Xanthenedione derivatives, new promising acetylcholinesterase inhibitor agents (Englisch)

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62nd International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA), August 31-September 4, Guimarães, Portugal. ; Acetylcholinesterase inhibitors (AChEIs) are employed in medicine mostly for correcting the effects of insufficient levels of acetylcholine [1]. Xanthones are a class of secondary metabolites associated with important pharmacological properties, being some of its derivatives AChEIs [2]. Xanthenedione derivatives are not widely spread in nature but their synthesis and bioactivities evaluation is still a hot topic. Following our interest in the synthesis of biologically active compounds, several xanthene-1,9(2H)-diones (2a-2f) were synthesized by simple and efficient methodologies from (E,E)-3-cinnamoyl-5-hydroxy-2-styrylchromones (Scheme 1) [3] and their acetylcholinesterase activity evaluated by a modification of the Ellman's method [4]. The results (Table 1) showed that variations in the substitution and hydroxylation pattern seem to be important for their activity, being the xanthenedione bearing a catechol unit the most potent AChEI, even more active than galantamine, an AChEI alkaloid used clinically in early stages of Alzheimer's disease. SAR studies showed that the presence of hydroxyl 3-aryl and 4-benzylidene moieties is essential for the activity. Furthermore xanthenedione 2c showed a combination of partially competitive and non-competitive inhibition, while xanthenedione 2e shows an almost pure competitive type inhibition. The most active xanthenediones 2e and 2c present zero violations of Lipinski's 'rule of five' and xanthenedione 2c combine higher AChE activity with good oral bioavailability properties (TPSA < 140 Å2). The results suggest that they may be excellent templates for drugs to be used in the prevention and treatment of neurodegenerative diseases. ; Azores University, FRC/Azores for funding CIRN, FCT for funding QOPNA (project PEst-C/QUI/UI0062/2013; FCOMP-01 – 0124-FEDER-037296 ; info:eu-repo/semantics/publishedVersion