Full Paper Synthesis and Evaluation of Chroman-4-One Linked to N-Benzyl Pyridinium Derivatives as New Acetylcholinesterase Inhibitors Saman Arab 1 , Seyed-Esmail Sadat-Ebrahimi 1 , Maryam Mohammadi-Khanaposhtani 1 , Alireza Moradi 2 , Hamid Nadri 2 , Mohammad Mahdavi 1 , Setareh Moghimi 1 , Mehdi Asadi 1 , Loghman Firoozpour 3 , Morteza Pirali-Hamedani 1 , Abbas Shafiee 1 , and Alireza Foroumadi 1,3 1 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran 3 Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran A novel series of chroman-4-one derivatives containing the N-benzyl pyridinium moiety were designed, synthesized, and evaluated for their acetylcholinesterase (AChE) inhibitory activities. Among the various synthesized compounds, (E)-1-(2,3-dibromobenzyl)-4-((7-ethoxy-4-oxochroman-3- ylidene)methyl)pyridinium bromide (8l) depicted the most potent anti-AChE activity (IC 50 ¼ 0.048 mM). In addition, the molecular modeling study allowed us to detect possible binding modes that are in full compliance with the observed results through in vitro experiments. Keywords: Acetylcholinesterase / Alzheimer’s disease / Chroman-4-one / Docking study / N-Benzyl pyridinium Received: April 24, 2015; Revised: June 17, 2015; Accepted: June 23, 2015 DOI 10.1002/ardp.201500149 : Additional supporting information may be found in the online version of this article at the publisher’s web-site. Introduction Alzheimer’s disease (AD) is an age-related disease leading to progressive decline in cognition and memory [1]. There are two main hypotheses in the pathogenesis of AD: reduced levels of acetylcholine and the polymerization of the amyloid b-peptide (Ab) in the brain [2]. Therefore, increasing the synaptic level of acetylcholine by means of acetylcholinester- ase inhibitors such as donepezil, rivastigmine, and galant- amine could be beneficial to ameliorate the symptoms of AD without any effect in the course of the disease [3]. The suitable route to prevent the disease progression has been reported by the assistance of various compounds with anti- amyloid potency such as melatonin, rifampicin, benzofuran, and acridinone derivatives which are in clinical trial [4]. It is well known that AChE, in addition to the hydrolysis of acetylcholine, interacts with Ab through peripheral anionic site (PAS) and accelerates the polymerization of Ab pep- tides [5–7]. Thus, applying dual binding site AChE inhibitors which interact with both active site and PAS, would be a new therapeutic approach for seeking new drug candidates against AD [8, 9]. According to molecular and biological studies on donepezil (Fig. 1A), the most popular approved therapies for AD, this drug could be regarded as a dual binding site AChE inhibitor [10, 11]. Docking study evidences have also shown that donepezil interacts with the catalytic site and PAS through benzyl piperidine moiety and indanone ring, respectively [12]. In recent years, our research group has reported the synthesis of various new AChE inhibitors [13–16]. In this study, we decided to design efficient dual AChE inhibitors based on our previous reports on the potent donepezil analogs (Fig. 1B and C) [17–19]. Accordingly, a novel series of N-benzyl- Correspondence: Dr. Alireza Foroumadi, Department of Medici- nal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. E-mail: aforoumadi@yahoo.com Fax: þ98-21-66461178 Arch. Pharm. Chem. Life Sci. 2015, 348, 643–649 Archiv der Pharmazie ARCH RCH P HARM HARM ß 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com 643