Aporphinoid alkaloids derivatives as selective cholinesterases inhibitors: biological evaluation and docking study

VALERIA CAVALLARO; ANA PAULA MURAY; CARLOS RODOLFO PUNGITORE; LUCAS GUTIERREZ

Molecular Informatics

Wiley-Verlag

Año: 2020 vol. 39 p. 1900125 - 1900134

Alzheimer ́s dementia is a neurodegenerativedisease that affects the elderly population and causesmemory impairment and cognitive deficit. Manifestation ofthis disease is associated to acetylcholine decrease; thus,Cholinesterase inhibition is the main therapeutic strategy forthe treatment of Alzheimer?s disease.In the present study, a series of aporphinoid alkaloids weretested as potential acetylcholinesterase (AChE) andbutyrylcholinesterase (BChE) inhibitors in vitro. Alkaloidsliriodenine (3) and cassythicine (10) were the best inhibitorsof both cholinesterases with IC50 values lower than 10 μM. Inaddition, these alkaloids demonstrated better inhibition ofBChE than reference drug galantamine.In addition, some alkaloids showed selective inhibition.Laurotetatine clorhydrate (13) selectively inhibit AChE overBChE. On the contrary, pachyconfine (7) interacted moreefficiently with BChE active site.Molecular modelling studies were performed in order toillustrate key interactions between most active compoundsand the enzymes and to explain their selectivity. Thesestudies reveal that the benzodioxole moiety exhibits stronginteractions due to hydrogen bonds that form with the Glu201(AChE) and Tyr440 (BChE) residues, which is reflected in theIC50 values.