Natural products as a source of cholinesterase inhibitors

Abstract

As the global population ages, the incidence of neurodegenerative diseases such as Parkinson’s disease and dementia including Alzheimer's disease (AD) rises. The characteristic cognitive, behavioral, and motor impairments of these conditions are often linked to dysregulated cholinergic system. Various neurodegenerative diseases have been associated with altered levels of the neurotransmitter acetylcholine (ACh) and changes in the expression and function of receptors in specific areas of the nervous system. For instance, while AD development is not fully understood, the AD cholinergic hypothesis considers that AD patients exhibit low ACh concentrations, and that many dementia symptoms could potentially stem from this deficiency. Moreover, it has been speculated that acetylcholine dysfunction might not be the primary pathological cause but rather a consequence of AD. Hence, one approach to developing new drugs to treat AD involves identifying compounds that can inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the two enzymes underlying ACh hydrolysis. Natural products offer wide structural diversity, which makes them an important source of bioactive compounds. This article reviews the literature on how natural compounds have contributed to the discovery and design of new cholinesterase inhibitors over the past two decades. The review encompasses a brief historical overview of inhibitors that are used to treat AD in clinical settings, a discussion of the different classes of natural products that act to inhibit AChE and BChE, and a concise presentation of the screening assays that are employed to identify AChE and BChE ligands.