321-64-2

Basic information

• Product Name: 1,2,3,4-TETRAHYDRO-9-ACRIDINAMINE
• Synonyms: 1,2,3,4-Tetrahydro-5-aminoacridine;1,2,3,4-tetrahydro-9-acridinamin;1,2,3,4-tetrahydro-9-amino-acridin;1,2,3,4-Tetrahydro-9-aminoacridine;5-Amino-6,7,8,9-tetrahydroacridine;Acridine, 1,2,3,4-tetrahydro-9-amino-;Acridine, 9-amino-1,2,3,4-tetrahydro-;Acridine, 9-aminotetrahydro-
• CAS NO: 321-64-2
• Molecular Formula: C₁₃H₁₄N₂
• Molecular Weight: 198.26
• EINECS: 206-291-2
• Mol File: 321-64-2.mol
• Article Data: 29

Chemical Properties

• Melting Point: 183.5℃
• Boiling Point: 325.59°C (rough estimate)
• Flash Point: 230.5°C
• Appearance: /
• Density: 0.9827 (rough estimate)
• Refractive Index: 1.4400 (estimate)
• PKA: 9?+-.0.20(Predicted)
• CAS DataBase Reference: 1,2,3,4-TETRAHYDRO-9-ACRIDINAMINE(CAS DataBase Reference)
• NIST Chemistry Reference: 1,2,3,4-TETRAHYDRO-9-ACRIDINAMINE(321-64-2)
• EPA Substance Registry System: 1,2,3,4-TETRAHYDRO-9-ACRIDINAMINE(321-64-2)

Safety Data

• Hazard Codes: T:Toxic
• Statements: R25:Toxic if swallowed.
• Safety Statements: S28A:After contact with skin, wash immediately with plenty of water.; S45:In case of accident of if you feel unwell, seek
• Hazardous Substances Data: 321-64-2(Hazardous Substances Data)

Usage

Description

In the 1950s, tacrine was used experimentally to reverse cholinergic coma in animals. In the 1960s, tacrine was used to reverse the effects of phencyclidine-like drugs. It was also marketed for many years as a respiratory stimulant. In 1993, the US Food and Drug Administration approved tacrine for the treatment of symptoms of mild to moderate Alzheimer’s disease.

Uses

The current use of tacrine is limited due to its poor oral bioavailability, the necessity for four daily doses, and serious side effects (including nausea, vomiting, dry mouth, indigestion, diarrhea, loss of appetite, urinary incontinence, collapse, convulsions, and hepatotoxicity). Currently, newer cholinesterase inhibitors (such as donepezil, rivastigmine, and galantamine) are preferred over tacrine.

Synthesis Reference(s)

Tetrahedron Letters, 4, p. 1277, 1963 DOI: 10.1039/jr9630005127

Toxicity evaluation

Tacrine has numerous mechanisms of action. The putative principal mechanism of action of tacrine for Alzheimer’s disease is reversible inhibition of acetylcholinesterase (AChE), which thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. Tacrine also inhibits butyrylcholinesterase activity. In addition, tacrine blocks sodium and potassium channels. Tacrine also acts as a histamine N-methyltransferase inhibitor. At a therapeutic dose, tacrine causes liver toxicity. Cytotoxicity studies using the human liver cell line HepG2 showed that a therapeutic blood concentration of tacrine induces reactive oxygen species production and glutathione depletion, suggesting that oxidative stress might be involved in tacrine hepatotoxicity.

InChI:InChI=1/C13H14N2/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,(H2,14,15)

Upstream product

• 118-92-3 anthranilic acid 
• 108-94-1 cyclohexanone 
• 1684-40-8 tacrine monohydrochloride 
• 607-28-3 3-(hydroxyimino)indolin-2-one 
• 91-56-5 indole-2,3-dione 
• 1885-29-6 anthranilic acid nitrile 
• 65197-42-4 9-hydrazino-1,2,3,4-tetrahydroacridine 
• 138829-42-2 N-(cyclohexen-1yl)-2-aminobenzonitrile 
• 56717-04-5 4-hydroxy-2,3-(tetramethylene)quinoline 
• 110166-26-2 aminacrine 
• 157996-60-6 9-amino-2,7-dibromoacridine 
• 157996-59-3 9-amino-2-bromoacridine 
• 540-23-8 p-toluidine hydrochloride 
• 28144-70-9 anthranilic acid amide 

Downstream Products

• 102873-43-8 2-chloro-N-(1,2,3,4-tetrahydroacridin-9-yl)acetamide 
• 5396-30-5 9-chloro-1,2,3,4-tetrahydroacridine 
• 1430326-14-9 (R)-N-(2-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)ethyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-16-1 (R)-N-(4-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)butyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-17-2 (R)-N-(5-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)pentyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-20-7 (R)-N-(9-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)nonyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-21-8 (R)-N-(10-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)decyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-27-4 (R)-N₁-(1-(4-methoxyphenyl)propan-2-yl)-N₁-(prop-2-ynyl)-N₆-(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine 

Relevant articles and documents

Bistacrine derivatives as new potent antimalarials

Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure–activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth.

Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimers disease

A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimers disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.

Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity

Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 μM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 μM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.

RETRACTED ARTICLE: Sanger's Reagent Sensitized Photocleavage of Amide Bond for Constructing Photocages and Regulation of Biological Functions

Photolabile groups offer promising tools to study biological processes with high spatial and temporal control. In the investigation, we designed and prepared several new glycine amide derivatives of Sanger's reagent and demonstrated that they serve as a new class of photocages for Zn2+ and an acetylcholinesterase (AChE) inhibitor. We showed that the mechanism for photocleavage of these substances involves initial light-driven cyclization between the 2,4-dinitrophenyl and glycine methylene groups to form acyl benzimidazole N-oxides, which undergo secondary photoinduced decarboxylation in association with rupture of an amide bond. The cleavage reactions proceed with modest to high quantum yields. We demonstrated that these derivatives can be used in targeted intracellular delivery of Zn2+, fluorescent imaging by light-triggered Zn2+ release, and regulation of biological processes including the enzymatic activity of carbonic anhydrase (CA), negative regulation of N-methyl-d-aspartate receptors (NMDARs), and pulse rate of cardiomyocytes. The successful proof-of-concept examples described above open a new avenue for using Sanger's reagent-based glycine amides as photocages for the exploration of complex cellular functions and signaling pathways.

Tacrine-Hydrogen Sulfide Donor Hybrid Ameliorates Cognitive Impairment in the Aluminum Chloride Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by progressive loss of memory and cognitive function, and is associated with the deficiency of synaptic acetylcholine, as well as chronic neuroinflmmation. Tacrine, a potent acetylcholinesterase (AChE) inhibitor, was previously a prescribed clinical therapeutic agent for AD, but it was recently withdrawn because it caused widespread hepatotoxicity. Hydrogen sulfide (H2S) has neuroprotective, hepatoprotective, and anti-inflammatory effects. In this study, we synthesized a new compound, a tacrine-H2S donor hybrid (THS) by introducing H2S-releasing moieties (ACS81) to tacrine. Subsequently, pharmacological and biological evaluations of THS were conducted in the aluminum trichloride (AlCl3)-induced AD mice model. We found that THS (15 mmol/kg) improved cognitive and locomotor activity in AD mice in the step-through test and open field test, respectively. THS showed strong AChE inhibitory activity in the serum and hippocampus of AD mice and induced increased hippocampal H2S levels. Furthermore, THS reduced mRNA expression of the proinflammatory cytokines, TNF-α, IL-6, and IL-1β and increased synapse-associated proteins (synaptophysin and postsynaptic density protein 95) in the hippocampus of AD mice. Importantly, THS, unlike tacrine, did not increase liver transaminases (alanine transaminase and aspartate transaminase) or proinflammatory cytokines, indicating THS is much safer than tacrine. Therefore, the multifunctional effects of this new hybrid compound of tacrine and H2S indicate it is a promising compound for further research into the treatment of AD.