Cognex (tacrine) / Shionogi - LARVOL DELTA

A strategy for improving blood-brain barrier permeability of ChE inhibitors through blood-brain barrier (BBB) transporter. (PubMed, Eur J Med Chem) - "Here, we present an active CNS-targeted strategy based on BBB endogenous transporters, specifically through the rational design of novel tacrine derivatives...Induced-fit molecular docking experiments further validated the high affinity of L3 for LAT1. In conclusion, this work not only provides lead compounds with high BBB permeability but also advances our understanding of utilizing endogenous transporters for brain-targeted delivery, offering a solid foundation for developing new CNS therapeutics."

Journal • Pain

Synthesis, multi-target evaluation and DFT analysis of 6-hydroxychromone derived hydrazones with carbonic anhydrase I-II/acetylcholinesterase inhibition and antioxidant activity. (PubMed, RSC Adv) - "Compound 3e was found to be highly selective for AChE and about six hundred fold more potent as compared to the standard inhibitor, tacrine...DFT-based FMO, MEP, and reactivity analyses demonstrated that the chromone-hydrazone derivatives exhibit narrow HOMO-LUMO gaps and well-defined electrostatic surfaces, supporting their suitability for efficient charge transfer and biological interaction. Moreover, computational simulations and ADME analysis proved that all of the synthesized molecules were druggable with good inhibitory potential."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Lipid droplet-regulated multipathway-induced type I interferon tempest for ferroptosis-immune synergistic therapy of tumors. (PubMed, J Control Release) - "Herein, Tacrine (TCR) and SR717 loaded hollow mesoporous manganese dioxide nanoparticles (TCR-SR717@HMMD NPs, termed as iTempest) was developed to trigger ferroptosis and abundant IFN-I (i.e., IFN-I tempest) in tumors through multiple pathways, whose feasibility and mechanism were verified by in vitro experiments...The excessive IFN-I can be finally degraded by acidic hydrolases in lysosomes, preventing local inflammation. Mouse body weight monitoring, hematological analysis, and histological examinations demonstrate good biocompatibility and biosafety for iTempest."

IO biomarker • Journal • Hematological Disorders • Inflammation • Oncology • CD8 • STING

Potent Multi-Target Inhibition of Cholinesterases and Carbonic Anhydrases by Iridium(III)-Phenanthroline Derivatives: Integrated Structure-Activity Relationship, Molecular Docking and Anticancer Cell Culture Studies. (PubMed, Drug Dev Res) - "Among the tested compounds, 2a demonstrated exceptional potency with IC50 values of 66.5 ± 9.06 nM for AChE and 26.45 ± 5.00 nM for BChE, significantly outperforming tacrine. Compound 4a also exhibited strong inhibition of hCA I (IC50 = 33.0 ± 7.09 nM) and hCA II (IC50 = 41.79 ± 8.09 nM), surpassing the reference drug acetazolamide...Cell viability assays showed that compounds 1a-4a decreased PC3 prostate cancer cell viability in a concentration-dependent manner, with IC50 values of 10.09, 3.95, 11.39, and 4.51 µM, respectively. This comprehensive study highlights iridium(III) complexes as multitarget therapeutic agents with potent anticholinesterase and carbonic anhydrase inhibitory properties, offering promise for treating neurodegenerative and metabolic disorders."

Journal • Preclinical • CNS Disorders • Genito-urinary Cancer • Metabolic Disorders • Oncology • Pain • Prostate Cancer • Solid Tumor

Design, synthesis and evaluation of new pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidines as tacrine-like acetylcholinesterase inhibitors. (PubMed, RSC Adv) - "In silico studies showed that 22 occupies the catalytic anionic site of hAChE and forms strong π-π stacking interactions with Trp86, similar to those of tacrine. This study demonstrates the potential use of methyl-substituted pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidines in the development of potent AChE inhibitors."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Phytochemical Profiling and Multi-Target Enzyme Inhibition Potential of Castanea sativa Mill. Leaf Extract: Integrated Experimental and Molecular Docking Studies. (PubMed, J Food Sci) - "UPLC-MS/MS analysis identified ellagic acid, chlorogenic acid, and quinic acid as major constituents, supported by high phenolic (190.556 mg GAE/g) and flavonoid (50.430 mg QE/g) contents...Notably, potent inhibitory effects were observed against carbonic anhydrase (CA) I-II, acetylcholinesterase (AChE) (IC50 = 0.0017 µg/mL), and α-glycosidase (IC50 = 0.0063 µg/mL), with AChE inhibition approaching that of tacrine and α-glycosidase inhibition surpassing acarbose by 2.3-fold. Molecular docking analyses further revealed specific interactions between major phytochemicals and enzyme active sites, supporting the in vitro findings. These results demonstrate that C. sativa leaves represent a promising, sustainable source of bioactive molecules with strong antioxidant and multi-target enzyme inhibition potential, suggesting possible applications in the management of oxidative stress-related conditions, neurodegenerative diseases, and metabolic disorders such as diabetes."

Journal • CNS Disorders • Diabetes • Metabolic Disorders • Pain

Innovative Approaches to Alzheimer's Treatment: Utilizing Tacrine Hybrids to Inhibit Amyloid Beta Aggregation as a Strategic Focus. (PubMed, Mini Rev Med Chem) - "By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • APP

Repurposed Arylidene-hydrazinyl-1,3-thiazoles as Multitarget Anti-Alzheimer's Agents via Combined Computational and Experimental Studies. (PubMed, ACS Omega) - "Derivatives 8 (IC50 = 0.117 μM) and 14 (IC50 = 0.092 μM) showed superior activity against AChE than reference tacrine (IC50 = 0.274 μM), while compound 13 (IC50 = 5.35 μM) showed comparable potency against BACE1 to quercetin (IC50 = 4.89 μM)...On the other hand, compounds 3, 11, and 14 displayed comparable binding conformations to donepezil...In silico ADMET profiling highlighted the appropriate drug-like properties of the thiazole ligands, which possessed low toxic effects and good pharmacokinetic properties. Overall, the multitarget profile exerted by our thiazole ligands suggests their potential qualification as anti-Alzheimer candidates in AD therapy."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Effect of blood microsampling (50 μL) on toxicological assessment in rats treated with tacrine, a drug known to have adverse effects that increase neutrophils. (PubMed, J Toxicol Sci) - "Although increase in neutrophils and repeated stereotypic behaviors were observed as toxic effects in the rats administered tacrine, we could not find any difference between the MS and non-MS groups, and also found that microsampling did not affect any other data from toxicological and toxicokinetic analysis. In conclusion, blood microsampling appeared to be a feasible technique for the toxicity study of tacrine and was considered to be applicable in the toxicity study of even drugs with toxic effects on hematological parameters, such as an increase in neutrophils."

Adverse events • Journal • Preclinical • Hematological Disorders

First Sustainable One-Pot Tandem Hantzsch Multicomponent Reaction/Click Reaction Approach for Novel Multitarget-Directed Ligands in Alzheimer's Disease. (PubMed, ACS Chem Neurosci) - "The rational design combined dihydropyridines (DHPs), known for calcium channel blocking and neuroprotective properties, with tacrine, a cholinesterase inhibitor. Notably, DHP IIIj and IIIk demonstrated a multitarget profile and effectively reversed scopolamine-induced amnesia in a mouse model, showcasing its antiamnesic properties. These results suggested that DHP IIIj and IIIk hold promise as innovative therapeutic candidates for AD, validating the potential of MTDL strategy and highlighting the one-pot tandem synthesis as a significant advancement in medicinal chemistry."

Journal • Alzheimer's Disease • CNS Disorders

A series of 4-thiomorpholinophenyl-thiosemicarbazones as cholinesterase inhibitors with anti-neuroblastoma effects. (PubMed, Bioorg Chem) - "All derivatives exhibited potent inhibition, with nanomolar IC50 values ranging from 11.36 to 34.17 nM (AChE) and 33.42 to 79.77 nM (BChE), comparable to standard drugs galantamine and tacrine...Compound 3l demonstrated selective cytotoxicity against SH-SY5Y cells (IC50 = 21.11 ± 0.42 μM) with minimal toxicity toward HEK-293 cells (IC50 = 69.49 ± 4.27 μM, SI = 3.3), comparable to sorafenib...ADME analysis suggested acceptable drug-like properties. These results highlight 3l and 3n as promising scaffolds for dual cholinesterase inhibition and selective anticancer activity."

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

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