Research paper Novel multitarget-directed ligands targeting acetylcholinesterase and s 1 receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase Julien Lalut a, 1 , Gianluca Santoni b, c, d, 1 , Delphine Karila a ,C  edric Lecoutey a , Audrey Davis a , Florian Nachon e , Israel Silman f , Joel Sussman g , Martin Weik b, c, d , Tangui Maurice h , Patrick Dallemagne a, ** , Christophe Rochais a, * a Centre d’Etudes et de Recherche sur le Medicament de Normandie, Normandie Univ, UNICAEN, CERMN, 14000, Caen, France b Univ Grenoble Alpes, IBS, F-38027, Grenoble, France c CNRS, IBS, F-38027, Grenoble, France d CEA, IBS, F-38027, Grenoble, France e Departement de Toxicologie et Risques Chimiques, Institut de Recherche Biomedicale des Armees, 91220, Bretigny-sur-Orge, France f Department of Neurobiology, Weizmann Institute of Science, 76100, Rehovot, Israel g Department of Structural Biology, Weizmann Institute of Science, 76100, Rehovot, Israel h Molecular Mechanisms in Neurodegenerative Diseases, MMDN Laboratory, University of Montpellier, Ecole Pratique des Hautes Etudes, Institut National de la Recherche et de la SanteMedicale, UMR-S1198, 34095, Montpellier, France article info Article history: Received 2 October 2018 Received in revised form 24 October 2018 Accepted 29 October 2018 Available online 8 November 2018 Keywords: Alzheimer's disease Acetylcholinesterase Sigma 1 receptors MTDL abstract Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT 4 receptor, which displays promising ac- tivities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole de- rivatives possessing interesting in vitro activities toward AChE and the s 1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition. © 2018 Elsevier Masson SAS. All rights reserved. 1. Introduction Along with the observed increase of life expectancy, senile de- mentia is becoming increasingly prevalent. As many of 46 million cases of dementia were reported worldwide in 2015 [1]. The most common dementia, Alzheimer's disease (AD), is characterized by a progressive and irreversible decline in memory and cognitive function as a consequence of neuronal dysfunction. According to the cholinergic hypothesis this decline is linked to a decrease in the levels of acetylcholine released at cholinergic synapses in certain areas of the brain. Indeed, until now, with one exception, the drugs authorized by the FDA for treatment of AD are acetylcholinesterase (AChE) inhibitors that provide symptomatic relief in the early stages of the disease [2]. However, with progression of AD, these drugs, including 1 [donepezil (DPZ)], rivastigmine and galanth- amine, lose their efficacy. One of the greatest challenges facing pharmacologists and medicinal chemists is the discovery and development of treatments that could exert a disease-modifying effect on AD [3]. To this end many studies have been directed to- wards clarifying the molecular origins of the disease. AD is princi- pally characterized by the formation in the brain of amyloid plaques whose main component is the Ab peptide, and of neurofibrillary * Corresponding author. ** Corresponding author. E-mail addresses: patrick.dallemagne@unicaen.fr (P. Dallemagne), christophe. rochais@unicaen.fr (C. Rochais). 1 These authors contributed equally to this work. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech https://doi.org/10.1016/j.ejmech.2018.10.064 0223-5234/© 2018 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 162 (2019) 234e248