Chemical and Molecular Aspects on Interactions of Galanthamine and Its Derivatives with Cholinesterases

Abstract

Dual action of galanthamine as potent cholinesterase inhibitor and nicotinic modulator has attracted a great attention to be used in the treatment of AD. Consequently, galanthamine, a natural alkaloid isolated from a Galanthus species (snowdrop, Amaryllidaceae), has become an attractive model compound for synthesis of its novel derivatives to discover new drug candidates. Numerous studies have been done to elucidate interactions between galanthamine and its different derivatives and the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico experimental models. The in vitro studies revealed that galanthamine inhibits AChE in strong, competitive, long-acting, and reversible manner as well as BChE, although its selectivity towards AChE is much higher than BChE. The in silico studies carried out by employing molecular docking experiments as well as molecular dynamics simulations pointed out to existence of strong interactions of galanthamine with the active gorge of AChE, mostly of Torpedo californica (the Pasific electric ray) origin. In this review, we evaluate the mainstays of cholinesterase inhibitory action of galanthamine and its various derivatives from the point of view of chemical and molecular aspects.

Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer's Disease Therapy

“…The major alkaloids with recognized anti-AChE activity are the classical galantamine and huperzine A, which have been elegantly reviewed by Gulcan et al ( 2015 ) and Qian and Ke ( 2014 ), respectively. However, other recently described alkaloids of various subclasses deserve special emphasis because of their important inhibitory action on AChE.…”

Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone: A water-soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity

“…Inhibition assays of cholinesterases showed a weaker potency for AChE compared to galantamine, a reference drug used in the treatment of mild cognitive impairment associated to the early stage of AD (Gulcan et al, 2015). The short incubation times required for cholinesterase inhibition assay allowed a limited hydrolysis of 2, thus leading to activity profiles well distinguishable from parent hydrazone 1.…”

Cognitive Enhancing and Antioxidative Potentials of Velvet Beans (Mucuna pruriens) and Horseradish (Moringa oleifera) Seeds Extracts: A Comparative Study

“…Furthermore, side effects such as nausea or vomiting, hepatotoxicity, dyspepsia, myalgia and anorexia dizziness exhibited by these drugs have been reported (Chaiyana and Okonogi ; Gulcan et al . ). This information has led to the continuous search of co‐inhibitor of ChEs and MAO activities, and natural products rich in polyphenolic compound have been reported to show promising effects in preserving brain functions and forestalling the age‐related memory loss with zero or reduced side effects (Conforti et al .…”

“…Recently, there is an increase in interest, most especially in developing countries, on the use of medicinal plant and/or its extract as source of ChEs and MAO inhibitors in the management of cognitive dysfunction/neurodegenerative diseases, as against the use of conventional synthetic inhibitor/drug-based therapy that has selective AChE and poor BChE inhibition, while reports showed simultaneously hydrolysis of ACh by both AChE and BChE (Chaiyana and Okonogi 2012;Ademosun et al 2016). Furthermore, side effects such as nausea or vomiting, hepatotoxicity, dyspepsia, myalgia and anorexia dizziness exhibited by these drugs have been reported (Chaiyana and Okonogi 2012;Gulcan et al 2015). This information has led to the continuous search of co-inhibitor of ChEs and MAO activities, and natural products rich in polyphenolic compound have been reported to show promising effects in preserving brain functions and forestalling the age-related memory loss with zero or reduced side effects (Conforti et al 2007;Orhan et al 2004).…”