Abstract
In the brain of patients with chronic Alzheimer’s disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, development of new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)‑lophine analogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions were performed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps for unsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of them inhibit AChE. All the compounds, except 7a, 7b and 7c, displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (half maximal inhibitory concentration (IC50) 32.25-0.03 μM). The enzyme kinetic and docking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studies showed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6 astroglial cell lines.
Highlights
The serine hydrolases acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are structurally related enzymes that co-regulate the metabolism of the neurotransmitter acetylcholine (ACh).Cholinesterase inhibitors (ChEIs) are a class of drugs that have been used in the management of various human ailments, including Alzheimer’s disease (AD),[1] Parkinson’s disease,[2] glaucoma,[3,4] myasthenia gravis,[5] Lewy bodies’ disease,[6] and chronic pain in elderly.[7]Alzheimer’s disease is known as a neurodegenerative disorder with major importance and the principal cause of dementia among the elderly
According to the results, the compounds 5b and 12b showed no or slightly cytotoxic effects in all cellular models at the tested concentrations, exhibiting an IC50 higher than 125 μM. These results suggest that the compounds have a degree of safety because there is a large difference between the IC50 for BuChE inhibition (IC50 = 0.208 μM for 5b and 0.071 μM for 12b) and the concentration to which all cell lines were exposed in the cytotoxic assay
Two new series of bis(n)-lophine analogues were synthesized through a one-pot four component reaction performed in a microwave reactor
Summary
The serine hydrolases acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are structurally related enzymes that co-regulate the metabolism of the neurotransmitter acetylcholine (ACh).Cholinesterase inhibitors (ChEIs) are a class of drugs that have been used in the management of various human ailments, including Alzheimer’s disease (AD),[1] Parkinson’s disease,[2] glaucoma,[3,4] myasthenia gravis,[5] Lewy bodies’ disease,[6] and chronic pain in elderly.[7]Alzheimer’s disease is known as a neurodegenerative disorder with major importance and the principal cause of dementia among the elderly. The bis(8)-lophine was the only active compound, showing a potent inhibition against AChE (half maximal inhibitory concentration (IC50) = 42.55 nM).
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