Research paper Synthesis and structure-activity relationship study of benzofuran- based chalconoids bearing benzylpyridinium moiety as potent acetylcholinesterase inhibitors Manizheh Mostofi a , Ghodsi Mohammadi Ziarani a , Mohammad Mahdavi b , Alireza Moradi c , Hamid Nadri c , Saeed Emami d , Heshmatollah Alinezhad e , Alireza Foroumadi b , Abbas Shafiee b, * a Department of Chemistry, Alzahra University, Vanak Square, P.O. Box 1993891176, Tehran, Iran b Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences, Tehran, Iran c Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran d Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran e Faculty of Chemistry, University of Mazandaran, Babolsar, Iran article info Article history: Received 17 June 2015 Received in revised form 30 August 2015 Accepted 31 August 2015 Available online 3 September 2015 Keywords: Acetylcholinesterase Alzheimer's disease Benzofuran Docking study Pyridinium abstract A series of benzofuran-based chalconoids 6aev were designed and synthesized as new potential AChE inhibitors. The in vitro assay of synthesized compounds 6aev showed that most compounds had sig- nificant anti-AChE activity at micromolar or sub-micromolar levels. Among the tested compounds, 3- pyridinium derivative 6m bearing N-(2-bromobenzyl) moiety and 7-methoxy substituent on the benzofuran ring exhibited superior activity. This compound with IC 50 value of 0.027 mM was as potent as standard drug donepezil. © 2015 Elsevier Masson SAS. All rights reserved. 1. Introduction Alzheimer's disease (AD) is a fatal and age-related neurode- generative disease causes a progressive dementia in the elderly population and is characterized by progressive cognitive impair- ments including memory loss, decline in motor and language skills and learning problems [1,2]. The reported data by WHO demon- strated that more than 30 million people are afflicted with AD worldwide, and the number of patients is expected to increase up to 100 million by 2050 [3]. Although extensive efforts have been made to understand the complex pathophysiology of AD but its etiology is not completely known. However, several factors have been identified which involved in the onset and progression of AD. The main factors are oxidative stress, biometals dysfunctions, deposit of abnormal pro- teins such as amyloid beta-peptide (Ab) and t-protein, and degeneration of cholinergic neurons in the central nervous system [4,5]. Particularly, the impairment of the cholinergic neurotrans- mission in the brain, results in a substantial acetylcholine (ACh) deficiency which leads to cognitive and memory deficits associated in AD patients [6e8]. Accordingly, one approach to improve cholinergic neurotransmission in the AD patients is to break down the ACh metabolism. ACh can be mainly hydrolyzed by acetylcho- linesterase (AChE) at the cholinergic synapses. Consequently, several AChE inhibitors such as donepezil, tacrine, rivastigmine, and galantamine have been developed and approved by FDA for AD treatment. These agents have some beneficial effects on cognitive and neuropsychiatric symptoms of AD [9,10]. The X-ray crystallographic study of AChE structure indicates that it consists of two distinct ligand binding sites, a catalytic anionic * Corresponding author. E-mail address: ashafiee@ams.ac.ir (A. Shafiee). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2015.08.061 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 103 (2015) 361e369