9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment

Махаева, Галина Ф.; Lushchekina, Sofya V.; Boltneva, Natalia P.; Serebryakova, Olga G.; Рудакова, Е. В.; Ustyugov, A. A.; Бачурин, С. О.; Shchepochkin, Alexander V.; Чупахин, О. Н.; Charushin, Valery N.; Richardson, Rudy J.

doi:10.1016/j.bmc.2017.09.028

Cited by 44 publications

(28 citation statements)

References 73 publications

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“…It is an important feature in AD marked by overproduction of reactive oxygen species (ROS), oxidation in neuronal lipids, proteins, DNA, and RNA leading to the dysfunction and loss of neurons [11] . As previously reported by several studies, AD brain suffers from a significant low content of antioxidant enzymes, which leads the brain to be more susceptible to toxic effects induced by Aβ [12] . Thus, antioxidants have been considered for a long time as an approach to slow down AD progression.…”

Section: Introductionmentioning

confidence: 67%

Neuroprotective efficacy of thymoquinone against amyloid beta-induced neurotoxicity in human induced pluripotent stem cell-derived cholinergic neurons

Alhibshi

Odawara

Suzuki

2019

Biochemistry and Biophysics Reports

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The natural antioxidant Thymoquinone (TQ) is the most abundant ingredient in the curative plant Nigella sativa seed's oil. An extensive number of studies have revealed that TQ is the most active and most responsible component for the plant's pharmacological properties. It has been documented in several studies that TQ has a wide range of protective activities and many neuropharmacological attributes. Amyloid beta (Aβ) is the major role player peptide in the progression of Alzheimer's disease (AD). Our current study has been implemented to explore the protective possibilities of TQ on Aβ1–42 -induced neurotoxicity. To test TQ's effect we used cultured human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons. The obtained results showed that Aβ1–42 caused cell death and apoptosis, which was efficiently attenuated by the co-treatment of TQ. Moreover, TQ restored the decrease in the intracellular antioxidant enzyme glutathione levels and inhibited the generation of reactive oxygen species induced by Aβ1–42. Furthermore, using the fluorescent dye FM1–43 we demonstrated that TQ was able to reduce synaptic toxicity caused by Aβ1–42. Thus, the findings of our study suggest that TQ holds a neuroprotective potential and could be a promising therapeutic agent to reduce the risk of developing AD and other disorders of the central nervous system.

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Section: Introductionmentioning

confidence: 67%

Neuroprotective efficacy of thymoquinone against amyloid beta-induced neurotoxicity in human induced pluripotent stem cell-derived cholinergic neurons

Alhibshi

Odawara

Suzuki

2019

Biochemistry and Biophysics Reports

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“…One cluster contains acridine derivatives, such as tacrine hydrochloride, hydroxytacrine maleate, and 9-aminoacridine monohydrochloride monohydrate, which have been shown to be effective inhibitors of BChE and AChE in the pharmacotherapy of AD. 36 Bambuterol hydrochloride, a known selective BChE inhibitor, 13 is a carbamate ester. Most carbamates are inhibitors of BChE and AChE.…”

Section: Discussionmentioning

confidence: 99%

Identification of Compounds for Butyrylcholinesterase Inhibition

Travers

et al. 2021

SLAS Discovery

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Butyrylcholinesterase (BChE) is a nonspecific cholinesterase enzyme that hydrolyzes choline-based esters. BChE plays a critical role in maintaining normal cholinergic function like acetylcholinesterase (AChE) through hydrolyzing acetylcholine (ACh). Selective BChE inhibition has been regarded as a viable therapeutic approach in Alzheimer’s disease. As of now, a limited number of selective BChE inhibitors are available. To identify BChE inhibitors rapidly and efficiently, we have screened 8998 compounds from several annotated libraries against an enzyme-based BChE inhibition assay in a quantitative high-throughput screening (qHTS) format. From the primary screening, we identified a group of 125 compounds that were further confirmed to inhibit BChE activity, including previously reported BChE inhibitors (e.g., bambuterol and rivastigmine) and potential novel BChE inhibitors (e.g., pancuronium bromide and NNC 756), representing diverse structural classes. These BChE inhibitors were also tested for their selectivity by comparing their IC50 values in BChE and AChE inhibition assays. The binding modes of these compounds were further studied using molecular docking analyses to identify the differences between the interactions of these BChE inhibitors within the active sites of AChE and BChE. Our qHTS approach allowed us to establish a robust and reliable process to screen large compound collections for potential BChE inhibitors.

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“…As can be seen from Table 1, the novel conjugates possessed rather low activity against CES, the enzyme responsible for the hydrolysis of numerous ester-containing drugs [73]. This is a desirable result, because the inhibition of CES by anticholinesterase compounds used by a patient may lead to unwanted drug-drug interactions [46,72,77].…”

Section: Inhibition Studies Of Ache Bche and Ces Structure-activity Relationshipsmentioning

confidence: 99%

New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

et al. 2020

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New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.

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9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer's disease treatment

Cited by 44 publications

References 73 publications

Neuroprotective efficacy of thymoquinone against amyloid beta-induced neurotoxicity in human induced pluripotent stem cell-derived cholinergic neurons

Neuroprotective efficacy of thymoquinone against amyloid beta-induced neurotoxicity in human induced pluripotent stem cell-derived cholinergic neurons

Identification of Compounds for Butyrylcholinesterase Inhibition

New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

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