5778-84-7

Upstream product

• 38487-86-4 2-amino-4-chlorobenzonitrile 
• 108-94-1 cyclohexanone 
• 5396-25-8 6,9-dichloro-1,2,3,4-tetrahydroacridine 
• 1014699-29-6 6-chloro-9-hydrazinyl-1,2,3,4-tetrahydroacridine 

Downstream Products

• 1430326-22-9 (R)-6-chloro-N-(3-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)propyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-23-0 (R)-6-chloro-N-(5-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)pentyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-24-1 (R)-6-chloro-N-(6-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)hexyl)-1,2,3,4-tetrahydroacridin-9-amine 
• 1430326-25-2 (R)-6-chloro-N-(8-(4-(2-(methyl(prop-2-ynyl)amino)propyl)phenoxy)octyl)-1,2,3,4-tetrahydroacridin-9-amine 

Relevant academic research and scientific papers

Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species

The in vitro neuronal cell death model based on the HT22 mouse hippocampal cell model is a convenient means of identifying compounds that protect against oxidative glutamate toxicity which plays a role in the development of certain neurodegenerative diseases. Functionalized acridin-9-yl-phenylamines were found to protect HT22 cells from glutamate challenge at submicromolar concentrations. The Aryl1-NHAryl2 scaffold that is embedded in these compounds was the minimal pharmacophore for activity. Mechanistically, protection against the endogenous oxidative stress generated by glutamate did not involve up-regulation of glutathione levels but attenuation of the late stage increases in mitochondrial ROS and intracellular calcium levels. The NH residue in the pharmacophore played a crucial role in this regard as seen from the loss of neuroprotection when it was structurally modified or replaced. That the same NH was essential for radical scavenging in cell-free and cell-based systems pointed to an antioxidant basis for the neuroprotective activities of these compounds.

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.

Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species

The in vitro neuronal cell death model based on the HT22 mouse hippocampal cell model is a convenient means of identifying compounds that protect against oxidative glutamate toxicity which plays a role in the development of certain neurodegenerative diseases. Functionalized acridin-9-yl-phenylamines were found to protect HT22 cells from glutamate challenge at submicromolar concentrations. The Aryl1-NH-Aryl2 scaffold that is embedded in these compounds was the minimal pharmacophore for activity. Mechanistically, protection against the endogenous oxidative stress generated by glutamate did not involve up-regulation of glutathione levels but attenuation of the late stage increases in mitochondrial ROS and intracellular calcium levels. The NH residue in the pharmacophore played a crucial role in this regard as seen from the loss of neuroprotection when it was structurally modified or replaced. That the same NH was essential for radical scavenging in cell-free and cell-based systems pointed to an antioxidant basis for the neuroprotective activities of these compounds.

Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine-Homoisoflavonoid hybrids

A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD).

A novel hybrid of 6-chlorotacrine and metal-amyloid-β modulator for inhibition of acetylcholinesterase and metal-induced amyloid-β aggregation

The number of people suffering from Alzheimer's disease (AD) is expected to increase dramatically in the coming decades. Currently, acetylcholinesterase inhibitors (AChEis) provide some relief of cognitive symptoms, while newer approaches, such as amyloid-β (Aβ)-targeted metal chelation, offer potential hope for slowing and/or reversing disease progression. This work details the synthesis and biochemical evaluation of a novel hybrid of 6-chlorotacrine and a metal-Aβ modulator that chemically combines an AChEi and an Aβ-targeted metal chelator into a single molecule. This hybrid shows potent inhibition of AChE under various conditions, interaction with Cu 2+ and Zn2+, control of metal-free and metal-induced Aβ aggregate assembly, and disaggregation of preformed metal-free and metal-associated Aβ aggregates. As such, the hybrid described herein represents a promising, new multifunctional compound for AD studies. The Royal Society of Chemistry 2013.

The divergent transformations of aromatic o-aminonitrile with carbonyl compound

A modified Friedlaender conversion of the cyclocondensation of aromatic o-aminonitriles with carbonyl compounds was discovered. Systematic studies reveal that both the new transformation and the classic Friedlaender annulation in the presence of ZnCl2 constitute a pair of divergent reaction, and thecontrolled PDF transformation of this divergent reaction was achieved in the present of bases.

Synthesis of quinolines via Friedlaender reaction catalyzed by CuBTC metal-organic-framework

Friedlaender condensation between 2-aminoaryl ketones and different carbonyl compounds, catalyzed by CuBTC was investigated by a combination of various experimental techniques and by density functional theory based modelling. CuBTC exhibiting hard Lewis a

Heterodimers and Methods of Using Them

Novel heterodimers of tetrahydroacridines and tetrahydroquinolinones are disclosed. The heterodimers are capable of acting as both acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. The heterodimers may be used to improve cognitive defects via treatment or prevention in both humans and non-humans.

Synthesis of tacrine derivatives under solventless conditions

(Chemical Equation Presented) Effects of microwave irradiation on the solid-phase synthesis of tacrine and its derivatives have been evaluated. Preparation of tacrine analogues under conventional conditions suffers from poor synthetic efficiency and usually gives low yield. Reaction of substituted anthranilonitrile with cyclohexanone under microwave irradiation gave a good to excellent yield of the corresponding substituted 9-amino-1,2,3,4- tetrahydroacridines.

SAR of 9-amino-1,2,3-4-tetrahydroacridine-based acetylcholinesterase inhibitors: Synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues

In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (ACHE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3,4- tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4- tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9- amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC50 value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC50 value was equal to 0.066 (±0.009) μM, corresponding to a pIC50 of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.