Target Enzyme in Alzheimer’s Disease: Acetylcholinesterase Inhibitors

Abstract

Alzheimer’s Disease (AD), affecting a large population worldwide is characterized by the loss of memory and learning ability in the old population. The enzyme Acetylcholinesterase Enzyme (AChE) is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD but these drugs provide only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time. The development of different strategies targeting the AChE enzyme along with other targets like Butyl Cholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals antioxidant properties and free radical scavenging capacity has been focused in recent years. Literature search was conducted for the molecules and their rational design which have shown inhibition for AChE and the other abovementioned targets. Several hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates, and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule. It is followed by optimization of the activity through structural modifications guided by structure-activity relationship studies. It has led to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity against other abovementioned targets for further pre-clinical studies.

Antioxidant, Antimicrobial, and Bioactive Potential of Two New Haloarchaeal Strains Isolated from Odiel Salterns (Southwest Spain)

“…Acetylcholinesterase catalyzes the hydrolysis of cholinergic neurotransmitters such as acetylcholine and others choline esters to terminate the synaptic transmission rapidly. The reversible inhibition of this enzyme is being explored as treatment for Alzheimer’s disease [ 66 ], while acetylcholinesterase activation is required in cholinergic crisis related to acetylcholine accumulations [ 67 ].…”

Synthesis of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl)pyrrolidine as acetylcholinesterase inhibitors

“…In the present study, we evaluated in vitro the anticholinesterase potential of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl)pyrrolidine compounds. AChE inhibitors are used to increase the acetylcholine level and thus improve the memory decline in AD patients 31 . Investigation of new anticholinesterase compounds is of most importance due to the fact that: (i) epidemiological data have shown the increasing prevalence of AD worldwide, especially due to increased life expectancy 32 , 33 ; (ii) The current drugs used to treat AD still cause many adverse effects, besides acting only to alleviate the symptoms of the disease, and therefore a palliative alternative therapy besides that presents limitation of loss of therapeutic efficacy with time 33 , 34 .…”

Inhibition of acetylcholinesterase activity and β‑amyloid oligomer formation by 6‑bromotryptamine�A, a multi‑target anti‑Alzheimer's molecule

“…In addition, Aβ oligomer-induced neurotoxicity is considered as the main cause of neuronal loss in AD (5). Due to the complexity of the pathology of this disease, a one-molecule multi-target strategy may be useful for identifying novel anti-AD drugs (6).…”