Novel coumarin derivatives bearing N-benzyl pyridinium moiety: Potent and dual binding site acetylcholinesterase inhibitors Masoumeh Alipour a , Mehdi Khoobi b , Alireza Foroumadi b , Hamid Nadri c , Alireza Moradi c , Amirhossein Sakhteman c , Mehdi Ghandi a , Abbas Shafiee b,⇑ a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran b Department of Medicinal Chemistry, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran c Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd 8915173143, Iran article info Article history: Received 9 June 2012 Revised 26 August 2012 Accepted 27 August 2012 Available online 7 September 2012 Keywords: Coumarin Benzylpyridinium Actylcholinesterase inhibitor Ellman’s method abstract A novel series of coumarin derivatives linked to benzyl pyridinium group were synthesized and biolog- ically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The enzyme inhibitory activity of synthesized compounds was measured using colorimetric Ellman’s method. It was revealed that compounds 3e, 3h, 3l, 3r and 3s have shown higher activity compared with donepezil hydrochloride as standard drug. Most of the compounds in these series had nanomolar range IC 50 in which compound 3r (IC 50 = 0.11 nM) was the most active compound against acetylcholinesterase enzyme. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Alzheimer’s disease (AD), a progressive and degenerative disor- der of the brain, is supposed to be the most common cause of dementia among the aged people. Approximately, 24 million peo- ple worldwide suffer from this disease. It was demonstrated that AD is mainly caused by the loss of cholinergic activity in some parts of the brain such as hippocampus which are related to learn- ing and cognition. 1,2 Thus, increasing the synaptic level of acetyl- choline (ACh) by means of acetylcholinesterase (AChE) inhibition could be helpful to alleviate AD’s symptoms. 3–7 In addition, some evidence suggests that butyrylcholinesterase (BuChE) levels are unchanged or even rise in advanced AD, while the activity of the acetylcholinesterase is decreased in certain area of the brain. 8–10 As a matter of fact, the inhibition of BuChE can raise ACh levels. 11,12 Consequently, dual inhibition of AChE/BuChE may be beneficial to improve AD symptoms without remarkable side effects. 13 Besides, it was revealed that AChE augments the neurotoxic ef- fect of amyloid beta through accelerating the formation of beta amyloid deposits in the brain. Therefore, the role of amyloid beta in beginning and progression of AD is a matter of debate. 14,15 It is well known that the enzyme interacts with beta amyloid through peripheral anionic site (PAS) and promotes the formation of fibrils. 16 According to these findings, designing the compounds able to interact with both active site and PAS of AChE would be a new therapeutic approach for effective management of AD’s symp- toms. 17,18 Coumarins, a groups of naturally occurring substances in many plants exhibit a wide range of biological activities such as anti-inflammatory, 19 anti-tumor, 20 hepatoprotective, 21 anti-HIV- 1, 22 antiviral, 23 antifungal, 24 antimicrobial, 25 anti-oxidant, 26 and antidepressant effects. 27 Moreover, the potent anticholinesterase activity of many synthetic coumarins was revealed similar to that observed in the natural compounds. 28–31 Many of these efforts were conducted by connecting the cou- marin scaffold, via different spacers, to the structures with high affinity towards the catalytic site of the enzyme. 32 Moreover, benzylpyridinium salts (Fig. 1) have been repre- sented an excellent acetylcholinesterase inhibitory in several re- ports. 33 In our previous work we have reported synthesis and anticholinesterase activity of new benzofuranone derivatives bear- ing benzyl pyridinium moiety (Fig. 1, X@O). 33a Observing a dra- matic decrease in anticholinesterase activity of the compounds lacking the benzyl pyridinium moiety, proved that this part is nec- essarily required for superior activity which was in accord with the previously reported data by Iimura. 33b Based on these findings and in pursuit of our previous study on coumarin scaffold, 34 we have presented a novel series of coumarin derivatives that were attached to benzyl pyridinium group through alpha beta unsaturated carbonyl linker (Fig. 2). An outstanding fea- ture of this linker is the conformational restriction caused by the 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.08.052 ⇑ Corresponding author. Tel.: +98 21 66406757; fax: +98 21 66461178. E-mail address: ashafiee@ams.ac.ir (A. Shafiee). Bioorganic & Medicinal Chemistry 20 (2012) 7214–7222 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc