Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer's Disease.

Mike Jones,Jun Wang,John Gilmer,Shona Harmon,Beata Kling,Jörg Heilmann

doi:10.3390/molecules21040440

Abstract

Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid or lipoic acid groups producing potent selective inhibitors of butyrylcholinesterase (BuChE). The hybrid compounds were non-toxic to the murine hippocampal cell line HT-22 and lipoate esters were neuroprotective at 10 and 25 µM when the cells were challenged with glutamate (5 mM) in a similar manner to the positive control quercetin. The benzyl carbamate 7a was a potent inhibitor of BuChE (IC50 150 nM) and it was effective in reducing glutamate toxicity to neuronal cells at >5 µM. Representative compounds exhibited an antioxidant effect in the oxygen radical absorbance capacity assay as the lipoate 7d was not active, whereas the ferulate 8a showed a weak, but significant, activity with 0.635 ± 0.020 Trolox Equivalent.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disease, with more than 20 million cases worldwide [1]
AD is characterised by global cognitive decline and associated neuropathological findings which may include neuronal loss, neurofibrillary tangles, neuritic plaques and amyloid angiopathy
We chose benzyl [22], benzyl carbamates were most potent irrespective of the identity of the the most potent carbamate because, in the isosorbide-2-carbamate-5-ester compounds already reported [22], benzyl compound we reported was a 2-benzyl carbamate with a 5-salicylate group which had an

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease, with more than 20 million cases worldwide [1]. Cholinergic loss is the single most replicated neurotransmitter deficiency in AD, and AChE has been a drug target for the treatment of AD since the emergence of this cholinergic hypothesis over 30 years ago [2]. This followed recognition that the cognitive impairments in AD correlated with cholinergic deficits such as reduced synaptic acetylcholine synthesis and choline acetyltransferase (ChAT) activity. Selective inhibitors of acetylcholinesterase (AChE; EC 3.1.1.7) e.g., donepezil and unselective inhibitors (ChEIs) e.g., rivastigmine, induce dose-limiting adverse effects such as bradycardia, nausea, and diarrhea [3,4]

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