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

Abstract

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 (IC 50 150 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.

Butyrylcholinesterase - BuChE: A Potential Target for Development of Drugs for Alzheimer's Disease Treatment

“…O derivado híbrido 2-benzilcarbamato-isossorbida-5-lipoato (11a), mais potente e seletivo inibidor da BuChE dentre os compostos estudados no trabalho em questão, mostrou mecanismo de inibição pseudo-irreversível e foi o melhor como neuroprotetor em linhagem de células hipocampais murinas, no modelo de citotoxicidade induzida por glutamato. 63 Em 2017, Wu e colaboradores descreveram uma série de treze carbamatos desenhados como análogos estruturais do bambuterol (BMB) (13), um pró-fármaco do agonista β-adrenérgico terbutalina. O BMB (13) é um potente inibidor de BuChE, porém com limitações como a incapacidade de atravessar a barreira hematoencefálica (BHE) e a possibilidade de ocorrência de efeitos colaterais cardíacos, causados pelo seu metabólito ativo.…”

Cholinesterases and the fine line between poison and remedy

“…This hypothesis opened the door to examine potential therapeutic benefits of cholinesterase inhibitors [95–97]. Since that time, many natural and synthetic cholinesterase inhibitors that bind selectively or show multifunctional characteristics have been evaluated to treat Alzheimer’s disease (see recent reviews [98–102].…”

Incorporation of an Isohexide Subunit Improves the Drug-like Properties of Bioactive Compounds

“…As a component of the prodrug isosorbide mononitrate, an FDA approved treatment for angina, 1 confers useful drug-like properties, including excellent solubility and permeability, and favorable metabolic stability. The adoption of 1 and the two other isohexide stereoisomers, namely, isoidide ( 2 ) and isomannide ( 3 ), as “green” components of polymers, plasticizers, liquid crystals, and other materials is an active area of research. − There are now a variety of examples of the incorporation of isohexides into bioactive scaffolds. − …”