Xanthenedione derivatives, new promising acetylcholinesterase inhibitor agents

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.

Tab. 1: Acetylcholinesterase inhibitory effect of xanthenediones (2) and some intermediates (1).

Compounds	Anti-AChE IC50 (µM ± SD, n = 4)
1a	> 381
1c	122 ± 2.1
2a	> 381
2b	> 355
2c	41.1 ± 6.1
2 d	> 325
2c	31.0 ± 0.09
2f	> 325
Galanthamine	211.8 ± 9.5

Acknowledgements: Thanks are due to FCT, EU, QREN, FEDER and COMPETE, for funding the QOPNA research unit (project PEst-C/QUI/UI0062/2013; FCOMP-01 – 0124-FEDER-037296) and the Portuguese National NMR Network and also Azores University and FRC/Azores for funding CIRN.

Keywords: Xanthones, xanthene-1,9(2 H)-diones, acetylcholinesterase inhibitors, synthesis

References:

[1] Houghton, PJ, Ren, Y, Howes, MJ. Acetylcholinesterase inhibitors from plants and fungi. Nat. Prod. Rep. 2006; 23: 181 – 199.

[2] Brígida R. Pinho, BR, Ferreres, F, Valentão, P, Andrade, PB. Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment. J. Pharm. Pharmacol. 2013; 65: 1681 – 1700.

[3] Pinto, DCGA, Seca, AML, Leal, SB, Silva, AMS, Cavaleiro, JAS. A novel short-step synthesis of new xanthenedione derivatives from the cyclization of 3-cinnamoyl-2-styrylchromones. Synlett 2011; 2005 – 2008.

[4] Barreto MC, Arruda M, Rego E, Medeiros JS, Rainha N. Cell-free assays. In: Barreto MC, Simões N. Determination of Biological Activities. A Laboratory Manual, N. Universidade dos Açores, Ponta Delgada; 2012: 65 – 81.