Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Abstract

Objectives 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. Key findings 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. Summary The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.

Antioxidant and anticholinesterase activities of the essential oil of Eugenia dysenterica DC.

“…2011). 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 (Konrath et al, 2013).…”

Subthreshold Concentrations of Melatonin and Galantamine Improves Pathological AD-Hallmarks in Hippocampal Organotypic Cultures

“…It is a centrally acting, selective, reversible, and competitive AChEI, as well as from an allosteric modulator of the neuronal nicotinic receptor for acetylcholine, improving cholinergic transmission. Interestingly, it has shown to be protective in different models related to AD, ischemia, Huntington's disease, or amyotrophic lateral sclerosis (ALS) [12,[15][16][17].…”

Neurocognitive Improvement Through Plant Food Bioactives: A Particular Approach to Alzheimer’s Disease

“…Particularly to AD, a multitude of studies have shown that they act as prominent brain health improvers, being useful not only to prevent but also to block and even avert neurological dysfunctions (Marco and Carreiras 2006;Essa et al 2012;Smid et al 2012;Spencer et al 2012;Konrath et al 2013;Ahmed et al 2015). Furthermore, it is convenient to highlight that the majority of chemical drugs are plant-derived mimetic; notwithstanding, in the whole plant, different proportions of phytochemicals, their synergisms, antagonisms, and polyvalent reactions improve the bioactive potential and also block some harmful substances.…”