Novel benzimidazole-based pseudo-irreversible butyrylcholinesterase inhibitors with neuroprotective activity in an Alzheimer's disease mouse model

Abstract

Benzimidazole-based inhibitors of butyrylcholinesterase were designed and tested for their activity and selectivity in vitro, leading to compound (11d) that attenuated Aβ25-35-induced learning impairments in an Alzheimer's disease mouse model.

Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model

“…Different to AChE, levels of butyrylcholinesterase (BChE) seem to increase during disease progression, marking it as a promising target for mid- and late-stage treatment of AD . Several studies by us and others could already underline beneficial effects of BChE inhibition in vivo regarding neuroprotective properties. ,,,,− …”

“…Key structures targeting BChE and/or CB 2 R. (a) Carbamate-based ChEIs; (b) benzimidazole CB 2 R agonist developed by AstraZeneca; and (c) selection of recently reported CB 2 R/BChE hybrid molecules. − …”

“…Respective molecules consist of the 2-benzylbenzimidazole core, modified on one of its phenolic positions by small, lipophilic carbamates to fit into the orthosteric pocket of cannabinoid receptors, as well as interacting with the active center of h BChE (Figure ). We explored this scaffold first in 2022, designing and obtaining BChE-selective inhibitors but lacking CB 2 R activity . For the construction of BChE/CB 2 R hybrids, we utilized smaller carbamate units in different positions of the benzimidazole core, mimicking benzimidazole-based agonists, described by Pagé et al, to introduce CB 2 R affinity to the benzimidazole-carbamate scaffold of compound 3 …”

Highly efficient, catalyst-free, one-pot sequential four-component synthesis of novel spiroindolinone-pyrazole scaffolds as anti-Alzheimer agents: in silico study and biological screening

“…The consistent loss of cholinergic neurons and a considerable decline in choline acetyltransferase activity are the most prominent phenotypes of AD progression. 3,4 As a result, cholinergic system dysfunction happens with synaptic damage accompanied by neuronal loss in the brain, particularly in the hippocampus and cerebral cortex. 5…”

“…The consistent loss of cholinergic neurons and a considerable decline in choline acetyltransferase activity are the most prominent phenotypes of AD progression. 3,4 As a result, cholinergic system dysfunction happens with synaptic damage accompanied by neuronal loss in the brain, particularly in the hippocampus and cerebral cortex. 5 Acetylcholine (ACh) is known as one of the main neurotransmitters in the central nervous system (CNS), synthesized from acetyl coenzyme A and choline by the enzyme choline acetyltransferase.…”