Derivatives of Solanocapsine as Inhibitors of Acetylcholinesterase

JOSÉ L. BORIONI; MANUELA E. GARCÍA; VALERIA CAVALLARO; ANA PAULA MURRAY; ALICIA PEÑÉÑORY; MARCELO PUIATTI; ADRIANA PIERINI

Santiago

Congreso; 10th Congress of the World Association of Theoretical and Computational Chemists; 2014

WATOC

The investigation of natural products in medicinal chemistry is really essential today. In this context, inhibitors of acetylcholinesterase (AChE) are actively search for a treatment of Alzheimer?s disease (AD)[1]. The AChE enzyme has a catalytic site at the bottom of deep narrow catalytic gorge and a peripheral anionic site (PAS) at the entrance.Achieving strong AChEinhibitors (AChEI) that interact with the catalytic site does not represent a significant improvement unless concomitant inhibition of the PAS, which is associated with a neurotoxic cascade characteristic of AD [2]. Simultaneous interaction with both sites of AChE has been suggested to be important in designing powerful and selective AChEI [3]. In order to achieve interaction throughout all the active site, newAChEIs include two components separated by a spacer group with a suitable length.Because of this, we employed as a template a steroidal alkaloid, isolated from SolanumpseudocapsicumL. withan IC50 of 3.22 µM, Solanocapsine (1). Based on the above strategy, a series of new derivatives of 1were synthesized and their inhibitory activities on AChE tested. Structure?activity relationships through molecular docking studies and molecular dynamicswere then discussed. Based on these results new derivatives are proposed.