Cognex (tacrine) / Shionogi - LARVOL DELTA

Hybrid molecules with dual inhibition of acetylcholinesterase and Tau hyperphosphorylation: design, inhibitory activity evaluation, apoptosis assessment, and mechanistic exploration. (PubMed, Chem Biol Interact) - "To address this need, the present study designed a series of hybrid molecules by integrating three pharmacophoric scaffolds with established P-Tau-modulating activity (phenothiazine, dibenzazepine and benzothiazepinones) into AChE-inhibiting frameworks: indanone (derived from the clinical AChE inhibitor Donepezil) or 9-chloro-1,2,3,4-tetrahydroacridine (derived from Tacrine, another clinically approved AChE inhibitor)...Notably, the indanone-phenothiazine hybrid compound C11 stood out as the most promising candidate, it achieved the lowest P-Tau/total Tau (T-Tau) ratio (5.30 × 10-6) in okadaic acid (OA)-induced SH-SY5Y cells, outperforming hydromethylthionine mesylate (5.40 × 10-6), a leading clinical candidate for Tau aggregation inhibition...Concurrently, C11 modulated the expression of glycogen synthase kinase-3β (GSK-3β), a critical kinase driving P-Tau formation."

Journal • CNS Disorders

Dual targeting of neuroblastoma and cholinesterase by morpholino/pyrrolidino-sulfonyl-indole thiosemicarbazones: Synthesis, characterization, enzyme inhibition, cytotoxicity, docking and dynamics studies. (PubMed, Bioorg Chem) - "Compounds 6h and 7h stood out as the most potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC50 values as low as 0.15 μM and 0.12 μM, respectively, outperforming reference drugs tacrine and galantamine. Molecular dynamics simulations over 250 ns confirmed complex stability with low RMSD and RMSF values. These combined results highlight 6h and 7h as promising multitarget therapeutic candidates for neurodegenerative diseases and cancer."

Journal • CNS Disorders • Neuroblastoma • Oncology • Pain • Solid Tumor

Traditional Herbal Medicine Ga-Mi Gongjindan Improves Muscarinic Cholinergic Dysfunction through Regulation of BDNF/CREB Signaling Pathway Using a Scopolamine-Induced Cognitive Impairment of Mouse Model. (PubMed, Brain Res Bull) - "GJD exerted significant neuroprotective effects in a scopolamine-induced model of cognitive dysfunction, potentially via modulation of cholinergic and BDNF/CREB signaling pathways. These findings provide a scientific rationale for the traditional use of GJD in cognitive disorders and support its further development as a candidate for treating neurodegenerative diseases such as AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Inflammation • Pain • CHAT • NTRK2

2-Oxoindolin-thiazoline hybrids as scaffold-based therapeutics for T2DM-associated cognitive impairment: design, synthesis, in vitro and in silico studies. (PubMed, RSC Med Chem) - "Biological evaluations demonstrated that compounds 3d and 3h exhibit potent inhibitory activity against α-glucosidase (α-Glu) and α-amylase (α-Amy), surpassing the efficacy of acarbose...Furthermore, compounds 3i and 4i exhibited significantly higher inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) compared to the reference drug tacrine...Molecular docking and dynamics simulations corroborated these findings by revealing stable and favorable interactions within the active sites of both enzymes. Additionally, in silico ADME profiling indicated desirable pharmacokinetic properties, further supporting the therapeutic potential of these compounds as dual-action agents for the management of Alzheimer's disease and type 2 diabetes mellitus."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Diabetes • Metabolic Disorders • Pain • Type 2 Diabetes Mellitus

Fluorocyclopropyl-Containing Tacrine Derivatives as Potent and Selective Dual CDK2/CDK9 Inhibitors for the Treatment of Colorectal Cancer. (PubMed, J Med Chem) - "Importantly, ZLMT-72 (10 mg/kg) displayed robust antitumor efficacy in both subcutaneous (TGI = 50.6%) and orthotopic (TGI = 84.3%) xenograft tumor models of HCT116, alongside favorable pharmacokinetic properties and a promising safety profile. Collectively, ZLMT-72, as a potent dual CDK2/9 inhibitor, holds substantial therapeutic potential for CRC treatment."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CDK9

Pyranotacrines as prospective multi-target compounds against Alzheimer's disease. (PubMed, Bioorg Med Chem) - "A series of tacrine-based 4-H-pyran derivatives were synthesized and biologically estimated as multifactorial ligands against Alzheimer's disease...Moreover, its inhibitory activity against BuChE was 8-folds more active than rivastigmine with IC50 = 0.09 ± 0.016 μM...Additionally, it showed higher anti-oxidative activity with 10.36 TE and chelating anchors activity for metal ions. The safety of 6c towards SH-SY5Y normal cells and HepG2 cancer cells was interesting with safety index ratio (Si = 2273), in addition to its BBB permeability and pharmacokinetic profile."

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

Integration of Machine Vision and PLC-Based Control for Scalable Quality Inspection in Industry 4.0. (PubMed, Sensors (Basel)) - "The proposed platform combines a Cognex In-Sight 2802C smart camera (Cognex Corporation, Natick, MA, USA) with an Allen-Bradley Compact GuardLogix PLC through Ethernet/IP implicit cyclic exchange...These findings demonstrate a replicable integration framework that supports intelligent manufacturing. Future research will focus on hybrid AI-PLC architectures, extended validation on industrial production lines, and predictive maintenance enabled by edge computing."

Journal

Effects of a Natural Polyherbal Extract on Alleviating Scopolamine-Induced Memory Deficits in C57BL/6 Mice via Enhancing Cholinergic Function. (PubMed, Curr Issues Mol Biol) - "Male C57BL/6 mice (10 weeks old, n = 36) were divided into four groups: control (saline), scopolamine (1 mg/kg, i.p.), tacrine (10 mg/kg, oral), and NPX (1000 mg/kg, oral). NPX alleviated scopolamine-induced memory impairment through enhancement of cholinergic signaling and mitigation of neurodegenerative markers. The findings suggest that NPX may serve as a promising plant-derived candidate for managing memory-related disorders, including AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Pain • CASP3 • CHAT

Comprehensive Elucidation of the Biochemical Activity and Phytochemical Content of an Uninvestigated Valuable Species: Anthemis tricornis Eig. (PubMed, Chem Biodivers) - "Quercetin (1.47 mg/g extract), cosmosiin (6.45 mg/g extract), chlorogenic acid (5.89 mg/g extract), quinic acid (24.01 mg/g extract), cynaroside (14.13 mg/g extract), and luteolin (1.92 mg/g extract) were found in the species' EtOH extract at surprisingly high concentrations, as shown by LC-MS/MS data. Inhibitory studies were conducted on acetylcholinesterase (AChE), α-amylase, and human carbonic anhydrase II (hCA II) enzymes, with IC50 values obtained for each enzyme. The study demonstrated that the extract moderately reduced hCA II, AChE, and α-amylase activity, with higher IC50 values than acetazolamide, tacrine, and acarbose."

Journal • Pain

7-SUBSTITUTED TACRINE DERIVATIVES: OVERCOMING TACRINE´S HEPATOTOXICITY WHILE ENHANCING THERAPEUTIC POTENTIAL IN ALZHEIMER'S DISEASE (WCN 2025) - "Overall, our findings emphasize the importance of rational drug design in overcoming the hepatotoxicity barriers associated with THA. These novel multi-target-directed ligands represent promising candidates for further preclinical development in the treatment of AD."

Alzheimer's Disease • CNS Disorders • GRIN2B

Comparative analysis of chemical composition and biological activities of Punica granatum L. Extracts: UPLC-MS/MS profiling, antioxidant capacity, enzyme inhibition, and molecular docking. (PubMed, Food Res Int) - "For carbonic anhydrase I and II, the extracts showed notable inhibition (IC₅₀ = 0.0221, 0.0344 μg/mL), although not reaching the efficacy of acetazolamide (IC₅₀ = 0.0061, 0.0072 μg/mL). Both extracts exhibited potent acetylcholinesterase inhibitory activity (IC₅₀ = 0.0017 μg/mL), closely approximating the efficacy of tacrine (IC₅₀ = 0.0010 μg/mL). The ethanol extract also showed remarkable α-glucosidase inhibition (IC₅₀ = 0.0052 μg/mL), being 2.8-fold more potent than the acarbose (IC₅₀ = 0.0147 μg/mL)-a noteworthy result, as natural compounds rarely exceed pharmaceuticals in such assays. Molecular docking confirmed ellagic acid's interaction with the target enzymes. These findings underscore pomegranate leaves as a valuable natural source of bioactive compounds, with promising applications in the management of diabetes, neurodegenerative disorders, and glaucoma -attributable to..."

Clinical • Journal • CNS Disorders • Diabetes • Glaucoma • Metabolic Disorders • Ophthalmology

Novel Isoindole-1,3-Dione-Isoxazole Hybrids: Synthesis, Characterization, Evaluation of Their Inhibitory Activities on Carbonic Anhydrase and Acetylcholinesterase. (PubMed, J Biochem Mol Toxicol) - "All compounds were determined to have a higher binding affinity than Tacrine (-7.04 kcal/mol) and AZA (-6.12 and -6.24 kcal/mol). The results of inhibition tests showed that some isoxazole derivatives (9-12) showed significant inhibitory effects against both CA and AChE enzymes."

Journal • Alzheimer's Disease • CNS Disorders • Epilepsy • Glaucoma • Ophthalmology • Pain

Structural, nonlinear optical, and molecular docking studies of schiff base compounds as multi-target inhibitors of AChE, BChE, and carbonic anhydrases. (PubMed, Sci Rep) - "The compounds exhibited excellent predicted inhibition constants (Ki), with APhIM being particularly potent against AChE (Ki = 0.42 µM) and BChE (Ki = 0.83 µM), outperforming the standard drug Tacrine...Furthermore, in silico ADMET profiling indicated favorable drug-likeness, high gastrointestinal absorption, and low toxicity risks. The results underscore the dual potential of these Schiff bases as promising scaffolds for the development of NLO materials and as multi-target therapeutic agents, offering a robust basis for future applications in optoelectronics and drug discovery."

Journal • CNS Disorders • Pain

Synthesis of Tacrine/Amiridine Conjugates with Aminomethylidene Derivatives of Trifluoroacetoacetic Ester and their Biological Potential for the Therapy of Alzheimer's Disease. (PubMed, ChemMedChem) - "Both types of conjugates displace propidium from the AChE peripheral anionic site at the level of and above that of donepezil, and are capable of blocking self-aggregation of β-amyloid (up to 49.5%). The compounds demonstrate very weak antioxidant activity (tacrine conjugates) or its absence (amiridine). Thus, new conjugates are potential multitarget anti-AD agents with high selectivity toward BChE for amiridine derivative 5b."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Multifunctional Tacrine-Quinoline Hybrids as Cholinesterase Inhibitors, Aβ Aggregation Blockers, and Metal Chelators for Alzheimer's Therapy. (PubMed, Molecules) - "UV-vis spectrometry confirmed the chelation of Cu2+ and Zn2+ ions by the 8-hydroxyquinoline moiety. These findings highlight the tacrine-quinoline scaffold as a promising platform for the discovery of a multitarget-directed anti-AD drug."

Journal • Alzheimer's Disease • CNS Disorders • Pain

New methyl/benzyl-1,2,4-triazole-3-one Derivatives: Synthesis, Characterization (IR, NMR), Antidiabetic, Anti-Alzheimer, and Molecular Docking Study. (PubMed, J Biochem Mol Toxicol) - "Acarbose was used as a standard for alpha glycosidase and alpha amylase enzymes, while tacrine molecule was used as a standard for acetylcholinesterase enzyme. Except for molecules 5a, 5b and 5 f, all other molecules were found to be more active than the standard. Molecular docking simulations were conducted to explore the interactions of 3e and 3 f compounds with Human Acetylcholinesterase, using tacrine as a reference molecule, to evaluate binding affinities and key ligand-protein interactions."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Pyrrolidine-based hybrid compounds: design, synthesis, in vitro and in vivo pharmacological properties and molecular docking studies. (PubMed, Future Med Chem) - "Compound 6b was the most potent inhibitor (hCAII Ki 75.79 ± 2.83 nM, AChE Ki 43.17 ± 10.44 nM), outperforming acetazolamide (Ki 299.33 ± 45.44 nM) and tacrine (Ki 103.47 ± 11.54 nM). Compound 6a showed the strongest antioxidant effect (72.30% DPPH), antibacterial activity against A. baumannii (MIC 125 µg/ml, comparable to ampicillin), and superior anti-TB potency (MIC 31.25 µg/ml)...The hybrids validate a focused dual-target strategy. Compound 6b is the most potent hCAII and AChE inhibitor, while 6a emerges as a broader multi-target lead with antioxidant, antimicrobial, anti-inflammatory, and antidepressant potential."

Journal • Preclinical • Infectious Disease • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • Tuberculosis • PTGS2

Boron Containing Curcumin-Like Compound as an Acetylcholinesterase Inhibitor and Anticancer Agent: Synthesis, Biological Evaluation, and Computational Insights. (PubMed, Cell Biochem Biophys) - "Compound A exhibited a potent AChE inhibitory activity (IC50 = 22.89 ± 2.32 nM), demonstrating that it was more effective than the known inhibitors donepezil (IC50 = 28.32 ± 3.27 nM) and tacrine. Additionally, MM/GBSA calculations demonstrated that Compound A had the highest binding free energies (-88.89 ± 8.34 kcal/mol for AChE and -73.25 ± 8.83 kcal/mol for BChE) compared to curcumin (-67.87 ± 5.48 kcal/mol for AChE and -51.68 ± 5.28 kcal/mol for BChE) and tacrine (-56.67 ± 2.22 kcal/mol for BChE) were calculated. Overall, these findings suggest that Compound A is a promising agent with its potent AChE inhibitory activity and anticancer potential, making it a valuable candidate for further research in neurodegenerative diseases and cancer therapy."

Journal • Alzheimer's Disease • Breast Cancer • CNS Disorders • Colorectal Cancer • Oncology • Pain • Solid Tumor

Synthesis and Evaluation of Tacrinocerins, Tacrine Hybrids with α-Onocerin from Phlegmariurus nummulariifolius (Blume) Ching, as a Novel Class of Acetylcholinesterase Inhibitor. (PubMed, Chem Asian J) - "It showed moderate to low toxicity to neuronal and hepatic cells, while also demonstrating significant anticancer activity against MOLT-3 cells and excellent multitarget chemopreventive potential. This research successfully identified 4c as a leading dual-action agent, providing a strong foundation for designing next-generation tacrinocerins with optimized therapeutic indices."

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

Synthesis, Biological Evaluation and Molecular Docking of Novel Sulfonamide Derivatives as Dual Inhibitors of Carbonic Anhydrase Isoenzymes I/II and Acetylcholinesterase. (PubMed, J Biochem Mol Toxicol) - "Among the synthesized derivatives, compound 3 demonstrated the highest inhibitory effect against hCA I with an Ki of 49.45 ±  9.13 nM, exhibiting approximately 4.8-fold stronger inhibition than acetazolamide (AZA)...In the AChE inhibition assay, both compounds 3 and 2 showed superior activity over the reference drug tacrine (TAC), with Ki values of 148.67  ±  78.78 nM and 151.21  ±  11.78 nM, respectively, corresponding to 2.17-fold and 2.13-fold greater potency than TAC...These results emphasize the importance of present structural motifs for the various interactions. These findings support the rational design of multifunctional sulfonamides as promising scaffolds for the development of potent enzyme inhibitors targeting both CA and AChE-related pathologies."

Journal • Pain

Design, Synthesis, and Molecular Docking Studies of Novel Pyrazoline-Thiazoles as Cholinesterase Dual-Target Inhibitors for the Treatment of Alzheimer's Disease. (PubMed, ACS Omega) - "The molecular docking results of compound 3g with high inhibitory activity for AChE experimentally showed that it has a strong inhibitory effect close to that of the reference inhibitor tacrine. The compound 3g was found to have the highest activity in its interaction with the BChE (4BDS) protein with a low docking score (-5.555 kcal/mol). Furthermore, the prediction of ADME properties of compounds 3f and 3g was determined through Swiss ADME."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Synthesis of novel benzene bissulfonamides with carbonic anhydrase and choline esterase inhibitory properties. (PubMed, Bioorg Chem) - "In contrast, the reference inhibitor Tacrine displayed markedly higher potency, with IC50 values of 123.65 ± 4.41 nM for AChE and 8.39 ± 0.28 nM for BChE...Furthermore, ADME and Induced-Fit Docking (IFD) simulations were conducted to elucidate the similarities of the drugs and the mechanisms of inhibition exhibited by the synthesized compounds. The synthesized species may significantly contribute to discovering new pharmaceutical agents for treating diseases such as Alzheimer's and glaucoma, which represent significant chronic global health concerns."

Journal • Alzheimer's Disease • CNS Disorders • Glaucoma • Ophthalmology • Pain

Investigation of Biopesticides for the Pest Control Through Inhibition of the Acetylcholinesterase Purified from Loxostege sticticalis (L.) (Lepidoptera: Crambidae). (PubMed, Appl Biochem Biotechnol) - "Inhibition studies of AChE were realized with tacrine, edrophonium chloride, and cypermethrin, which are known inhibitors of AChE, as well as aqueous extracts of certain plant leaves...In addition, the oleuropein and phenolic substance amounts of these plant extracts were determined and correlated with the IC50 values. Consequently, the plant extracts used in this study may be recommended as an alternative biopesticide source to control such pests via AChE inhibition."

Journal • Pain

Unlocking Therapeutic Potential of Novel Thieno-Oxazepine Hybrids as Multi-Target Inhibitors of AChE/BChE and Evaluation Against Alzheimer's Disease: In Vivo, In Vitro, Histopathological, and Docking Studies. (PubMed, Pharmaceuticals (Basel)) - "Derivative 15 demonstrated remarkable BChE-inhibitory efficacy, on par with tacrine, with IC50 values of 0.70 µM. Compounds 13 and 15 reduced escape latency and raised residence time, with almost equal activity to donepezil. According to these findings, the designed hybrids constitute multipotent lead compounds that could be used in the creation of novel anti-AD medications."

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

New 1E,1'E-hydrazine-bis(phenoxy-1,2,3-triazol-acetamide) derivatives as potent inhibitors against acetylcholinesterase, butyrylcholinesterase, and α-glucosidase. (PubMed, RSC Adv) - "In this regard, all the synthesized compounds were more potent than the standard inhibitors tacrine and donepezil against BChE, and most of these compounds were more potent than tacrine against AChE. Moreover, most of the target synthesized compounds were more potent than the standard inhibitor acarbose against α-glucosidase...Furthermore, docking studies demonstrated that compound 10k interacted with both the catalytic and peripheral anionic sites of AChE and BChE. This property led to the better efficacy of the compound in the treatment of AD."

Journal • Alzheimer's Disease • CNS Disorders • Diabetes • Metabolic Disorders • Neuroblastoma • Oncology • Pain • Solid Tumor