Rational design, synthesis and biological evaluation of 1,3-dihydroxyxanthones derivatives: New agents against acetylcholinesterase

MENÉNDEZ, CINTIA A.; BISCUSSI, BRUNELLA; MURRAY, ANA PAULA; APPIGNANESI, GUSTAVO A.; GERBINO, DARÍO C.

Colonia

Simposio; 20th European Symposium on Organic Chemistry (ESOC 2017); 2017

Alzheimer´s disease (AD), a progressive and degenerative disorder, has become oneof the severe problems among the aged population all over the world. The use ofcholinesterase inhibitor drugs has become the most predominant treatment strategy forAD.In a recent study a series of novel 1,3-dihydroxyxanthone Mannich bases derivativeswas identified as antiacetylcholinesterase agents. [1] Inspired by this work, we carriedout theoretical studies with the aim of establishing which the main interactions betweenthese compounds and acetylcholinesterase (AChE) presumably are, in order tounderstand and rationalize the previous experimental results. Subsequently, we havemade rational modifications with the objective of achieving a potentiation of theirinhibitory effect. On the basis of the virtual screening, we synthesized a small library ofnew functionalized xanthones, which exhibited good inhibitory activities with IC50 valuesunder micromole level concentration against AChE.Molecular Docking and Molecular Dynamics studies were carried out, which enabled toidentify two main regions of interaction. On the one hand, the fused tricyclic systemmainly interacts, through -stacking, with Trp 84 of AChE, and to a lesser extent withPhe 330 and Tyr 334. On the other hand, the positively charged amino group coulddevelop a saline bridge with Glu 199 of AChE. With this in mind, the next structuralmotif was proposed:1,3-dihydroxyxanthone derivatives 1 with linkersof 3 to 6 methylenes as well as different aminogroups were synthesized from salicylic acid andphloroglucinol as starting material andsubsequent selective O-alkylation.AChE activity was measured through Ellman´scolorimetric method, with tacrine as referenceinhibitor.In conclusion, a new series of 1,3-dihydroxyxanthone derivatives 1 was designed and their inhibitory actitivity againstAchE was evaluated. These synthetic compounds exhibited potent AChE inhibitioncompared to the results reported by Wang et al. Particularly, xanthone 1c with a 5carbon linker and a piperidine group showed the best inhibitory effect on AChE (IC50:0.46 µM). In this context, 1c could be considered as a potential drug candidate for ADtreatment.