Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold

Bosak, Anita; Ramić, Alma; Šmidlehner, Tamara; Hrenar, Tomica; Primožič, Ines; Kovarik, Zrinka

doi:10.1371/journal.pone.0205193

Cited by 27 publications

(20 citation statements)

References 36 publications

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“…Finally, the development of new acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors represents a viable approach to alleviate Alzheimer’s disease [ 31 ]. The inhibition of BuChE and AChE is of great interest for the study of the treatment and slowing down of Alzheimer’s disease [ 12 , 32 ] and other neurodegenerative diseases. The inhibitory activity of Lepechinia paniculata EO for the two enzymes evaluated has not been previously described in the literature, so new studies are necessary to establish its potential pharmacological use.…”

Section: Discussionmentioning

confidence: 99%

Chemical Composition and Anticholinesterase Activity of the Essential Oil of Leaves and Flowers from the Ecuadorian Plant Lepechinia paniculata (Kunth) Epling

et al. 2021

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This work aimed to study the chemical composition, cholinesterase inhibitory activity, and enantiomeric analysis of the essential oil from the aerial parts (leaves and flowers) of the plant Lepechinia paniculata (Kunth) Epling from Ecuador. The essential oil (EO) was obtained through steam distillation. The chemical composition of the oil was evaluated by gas chromatography, coupled to mass spectrometry (GC–MS) and a flame ionization detector (GC-FID). The analyses led to the identification of 69 compounds in total, of which 40 were found in the leaves and 29 were found in the flowers of the plant. The major components found in the oil were 1,8-Cineole, β-Pinene, δ-3-Carene, α-Pinene, (E)-Caryophyllene, Guaiol, and β-Phellandrene. Flower essential oil showed interesting selective inhibitory activity against both enzymes AChE (28.2 ± 1.8 2 µg/mL) and BuChE (28.8 ± 1.5 µg/mL). By contrast, the EO of the leaves showed moderate mean inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with IC50 values of 38.2 ± 2.9 µg/mL and 47.4 ± 2.3 µg/mL, respectively.

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Section: Discussionmentioning

confidence: 99%

Chemical Composition and Anticholinesterase Activity of the Essential Oil of Leaves and Flowers from the Ecuadorian Plant Lepechinia paniculata (Kunth) Epling

et al. 2021

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“…All isolated compounds exhibited in the 1 H NMR spectrum a singlet in the range of 7.78-7.81 ppm, which was attributed to the proton on the position 2 of the oxazole ring due to the influence of nitrogen and oxygen found in its immediate vicinity unshaded and shifted to a lower field (Figure 2 and Supplementary Figures S1-S19). The protons located at position 4 of the oxazole ring showed a singlet in the range of 6.95-6.99 ppm, the ethylenic protons are visible as doublets in the range of 6.99-7.08 ppm with coupling constants between 16 Hz and 17 Hz, characteristic for trans-isomers. For compounds trans-17 and trans-18, the characteristic signals for the furan or thiophene ring are also visible with characteristic coupling constants (See experimental and Supplementary Figure S16).…”

Section: Synthesis and Photochemistry Of Novel Oxazole Benzylaminesmentioning

confidence: 99%

“…15 . Many other compounds acting as inhibitors of cholinesterase are therefore considered as potential AD therapeutics [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives

Šagud

Hrvat

Grgičević

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC 50 in mM range) and AChE poorly (IC 50)100 mM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors. HIGHLIGHTS Series of oxazole benzylamines were designed and synthesised The tested compounds showed binding selectivity for BChE Naphthoxazoles were more potent AChE inhibitors ARTICLE HISTORY

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“…Quaternized quinuclidine-3-ols [ 32 ] and their conjugates with imidazolium and pyridinium were determined to reversibly inhibit AChE [ 27 , 33 ]. Additionally, Cinchona-based alkaloids cinchonines and cinchonidines, quaternized with groups diverse in size, displayed anticholinesterase potency, pointing those compounds out as very potent human cholinesterase reversible inhibitors [ 34 ]. Two quinuclidinium-based carbamates were determined to be weak carbamylating agents of AChE [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Quinuclidine-Based Carbamates as Potential CNS Active Compounds

et al. 2021

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The treatment of central nervous system (CNS) diseases related to the decrease of neurotransmitter acetylcholine in neurons is based on compounds that prevent or disrupt the action of acetylcholinesterase and butyrylcholinesterase. A series of thirteen quinuclidine carbamates were designed using quinuclidine as the structural base and a carbamate group to ensure the covalent binding to the cholinesterase, which were synthesized and tested as potential human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The synthesized compounds differed in the substituents on the amino and carbamoyl parts of the molecule. All of the prepared carbamates displayed a time-dependent inhibition with overall inhibition rate constants in the 103 M−1 min−1 range. None of the compounds showed pronounced selectivity for any of the cholinesterases. The in silico determined ability of compounds to cross the blood–brain barrier (BBB) revealed that six compounds should be able to pass the BBB by passive transport. In addition, the compounds did not show toxicity toward cells that represented the main models of individual organs. By machine learning, the most optimal regression models for the prediction of bioactivity were established and validated. Models for AChE and BChE described 89 and 90% of the total variations among the data, respectively. These models facilitated the prediction and design of new and more potent inhibitors. Altogether, our study confirmed that quinuclidinium carbamates are promising candidates for further development as CNS-active drugs, particularly for Alzheimer’s disease treatment.

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Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold

Cited by 27 publications

References 36 publications

Chemical Composition and Anticholinesterase Activity of the Essential Oil of Leaves and Flowers from the Ecuadorian Plant Lepechinia paniculata (Kunth) Epling

Chemical Composition and Anticholinesterase Activity of the Essential Oil of Leaves and Flowers from the Ecuadorian Plant Lepechinia paniculata (Kunth) Epling

Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives

Quinuclidine-Based Carbamates as Potential CNS Active Compounds

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