Novel benzimidazole-based pseudo-irreversible butyrylcholinesterase inhibitors with neuroprotective activity in an Alzheimer's disease mouse model. Issue 8 (20th June 2022)

• Record Type: Journal Article
• Authors: Spatz, Philipp; Zimmermann, Thomas; Steinmüller, Sophie; Hofmann, Julian; Maurice, Tangui; Decker, Michael
• Is Part Of: RSC medicinal chemistry. Volume 13:Issue 8(2022)
• Page Start: 944
• Page End: 954
• Publication Date: 2022-06-20
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d2md00087c
• Languages: English
• ISSNs: 2632-8682

Abstract

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. 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.