engleski

Evaluation of 4-aminoquinolines as potential MTDL ligands for the treatment of Alzheimer`s disease

Derivatives of 4­aminoquinolines have been present in medicine for decades thanks to their antimalarial properties. They also show anti­ inflammatory, anti­infective, antithrombotic, as well as antitumoral properties which candidates them for repurposing in treatment of other diseases. Their ability to pass the blood­brain barrier and inhibit the activity of cholinesterases makes them promising agents for the treatment of neurodegenerative diseases, whose aetiology encompasses the decrease of neurotransmitter acetylcholine levels. The aim of our study was to determine whether 4­ aminoquinolines have the potential to be used as multi­target directed ligands (MTDLs) in treating Alzheimer’s disease acting as inhibitors of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE), and as inhibitors of β­secretase (BACE1). BACE1 is the aspartic protease responsible for the cleavage of the amyloid precursor protein (APP) and formation of self­ aggregating amyloid β peptides and senile plaques. Our results showed that all of the 12 tested 4­aminoquinoline derivatives reversibly inhibited the activity of both AChE and BChE with dissociation constants of the enzyme­ aminoquinoline complex (Ki) in low micro­ to nanomolar range, the most potent being DO250 and DO251. It was determined that our compounds display certain inhibitory potential against BACE1, the most potent being DO250, DO251, DO256 and DO266 which showed an up to 18% decrease in BACE1 activity for 1.0 µM compounds. Based on these results, we conclude that compounds DO250 and DO251 could be promising leads for further evaluations and structural refinements in the search for potent MTDLs for treating Alzheimer’s disease.

4-aminoquinolines ; Alzheimer`s disease ; cholinesterases ; BACE1 ; MTDL

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