Available online www.jocpr.com Journal of Chemical and Pharmaceutical Research, 2015, 7(3):351-358 Research Article ISSN : 0975-7384 CODEN(USA) : JCPRC5 351 Synthesis, molecular docking and design of Tetrahydroquinolines as acetylcholinesterase inhibitors Margarita Gutiérrez *a , Bárbara Arévalo a , Gonzalo Martínez b , Francisco Valdés a , Gabriel Vallejos c , Unai Carmona d and Aurelio San Martin e a Laboratorio Síntesis Orgánica, Instituto de Química de Recursos Naturales, Programa de Investigación en Quimica y Bio-Organica de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, 3460000, Chile b Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile c Laboratorio de Bio-Organica, Instituto de Ciencias Quimicas, Facultad de Ciencias, Universidad Austral de Chile, Casilla 567, Valdivia, Chile d CIC nanoGUNE, Tolosa Hiribidea 76, 20018 Donostia-San Sebastian, Spain e5 Departamento de Química, Facultad de Ciencias, Universidad de Chile, casilla 653, Santiago, Chile. Facultad de Ciencias. Universidad de Magallanes ____________________________________________________________________________________________ ABSTRACT A series of tetrahydroquinolines (Compounds 1-8) were synthesized using Povarov reactions, subsequently characterized using spectroscopic methods and evaluated as Acetylcholinesterase/Butirylcholinesterase inhibitors. Bioinformatics tools analyzed active site interactions, leading to the design of a more active new compound. The most potent compound showed moderate in vitro activity (IC 50 of 215μM) against AChE, while bioinformatics tools such as molecular docking and de novo design allowed establishment of binding sites and design of a new molecule with better activity, decreasing IC 50 from 618 μM to 215μM. This study describes the application of bioinformatics tools in drug design. Keywords: Quinolines, Alzheimer’s disease, cholinesterase inhibitors, tetrahydroquinolines, ligand-protein interactions. ____________________________________________________________________________________________ INTRODUCTION Quinolines are a heterocycle with marked biological activity in different therapeutic targets, and are present in different natural sources. Compounds containing quinoline structures are widely used as antiasthmatics, antimalarials, anti-virals, anti-inflammatories, antibacterials, antifungals, and anticarcinogens [1]. Synthetic quinoline derivatives have been reported as base structures in the synthesis new compounds with diverse biological activity including fungicides, virucides, biocides, alkaloids, rubber chemicals and flavoring agents [2]. These and other structural and functional features mean that research efforts have focused on obtaining new, structurally diverse structures to enhance the above activities or act on new therapeutic targets. Tetrahydroquinolines (THQs) are a group of quinoline derivatives of interest in the area of organic synthesis because of their proven pharmacological properties [3], including anti-HIV[4], anti-cancer[5] and anti- malarial[6]activity, inhibition of the cholesteryl ester transfer protein [7] and anti-diabetic [8] properties, among others. Alzheimer's disease (AD) is a neurodegenerative disorder affecting a large part of the world's adult population, associated with different causes such as tau protein hyperphosphorylation [9], amyloid-β peptide accumulation[10], mutations in 17q21 chromosome genes [11] and acetylcholine neurotransmitter decreases [12] among others.