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Donepezil–tacrine hybrid related derivatives as new dual binding site inhibitors of AChE

A new series of donepezil–tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. These new hybrids combined a tacrine, 6-chlorotacrine or acridine unit as catalytic binding site and indanone (the heterocycle present in donepezil) or phthalimide moiety as peripheral binding site of the enzyme, connected through a different linker tether length. One of the synthesised compounds emerged as a potent and selective AChE inhibitor, which is able to displace propidium in a competition assay. These results seem to confirm the ability of this inhibitor to bind simultaneously to both sites of the enzyme and make it a promising lead for developing disease-modifying drugs for the future treatment of Alzheimer’s disease. To gain insight into the molecular determinants that modulate the inhibitory activity of these compounds, a molecular modelling study was performed to explore their binding to the enzyme.


A new series of donepezil–tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that are able to bind simultaneously to the peripheral and catalytic sites of the enzyme. The designed compounds may simultaneously alleviate cognitive deficits and behave as disease-modifying agents for the treatment of Alzheimer’s disease.


Alzheimer’s disease (AD) is the most common form of dementia accounting for about 50–60% of the overall cases of dementia among persons over 65 years of age. It is a progressive, degenerative disorder of the brain characterised by loss of memory and cognition. Brain regions that are associated with higher mental functions, particularly the neocortex and hippocampus, are those most affected by the characteristic pathology of AD.This includes the extracellular deposits of β-amyloid (derived from amyloid precursor protein, APP) in senile plaques,intracellular formation of neurofibrillary tangles (containing an abnormally phosphorylated form of a microtubule associated protein, tau) and the loss of neuronal synapsis and pyramidal neurons.7 Nevertheless, current treatment approaches in this disease continue being primarily symptomatic, with the major therapeutic strategy based on the cholinergic hypothesis and specifically on acetylcholinesterase (AChE) inhibition. Accordingly, during the last decade, several cholinergic drugs have been launched on the market, primarily AChE inhibitors indicated for the treatment of mild to moderate AD such as tacrine, donepezil,rivastigmine, or galantamine.More recently, memantine, a moderate affinity NMDA-receptor antagonists, has been approved for the treatment of moderate to severe AD.


Commercial available drugs for AD treatment.

The three-dimensional structure of AChE, as determined by X-ray crystallography, revealed that its active site can apparently be reached only through a deep and narrow ‘catalytic gorge’. Inhibitors directed to the active site prevent the binding of the substrate molecule (acetylcholine), or its hydrolysis, either by occupying the site with a high affinity molecule (tacrine) or by reacting irreversibly with the catalytic serine (organophosphates and carbamates). The peripheral site consists of a less well-defined area, located at the entrance of the catalytic gorge. Inhibitors that bind to that site include small molecules, such as propidium, and peptide toxins such as fasciculin. Parallel to the development of antidementia drugs, research efforts have been focused, among others, on the therapeutic potential of AChE inhibitors to slow the disorder progression. This fact was based on a range of evidences, which showed that AChE has secondary non-cholinergic functions.On the basis of these evidences, it was postulated that AChE binds through its peripheral site to the β-amyloid non-amyloidogenic form acting as a pathological chaperone and inducing a conformational transition to the amyloidogenic conformation with the subsequent amyloid fibril formation. In fact, AChE directly promotes in vitro the assembly of β-amyloid peptide into amyloid fibrils forming stable AChE–β-amyloid complexes Considering the non-cholinergic aspects of the cholinergic enzyme AChE, their relationship to Alzheimer’s hallmarks and the role of the peripheral site of AChE in all these functions, an attractive target for the design of new antidementia drugs emerged. Recent experimental results following this approach lead to the synthesis of several chemically diverse structures with potent AChE inhibition and interesting biological profile. These data corroborate the initial dual site AChE hypothesis and provided a new way to delay the neurodegenerative process.


Representative dual binding site hybrid AChE inhibitors.

Continuing our research on catalytic and peripheral binding site inhibitors, that include N-benzylpiperidine derivatives of 1,2,4-thiadiazolidinone and tacrine thiadiazolidinone compounds, they present here the synthesis, biological activity and propidium competition assay of novel dual binding site AChE inhibitors. These new dimeric compounds contain the tacrine heterocycle ring, which is recognised as a catalytic AChE inhibitor and indanone or related heterocycles as responsible for the binding to the peripheral site of the enzyme. These new family of inhibitors could be considered as donepezil–tacrine hybrid related derivatives. To study further the biological profile of these compounds, their butyrylcholinesterase (BChE) inhibitory activity was also evaluated. Finally, to explore the ability to bind the peripheral site of AChE, assays were also performed to explore the capacity to displace propidium binding.


  1. Alonso, D., Dorronsoro, I., Rubio, L., Muñoz, P., García-Palomero, E., Del Monte, M., Bidon-Chanal, A., Orozco, M., Luque, F. J., Castro, A., Medina, M., & Martínez, A. (2005). Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorganic & medicinal chemistry, 13(24), 6588–6597. https://doi.org/10.1016/j.bmc.2005.09.029