Full Paper 9H-Carbazole Derivatives Containing the N-Benzyl-1,2,3-triazole Moiety as New Acetylcholinesterase Inhibitors Hamidreza Akrami 1,2 , Bibi F. Mirjalili 2 , Mehdi Khoobi 1 , Alireza Moradi 3 , Hamid Nadri 3 , Saeed Emami 4 , Alireza Foroumadi 1 , Mohsen Vosooghi 1 , and Abbas Shafiee 1 1 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran 2 Department of Chemistry, College of Science, Yazd University, Yazd, Iran 3 Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran 4 Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran A series of triazole-containing carbazole derivatives were designed as new anti-acetylcholinesterase (AChE) agents. The target compounds 6a–q were simply prepared via a one-pot three-component click reaction of N-propargyl-9H-carbazole, sodium azide, and an appropriate benzyl halide. The in vitro anti-cholinesterase assay showed that the unsubstituted benzyl derivative 6p along with the 2-F, 2-Me, 3-Me, 3-MeO, and 3-F analogs (6a, 6c, and 6g–i) had significant anti-AChE activity (IC 50 s  3.8 mM). Among them, the 2-methylbenzyl derivative 6c with an IC 50 value of 1.9 mM was the most active compound. The SAR studies revealed that small halogen atoms such as the fluorine atom or electron- donating groups such as methyl or methoxy at the ortho or meta positions of the benzyl pendent group could be tolerated or improved the anti-AChE activity. Keywords: Acetylcholinesterase / Alzheimer's disease / Click chemistry / Docking study / 9H-Carbazole / Triazole Received: September 27, 2014; Revised: February 2, 2015; Accepted: February 6, 2015 DOI 10.1002/ardp.201400365 : 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 a chronic, irreversible, and progressive neurodegenerative disorder that produces severe cognitive impairment in elderly individuals. Although, the early stages of AD associate with mild cognitive decline and progressive memory loss, at the late stages patients exhibit personality alteration and consumption of bodily func- tions [1]. AD is the main neurological cause of dementia and is a growing health crisis around the world. Currently, 38 million people suffer from AD worldwide, elderly adults in most cases [2]. It is estimated that those numbers will approximately double every 20 years and reach 115 million in 2050 [3]. At the molecular level, AD is characterized by the pre- synaptic decrease of acetylcholine (ACh), extracellular deposition of amyloid-b (Ab) plaques, and intracellular accumulation of hyper-phosphorylated tau protein and neurofibrillary tangles (NFTs) [1]. Although remarkable development has been made at the present time in our data about AD pathogenesis, there is still no effective treatment to mitigate the neurological deficits associated with AD or to prevent the disease. Currently, patients suffering from AD may be treated with approved acetylcho- linesterase (AChE) inhibitors such as rivastigmine, donepezil, and galantamine (I). However, AChE inhibitors ameliorate the symptoms of AD, but the clinical efficacy of them is considered to be very limited [4]. Correspondence: Dr. Abbas Shafiee, Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran. E-mail: ashafiee@ams.ac.ir Fax: þ98 21 66461178 Arch. Pharm. Chem. Life Sci. 2015, 348, 366–374 Archiv der Pharmazie ARCH RCH PHARM HARM ß 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com 366