ARTICLE IN PRESS JID: JTICE [m5G;August 17, 2015;13:55] Journal of the Taiwan Institute of Chemical Engineers 000 (2015) 1–16 Contents lists available at ScienceDirect Journal of the Taiwan Institute of Chemical Engineers journal homepage: www.elsevier.com/locate/jtice Synthesis and in silico analysis of the quantitative structure–activity relationship of heteroaryl–acrylonitriles as AChE inhibitors ✩ Pedro De-la-Torre a,b,∗ , Adriana V. Treuer a , Margarita Gutierrez a , Horacio Poblete b,c , Jans H. Alzate-Morales b , Jorge Trilleras d , Luis Astudillo-Saavedra a , Julio Caballero b,∗∗ a Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), Institute of Chemistry of Natural Resources, Universidad de Talca, Casilla 747, Talca, Chile b Center for Bioinformatics and Molecular Simulation, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile c Institute of Computational Comparative Medicine, Nanotechnology Innovation Center of Kansas State, and Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506-5802, USA d Heterocyclic Compounds Research Group, Chemistry Program, Universidad del Atlántico, Km 7 vía Puerto Colombia, Barranquilla, Colombia article info Article history: Received 5 April 2015 Revised 16 July 2015 Accepted 20 July 2015 Available online xxx Keywords: Heteroaryl–acrylonitriles Quantitative structure–activity relationships CoMSIA Knoevenagel condensation Cholinesterases abstract Alzheimer disease (AD) is a neurodegenerative disorder that causes damages in brain due to factors such as oxidative stress, low-levels of the neurotransmitter acetylcholine, β -amyloid protein aggregation, etc. It is necessary the design of novel efficient drugs for AD treatment to counteract the increase of people suffering from AD. Recently, heteroaryl–acrylonitrile derivatives have emerged as a new family of acetylcholinesterase inhibitors (AChEIs). The analysis of the structure–activity relationship of these compounds could help to elu- cidate the main molecular features that contribute to the activity of these compounds. In this paper, we per- formed 3D-QSAR analyses through a Comparative Similarity Indices Analysis (CoMSIA) to determine the key- factors for the activity of E/Z-heteroaryl–acrylonitriles reported in literature and novel derivatives that are reported in this work for the first time. The novel derivatives were synthetized in order to enlarge the library of compounds available in literature. They were synthetized via microwave-assisted Knoevenagel reaction and their biological activities as AChE/BuChE inhibitors were explored by the Ellman’s spectrophotometric method. The best CoMSIA model included both electrostatic and hydrogen bond donor fields (CoMSIA-ED model) and provided the best statistical results with a highest Q 2 value of 0.901. The model also had satis- factory predictions of external compounds. Our in silico study provided a new tool for predicting the affinity of heteroaryl–acrylonitriles as AChEIs to the scientific community. It can be used for guiding the design and synthesis of novel, selective, and more potent AChEIs. © 2015 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved. 1. Introduction Alzheimer disease (AD) is one of the most common forms of de- mentia in elderly people. It is a neurodegenerative disease that causes progressive damage to the central nervous system, which is man- ifested by cognitive deterioration and behavioral disorders. These effects are related to the neuronal cell death, due to the oxidative stress caused by the extracellular formation of senile amyloid-β - peptide (Aβ ) plaques [1,2] and hyperphosphorylated-tau oligomers ✩ This article is dedicated to the memory of Professor Luis Astudillo Saavedra, for his great passion for friendship and fraternity. ∗ Correspondence author at: Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), Institute of Chemistry of Natural Resources, Universidad de Talca, Casilla 747, Talca, Chile. Tel.: +56 71 2200389; fax: +56 71 2200448. ∗∗ Corresponding author. Tel.: +56 71 2201662; fax: +56 71 2201561. E-mail addresses: pdelatorre@utalca.cl, pldelatorrem@gmail.com (P. De-la-Torre), jcaballero@utalca.cl, jmcr77@yahoo.com (J. Caballero). [3], which entail the decreased levels of acetylcholine (ACh) and proteins such as acetylcholinetransferase (ChAT: involved in the synthesis of ACh) and acetylcholinesterase (AChE: responsible for the hydrolysis of the same neurotransmitter at nerve–nerve synapses and neuromuscular junctions) [4]. The worldwide cost of dementia care is currently over US$600 billion, or around 1% of global GDP: with the increase of people suffering from AD; these statistics could increase twice in the next 20 years [5–7]. Currently, there are two drug classes approved by FDA [8]. The first one, cholinesterase inhibitors, restore the levels acetyl- choline, (for instance, Aricept:donepezil [9], Exelon:rivastigmine tar- trate [10], Razadyne:galantamine [11], Cognex:tacrine [12,13], which was removed from the market in 2012). The second class is com- posed by the agonists of the N-methyl-d-aspartate (NMDA) re- ceptors (for instance: Namenda:memantine) [14]. Both classes are used to treat cognitive symptoms such as memory loss, confusion, and problems with thinking and reasoning of early Alzheimer’s disease [8]. http://dx.doi.org/10.1016/j.jtice.2015.07.022 1876-1070/© 2015 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved. Please cite this article as: P. De-la-Torre et al., Synthesis and in silico analysis of the quantitative structure–activity relationship of heteroaryl– acrylonitriles as AChE inhibitors, Journal of the Taiwan Institute of Chemical Engineers (2015), http://dx.doi.org/10.1016/j.jtice.2015.07.022