Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease.
OBJECTIVE
The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl- and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies.


RESULTS
Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors.


CONCLUSIONS
The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Eduardo Luis
EL
Konrath
Carolina dos Santos
Cdos S
Passos
Luiz Carlos
LC
Klein
Amélia T
AT
Henriques
D000470:Alkaloids / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D002802:Cholinesterases / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D039821:Monoterpenes / Q000627:therapeutic use; D054837:Quinolizidines / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000627:therapeutic use; D016875:tau Proteins / Q000502:physiology
D000470:Alkaloids; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007546:Isoquinolines; D039821:Monoterpenes; D054837:Quinolizidines; D014315:Triterpenes; D016875:tau Proteins; D002802:Cholinesterases
Alzheimer's disease; acetylcholinesterase inhibition; alkaloids; butyrylcholinesterase inhibition; plants