RESEARCH ARTICLE Synthesis, molecular modeling studies, ADME prediction of arachidonic acid carbamate derivatives, and evaluation of their acetylcholinesterase activity Tugce N. Kalin 1 | Deryanur Kilic 2 | Fatma Arslan 1 | Ozlem Colak 1 | Aliye Altundas 1 1 Department of Chemistry, Faculty of Science, Gazi University, Ankara, Turkey 2 Department of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey Correspondence Aliye Altundas, Department of Chemistry, Faculty of Science, Gazi University, 06500, Ankara, Turkey. Email: aaltundas@gazi.edu.tr or Deryanur Kilic, Department of Chemistry, Faculty of Science, Ataturk University, 25240, Erzurum, Turkey. Email: deryanurerdem@atauni.edu.tr Abstract In this work, a series of novel anandamide units containing carbamate were designed and synthesized. All the derivatives were evaluated in vitro for their inhibitory poten- tial against the electric eel acetylcholinesterase enzyme (AChE) and showed revers- ible inhibitions. The compounds 7a, 7d, 7e, and 7f are mixed inhibitors of AChE, while the compounds 7b, 7c, and 7g are uncompetitive (K i in the range 0.93–8.86 μM). The kinetic studies revealed that compounds 7b, 7c, 7f, and 7g inhibit considerably AChE activity. Molecular docking analyses were made to evaluate the binding type and interactions of the synthesized compounds to the ligand-binding site of hAChE. It was observed that the docking results were in parallel with the in vitro results. The adsorption, distribution, metabolism, and excretion properties were computed for the compounds, and were found within the acceptable range. This study suggests the compounds 7b, 7c, 7f, and 7g identified as novel reversible AChE inhibitors may be useful lead compounds for the treatment of Alzheimer's disease. KEYWORDS AChE inhibition, anandamide, carbamates, molecular docking 1 | INTRODUCTION Acetylcholinesterase (AChE, E.C. 3.1.1.7) belongs to the cholinester- ase enzyme family in vertebrates and invertebrates that regulate the synaptic availability of the neurotransmitter acetylcholine (ACh; Quinn, 1987; Johnson & Moore, 2012; Sussman, Harel, & Silman, 1992). AChE has been known to be responsible for the hydrolysis of ACh serving as a co-regulator of cholinergic transmission (Çoku gras¸, 2003; Giacobini, 2003; Sujayev et al., 2016). Alzheimer's disease (AD) is described as the degeneration of cho- linergic neurons in the central nervous system. It is particularly a chronic and progressive neurodegenerative disease that is associated with memory, higher intellectual functions, and consciousness (Çoku gras¸, 2003). The cholinergic deficiency in Alzheimer's disease is related to a decrease in the concentration of ACh and its levels can be controlled via AChE inhibitors. An increase in the ACh concentration can result in the alleviation of the symptoms of several diseases such as Parkinson's, ataxia, senile dementia, myasthenia gravis, and Alzheimer's disease (Bitencourt, Freitas, & Rittner, 2012; Ehrenstein, Galdzicki, & Lange, 1997; Imramovský et al., 2013). Like AChE, N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are also known to exist in the brain and the blood (Lewis & Maccarrone, 2009). Both AEA and 2-AG contain arachidonic acid, which is attached to the nitrogen of 1-ethanol amine and the secondary hydroxyl of glycerol, respectively. These are con- sidered to be the most important members of the endocannabinoid Received: 9 July 2019 Revised: 9 October 2019 Accepted: 12 October 2019 DOI: 10.1002/ddr.21621 Drug Dev Res. 2019;1–10. wileyonlinelibrary.com/journal/ddr © 2019 Wiley Periodicals, Inc. 1