med) - "From a curated library of 55 ZINC-derived compounds, virtual screening using AutoDock Vina identified lead candidates exhibiting superior binding affinities (-11.5 to - 8.0 kcal/mol for AChE; - 10.9 to - 7.4 kcal/mol for BChE) compared to marketed drugs donepezil and tacrine. ADMET predictions showed good intestinal absorption and CNS permeability; however, it will be necessary to improve both the solubility of these compounds as well as their CYP3A4-related liability. This multi-tiered computational strategy was able to identify both compounds 46 and 49 as highly promising candidates for further experimental validation as dual cholinesterase inhibitors that will be incorporated into efforts to develop new AD treatment approaches."

Journal • Alzheimer's Disease • CNS Disorders • Pain • CYP3A4

One destination, three routes: Tacrine-Celecoxib hybrids targeting cholinesterases, COX-2, and carbonic anhydrases in cognitive impairment linked to metabolic dysfunction. (PubMed, Eur J Med Chem) - "Consistent with its multitarget profile, biochemical analyses showed significant attenuation of oxidative stress and neuroinflammatory markers in the hippocampus. Finally, docking and molecular dynamics simulation studies provided a structural rationale for the observed in vitro activities of 10b, highlighting favorable binding modes within the active sites of COX-2, BuChE, and hCA IX."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Metabolic Disorders • CA9

Promising Flavonoid-Fused Aminoquinolines as Synthetic Alzheimer's Disease Models: Design, Synthesis, Anticholinesterase Activity, ADMET and Molecular Docking. (PubMed, Chembiochem) - "In vitro cholinesterase assays and in silico docking demonstrated that all newly modified tacrine analogs 3 exhibited higher HsBChE inhibitory activity compared to HsAChE. Specifically, the most effective human cholinesterase inhibitor was the compound (±)-7-amino-6-phenyl-6H-chromeno[4,3-b]quinoline (3aa), with an IC50 of 2.73 μM for HsAChE and 0.096 μM for HsBChE. These findings suggest that compound 3aa is a promising candidate for further assessment in synthetic Alzheimer's disease models."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Development of tacrine-based multitarget-directed ligands as dual AChE/EGFR inhibitors with neuroprotective activity. (PubMed, Bioorg Med Chem) - "Meanwhile, the epidermal growth factor receptor (EGFR) inhibitor gefitinib has shown anti-AD potential. Furthermore, they conferred significant neuroprotection against H2O2- and glutamate-induced neuronal damage. In vivo studies confirmed that both S24-1008 and S24-1017 effectively reversed cognitive deficits and enhanced learning and memory in mice, with no significant change in body weight observed."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Pain