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

CIANTIA A. MENÉNDEZ; BISCUSSI, BRUNELLA; ANA PAULA MURRAY; GUSTAVO A. APPIGNANESI; DARIO C. GERBINO

Colonia

Simposio; 20th European Symposium on Organic Chemistry (ESOC2017); 2017

Universität zu Köln

Alzheimer´s disease (AD), a progressive and degenerative disorder, has become one of the severe problems among the aged population all over the world. The use of cholinesterase inhibitor drugs has become the most predominant treatment strategy for AD. In a recent study a series of novel 1,3-dihydroxyxanthone Mannich bases derivatives was identified as antiacetylcholinesterase agents.[1] Inspired by this work, we carried out theoretical studies with the aim of establishing which the main interactions between these compounds and acetylcholinesterase (AChE) presumably are, in order to understand and rationalize the previous experimental results. Subsequently, we have made rational modifications with the objective of achieving a potentiation of their inhibitory effect. On the basis of the virtual screening, we synthesized a small library of new functionalized xanthones, which exhibited good inhibitory activities with IC50 values under micromole level concentration against AChE. Molecular Docking and Molecular Dynamics studies were carried out, which enabled to identify two main regions of interaction. On the one hand, the fused tricyclic system mainly interacts, through -stacking, with Trp84 of AChE, and to a lesser extent with Phe330 and Tyr334. On the other hand, the positively charged amino group could develop a saline bridge with Glu199 of AChE. With this in mind, the next structural motif was proposed: 1,3-dihydroxyxanthone derivatives 1 with linkers of 3 to 6 methylenes as well as different amino groups were synthesized from salicylic acid and phloroglucinol as starting material and subsequent selective O-alkylation. AChE activity was measured through Ellman´s colorimetric method, with tacrine as reference inhibitor. In conclusion, a new series of 1,3-dihydroxyxanthone derivatives 1 was designed and their inhibitory actitivity against AchE was evaluated. These synthetic compounds exhibited potent AChE inhibition compared to the results reported by Wang et al. Particularly, xanthone 1c with a 5 carbon 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 AD treatment.Literature:[1] Qin, J., Lan, W., Liu, Z., Huang, J., Tang, H. Wang, H. Chemistry Central Journal, 2013, 7 (1), 78.