# Synthesis of Novel Chalcones as Acetylcholinesteraseerase Inhibitors
## 1 Introduction  
Alzheimer's disease (AD), the most common cause of dementia in the elderly, is affecting millions of people worldwide. The ailment is characterized by a complex neurodegenerative process occurring in the central nervous system which leads to progressive cognitive decline and memory loss [1; 2]. The etiology of AD is not fully known, although factors including the low levels of acetylcholine (ACh), accumulation of abnormal proteins namely \(\beta\)-amyloid (\(\beta\)A) and \(\tau\)-protein, homeostasis irregularity of biometals, and oxidative stress are considered to play significant roles in the pathophysiology of AD [3; 4].  
At the present, clinical therapy for AD patients is primarily established upon the cholinergic hypothesis which suggests that the decline of the ACh level might lead to cognitive and memorydeficits, and drugs with the ability of inhibiting acetylcholinesterase (AChE) would control symptoms of the disease [5; 6]. AChE inhibitors including rivastgimine, donepezil and galantamine are given top priorities in the therapeutic treatment of AD. Mediated through the same mechanism, i.e., elevating the levels and duration of action of acetylcholine at synaptic clefts, these agents, however, only allow for the alleviation of the symptomatology in most patients and differ greatly in pharmacokinetic and pharmacodynamic profiles as well as result in adverse effects [7]. According to the crystallographic structural studies, AChE has a narrow 20 A gorge with two binding sites: the catalytic active site (CAS) at the bottom of the structure and the peripheral anionic site (PAS) near the entrance of the gorge [8; 9; 10]. Consequently, inhibitors that bind to either one or two of the sites could inhibit the AChE. In addition, recent studies have revealed that AChE could increase the formation of amyloid fibrils by interacting with the residues in the PAS of AChE, generating a more stable and toxic AChE-\(\beta\)A complex than single \(\beta\)A peptides alone [11]. Moreover, the dual binding inhibitors, which might simultaneously elevate the level of ACh and inhibit \(\beta\)-amyloid aggregation via binding to both the catalytic and peripheral sites of the enzyme, have become more promising in AD treatment [12; 13; 14].  
Flavonoids, a group of naturalcompounds with low molecular weight and low toxicity have increasingly attracted the interest of medicinal chemists due to their diversebioactivities. They express a variety of pharmacological properties, such as AchE-inhibitory [15; 16], antioxidant, anti-inflammatory, neuroprotective, vasodilator activities, as well as the inhibition of \(\beta\)A fibril formation [17; 18; 19]. Flavonoids also exhibit especially low toxicity, so they have been considered as promising anti-AD compounds. Of the synthetic flavonoids,alcone derivatives with either sulfonamide or amino moieties at position 4', represent AchE-inhibitory and \(\beta\)A anti-aggregating effects at the nanomolar concentrations [20].  
In this paper we describe the synthesis, pharmacological evaluation and molecular modeling of a series of new benzylaminochalcone derivatives as AChE inhibitors. The moiety of 2-hydroxybenzylamino was integrated into chalcone structures in the hope of enhancing hydrophobicity and promoting interactions with the active site of AChE via hydrogen bonds generated by hydroxyl groups. Phenyls in ring B are modified and replaced by substituted pyridinyl, furanyl and thiophenyl (Figure 1) with the aim of providing the molecules with the ability to bind at the AChE peripheral site and resulting in stronger AChE inhibition. Finally, molecular interactions between inhibitors and AChE revealed by molecular modeling studies would explain the results of an in vitro bioassay and help gain insight into the binding mode and structure-activity relationships of the novel compounds.