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

RSC Medicinal Chemistry Pub Date: 2022-06-20 DOI: 10.1039/D2MD00087C

Abstract

As levels of acetylcholinesterase (AChE) decrease while levels of butyrylcholinesterase (BChE) increase in later stages of Alzheimer's disease (AD), BChE stands out as a promising target for treatment of AD. Therefore, several benzimidazole-carbamates were designed based on docking studies to inhibit BChE selectively over AChE, while retaining a reasonable solubility. Synthesized molecules exhibit IC50 values from 2.4 μM down to 3.7 nM with an overall highly hBChE-selective profile of the designed compound class. After evaluation of potential neurotoxicity, the most promising compound was further investigated in vivo. Compound 11d attenuates Aβ25–35-induced learning impairments in both spontaneous alternation and passive avoidance responses at a very low dosage of 0.03 mg kg?1, proving selective BChE inhibition to lead to effective neuroprotectivity in AD.

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