5396-30-5

Usage

Uses

Used in Pharmaceutical Industry:
9-Chloro-1,2,3,4-tetrahydroacridine is used as an acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. It helps in preventing the breakdown of the neurotransmitter acetylcholine in the brain, thereby improving cognitive function in some patients with the condition.
Used in Research and Development:
9-Chloro-1,2,3,4-tetrahydroacridine is utilized in research settings to explore its potential in the development of new drugs and therapies for cognitive disorders. Its mechanism of action as an acetylcholinesterase inhibitor provides valuable insights into the understanding of Alzheimer's disease and the development of more effective and safer treatments.

InChI:InChI=1/C13H12ClN/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13/h1,3,5,7H,2,4,6,8H2

Upstream product

• 56717-04-5 4-hydroxy-2,3-(tetramethylene)quinoline 
• 13161-85-8 1,2,3,4,9,10-hexahydroacridin-9-one 
• 96447-10-8 spiro<2H-3,1-benzoxazine-2,1'-cyclohexan>-4(1H)-one 
• 28144-70-9 anthranilic acid amide 
• 111232-49-6 1-(4-methoxybenzyl)spiro-4'-one 
• 321-64-2 tacrin 
• 552-16-9 ortho-nitrobenzoic acid 
• 91-56-5 indole-2,3-dione 
• 87-25-2 2-ethoxycarbonylaniline 
• 1885-29-6 anthranilic acid nitrile 
• 110-82-7 cyclohexane 
• 118-92-3 anthranilic acid 
• 134-20-3 2-carbomethoxyaniline 
• 68-12-2 N,N-dimethyl-formamide 

Downstream Products

• 5782-90-1 9-(1-piperidinyl)-1,2,3,4-tetrahydroacridine 
• 7032-37-3 4-Morpholino-2,3-tetramethylenequinoline 
• 79000-43-4 9-phenoxy-1,2,3,4-tetrahydro-acridine 
• 321-64-2 tacrin 
• 113106-23-3 4-Cycloheptylamino-2,3-tetramethylenequinoline 
• 34811-11-5 4-Isobutylamino-2,3-tetramethylenequinoline 
• 111232-55-4 N-<4-<(1,2,3,4-tetrahydro-9-acridinyl)amino>-3-methoxyphenyl>methanesulfonamide 
• 316-87-0 4-n-Amylamino-2,3-tetramethylenequinoline 
• 113106-25-5 4-(3-Methyl-1-piperidyl)-2,3-tetramethylenequinoline 

Relevant academic research and scientific papers

Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis

To provide a further test of the dual binding site hypothesis proposed for acetylcholinesterase (AChE) inhibitor heptylene-linked bis-(9-amino-1,2,3,4-tetrahydroacridine) A7A, short-tether (ethylene-hexylene) homologs A2A-A6A were prepared. En route to these compounds, convenient and scaleable syntheses of useful pharmaceutical intermediate 9-chloro-1,2,3,4-tetrahydroacridine 3 and A7A were developed. AChE and butyrylcholinesterase (BChE) inhibition assays of A2A-A10A confirm that a seven methylene tether (A7A) optimizes AChE inhibition potency and AChE/BChE selectivity. Finally, these studies indicate that simultaneous binding of alkylene-linked 9-amino-1,2,3,4-tetrahydroacridine dimers to the catalytic and peripheral sites of AChE is possible with a tether length as short as 5 methylenes. Copyright (C) 1999 Elsevier Science Ltd.

Synthesis of novel vanillin derivatives: Novel multi-targeted scaffold ligands against Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide, normally affecting people aged over 65. Due to the multifactorial nature of this disease, a "multi-target-directed ligands" (MTDLs) approach for the treatment of this illness has generated intense research interest in the past few years. Vanillin is a natural antioxidant and it provides a good starting point for the synthesis of new compounds with enhanced antioxidant properties, together with many biological activities, including β-amyloid peptide aggregating and acetylcholinesterase inhibiting properties. Here we report novel vanillin derivatives, bearing a tacrine or a naphthalimido moiety. All compounds exhibited improved antioxidant properties using DPPH assay, with IC50 as low as 19.5 μM, FRAP and ORAC assays, with activities up to 1.54 and 6.4 Trolox equivalents, respectively. In addition, all compounds synthesized showed inhibitory activity toward acetylcholinesterase enzyme at μmolar concentrations using the Ellman assay. Computational docking studies of selected compounds showed interactions with both the catalytic anionic site and the peripheral anionic site of the enzyme. Furthermore, these compounds inhibited Aβ(1-42) amyloid aggregation using the fluorometric ThT assay, with compound 4 showing comparable inhibitory activity to the positive control, curcumin. At cellular level compound 4 (1 μM) showed significant protective effects in neuroblastoma SH-SY5Y cell line when treated with hydrogen peroxide (400 μM). In our opinion, vanillin derivatives could provide a viable platform for future development of multi-targeted ligands against AD.

Potent Acetylcholinesterase Selective and Reversible Homodimeric Agent Based on Tacrine for Theranostics

Acetylcholinesterase (AChE) has been an important biomarker for diagnosing Alzheimer's disease (AD), due to reduction in AChE activity in post-mortem brains of AD patients. A potent, selective, and reversible homodimeric inhibitor of AChE, 5-amino-N1,N3-bis(2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl)isophthalamide (compound 4), was synthesized by using 9-alkyl(1,2,3,4-tetrahydroacridine) pharmacophore with appended functionality. In the present work, we report the synthesis of this bivalent inhibitor of AChE. The homodimeric ligand structure was designed and studied with molecular docking tools, which revealed its high affinity and interactions with active site gorge of AChE, which includes both catalytic active site (CAS) and peripheral active site (PAS). The IC50 value of this bivalent inhibitor for AChE and BuChE were 0.54 ± 0.06 and 32.49 ± 1.2 nM, respectively, with a selectivity ratio of 60.16 toward AChE. The designed ligand also showed potent inhibitory properties on PAS activity as well as on AChE-induced amyloid aggregation with low cytotoxicity on rat hippocampal neurons. The AFM images further corroborated the Aβ1-42 aggregation inhibition by compound 4 to an extent similar to bis(7)-tacrine. Moreover, the bivalent ligand was also proven to be of neurogenic potential due to its ability to induce S-phase post-treatment in rat hippocampal neuronal cells. On the basis of initial results, the agent could be further explored for its theranostic value clinically, which gives the possibility of tracing the AChE levels by molecular imaging techniques in correlation with progression of neurocognitive disorders like AD for better therapy response and patient management.

The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents

Acetylcholinesterase (AChE) is an enzyme which terminates the cholinergic neurotransmission, by hydrolyzing acetylcholine at the nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pre-treatment option of the intoxicat

Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer's Disease Drug Discovery

Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3β (GSK-3β) and human acetylcholinesterase (hAChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3β/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most promising profile as a nanomolar inhibitor on both hAChE (IC50 = 6.5 nM) and hGSK-3β kinase activity (IC50 = 66 nM). It also showed good inhibitory effect on β-amyloid self-aggregation (inhibitory rate = 46%) at 20 μM. Western blot analysis revealed that compound 2f inhibited hyperphosphorylation of tau protein in mouse neuroblastoma N2a-Tau cells. In vivo studies confirmed that 2f significantly ameliorated the cognitive disorders in scopolamine-treated ICR mice and less hepatotoxicity than tacrine. This study provides new leads for assessment of GSK-3β and AChE pathway dual inhibition as a promising strategy for AD treatment.

Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates

In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1-14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1-13 showed good cholinesterases inhibitory activities in vit

Synthesis and biological evaluation of tacrine-thiadiazolidinone hybrids as dual acetylcholinesterase inhibitors

The synthesis of tacrine-thiadiazolidinone hybrids is described. These compounds are designed as dual acetylcholinesterase inhibitors binding simultaneously to the peripheral and catalytic sites of the enzyme. All tested compounds exhibit significant AChE inhibitory activity. Competition assays using propidium as reference of selective ligand for the peripheral anionic site on acetylcholinesterase indicates the influence of the designed compounds over the peripheral site. They can be considered as new leads in the optimization of Alzheimer's disease modifying agents.

Synthesis, physicochemical and biological studies of technetium-99m labeled tacrine derivative as a diagnostic tool for evaluation of cholinesterase level

In the present work the synthesis and physicochemical investigations of new tacrine analogues labeled with technetium-99m are reported. All obtained novel radioconjugates showed high stability in the presence of an excess of standard amino acids cysteine or histidine, as well as in human serum. Lipophilicity (Log?D values) of these compounds is within the range from 0.92 to 1.56. For the selected radioconjugate99mTc(NS3)(CN-NH(CH2)7Tac) (Log?D?=?1.56) the biological activity studies in the course of inhibition of acetylcholinesterase action have been performed (IC50?=?45.0?nM, estimated by means of Ellman's method). Biodistribution studies of this compound showed its uptake in brain on the level of 0.07%ID/g and its clearance through the hepatic and renal route in comparable degree. The ascertained presence of the radioconjugate in brain indicates its possibility to cross the blood-brain barrier. Molecular modeling of99mTc(NS3)(CN-NH(CH2)7Tac) radioconjugate showed that the main structural fragment is tacrine moiety which is responsible for most interactions within catalytic and peripheral active sites and provides the anti-acetylcholinesterase activity. The99mTc(NS3)(CN-NH(CH2)7Tac) radioconjugate may be considered to be a diagnostic tool for patients suffering from Alzheimer's disease as well as a marker to determine the physiological condition of liver and intestines.

NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity

A series of tacrine - NO donor hybrid compounds are synthesized and evaluated for cholinesterase inhibitory activity, cognition improving activity, and hepatotoxicity. The pharmacological results indicate that hybrid compounds 1, 2, and 3a potently inhibit cholinesterase in vitro and significantly improve the scopolamine-induced cognition impairment, whereas an analogue (3h) of 2 without the NO donor moiety does not. Compared to tacrine, 1 and 2 show much less hepatotoxicity. Molecular modeling studies suggest that 2 may interact with the catalytic and the peripheral anionic site of acetylcholinesterase.

Chiral bistacrine analogues: Synthesis, cholinesterase inhibitory activity and a molecular modeling approach

Cholinesterase enzymes are important targets for the therapy of Alzheimer’s disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo- and heterodimers of bis(7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedl?nder cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo- and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds.