Screening of Non‐Alkaloidal Natural Compounds as Acetylcholinesterase Inhibitors

Abstract

Acetylcholinesterase (AChE) inhibitors are currently the only approved therapy for the treatment of Alzheimer's disease, only a limited number of drugs are commercially available. A library of non-alkaloidal natural compounds was investigated. To this end, a convenient microtitre plate method for assaying AChE inhibition, which allows a complete kinetic analysis of AChE inhibitors, was developed. Seven active compounds with Ki values in the micromolar range were identified, six of which were xanthones. This is the first report that a promising potential for AChE inhibition exists in such non-nitrogenous natural compounds. Furthermore, four xanthones among these xanthones had already been described as monoamine oxidase (MAO) inhibitors, making then dual AChE/MAO inhibitors of great interest.

Xanthenedione Derivatives, New Promising Antioxidant and Acetylcholinesterase Inhibitor Agents

“…The two active compounds in the present work are much stronger inhibitors than those isolated from the fungus Amauroderma amoiensis, where the highest inhibition of the enzyme at 50 µM was only 46.3% [18]. The inhibition potencies of xanthenediones 5c and 5e is higher or of the same order of magnitude to those reported by a study comparing inhibition potency and inhibition types of six different xanthones [7]. Furthermore xanthenedione 5c has a mixed type inhibition of AChE, producing a combination of partially competitive and non-competitive inhibition while xanthenedione 5e shows an almost pure competitive type inhibition.…”

“…The yields in the formation of compounds 5d and 5f were lower and more degradation products were observed. Another interesting result was the fact that when (E,E)-3-cinnamoyl-5-hydroxy-2-styrylchromone (4g) was used as starting material, (E)-1,13-dihydroxy-6-(2-hydroxybenzylidene)-6,7-dihydro-7,13-methanobenzo [7,8]oxocino [4,3-b]chromen-14(13H)-one (6) was obtained as main product and 6,8-dihydroxy-13-(2-hydroxyphenyl) chromeno [4,3-c]xanthen-7(13H)-one (7) as a by-product (Scheme 1). These results can be explained by an intramolecular cyclization to a hemiketal compound [Scheme 2, path (a) to compound 6], and other intramolecular cyclization followed by aromatization to the xanthone 7 [Scheme 2, path (b)].…”

“…Inhibition of AChE will, therefore, allow the stimulatory activity of acetylcholine (ACh), which appears to be associated with cognitive processes, memory, myasthenia gravis, and glaucoma and as an antidote to various toxins [6]. From the literature [7], it is known that the xanthone ring itself did not appear to automatically confer activity; in fact the substitution pattern has a marked influence on the activity level. Since the prepared xanthenediones 5 are structurally related to xanthones they were evaluated for their anti-AChE activity ( Table 2).…”

“…The alkaloid galantamine (1, Figure 1) is used clinically in early stages of AD, nevertheless non-alkaloidal AChE inhibitors are being discovered, including xanthone derivatives [6,7]. Variations in the hydroxylation and methoxylation pattern seem to be important for their activity, as well as extra rings and a hydrophobic side chain as in 2 ( Figure 1) [7].…”

“…Variations in the hydroxylation and methoxylation pattern seem to be important for their activity, as well as extra rings and a hydrophobic side chain as in 2 ( Figure 1) [7]. As far as we are aware there are no reports on AChE inhibitors bearing a xanthenedione type structure, but we can find in the literature examples of derivatives that showed DPPH radical scavenging activity [8].…”