Title: Novel benzimidazole-based pseudo-irreversible butyrylcholinesterase inhibitors with neuroprotective activity in an Alzheimer's disease mouse model Spatz P, Zimmermann T, Steinmuller S, Hofmann J, Maurice T, Decker M Ref: RSC Med Chem, 13:944, 2022 : PubMed
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 IC(50) values from 2.4 microM 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 Abeta(25-35)-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.
