# Trimethoxycinnamates and Their Cholinesterase Inhibitory Activity
## 1 Introduction  
Nature is an inspirational and rich source of compounds with biological effects. More than a half of all small-molecule-approved drugs between 1981 and 2014 belong to groups of natural products or mimic natural products [1]. Many plant secondary metabolites [2] have also been used as model compounds for the subsequent development of synthetic drugs [3; 4; 5; 6]. One such example is a cinnamic acid and its derivatives, e.g., ocularic acids, caffe acid, ferulic acid or snapic acid, which are widely distributed in many plants and assure their many physiological processes. They also serve as precursors for other compounds in plants such as lignols, (iso)flavonoids, coumarins, aurones, stillbenes, catechin, phenylpropanoids, etc. [7]. Natural cinnamic acid also serves as a precursor for new synthetic compounds. Synthetic derivatives of cinnamic acid showed interesting antimicrobial, anticancer, antiparasitic, neurological, antioxidant, and anti-inflammatory activities in vitro [8]. 3,4,5-trimethoxycinnamic acid (TMA) is an ingredient isolated from the root of _Polygala temifolia_ Wildl. (_Polygalacae_), and its extracts have been used as traditional sedative drugs inChina, Japan and Korea [9; 10; 11]. TMCA has been reported to have antidepressant, anticonvulsant and sedative activity [9; 12; 13]. In recent years, a large number of TMCA derivatives with various biological effects have been synthesized, such as antinarcotic [14], antitumor [15; 16; 17; 18], antiviral [19; 20], anticonvulsant [21] and anti-inflammatory [21; 22] agents. Published articles indicate that TMCA and its ester and amide analogues exhibit central nervous system activity, including antinarcotic, neuroprotective, anti-Alzheimer's and anticonvulsant effects. It involves several targets, such as 5-hydroxytryptamine receptor, prostaglandin E\({}_{2}\) receptor 2 and nuclear factor erythroid 2-related factor 2, \(\beta\)-amyloid peptide (1-42), acetylcholinesteraseinesterase (AChE), and butylylcholinesteraseterase (BChE) [14; 22; 23; 24; 25]. Alzheimer's disease (AD) accounts for 60% to 80% of dementia cases and is becoming an increasingly common disease not only in Western countries but also in low- and middle-income countries. It is estimated that more than 50 million people worldwide suffered from dementia by 2020, and that number is expected to rise to 82 million in 2030 and 152 million in 2050. For example, by the middle of the century, the estimated number of Americans aged 65 and over with AD could rise to 13.8 million, a sharp increase from the estimated 5.8 million Americans aged 65 and over who suffer from AD today. The latest available statistics from 2018 show that AD was the sixth most common cause of death in the United States [26; 27]. The exact cause of Alzheimer's disease is still unclear. It is seemingly a multifactorial disease, which is also caused by stress, unfavorable environment, eating habits, family predisposition, etc. Several hypotheses are known, the most elaborate of which concern amyloid, tau protein and acetylcholine concentration. This cholinergic hypothesis is the oldest and has attracted the most attention [26; 27; 28]. Drugs used in clinical practice to alleviate AD modulate acetylcholine levels in the brain by inhibiting AChE [28; 29; 30; 31; 32; 33]. In the early stages of AD, AChE level increases much faster than the level of BChE. On the other hand, as AD progresses, AChE level decreases in the brain, but BChE level remains unchanged or even increased (e.g., in the hippocampus and temporal cortex). Moreover, in the later stages of AD, BChE replaces the function of AChE (i.e., hydrolysis of ACh) [34; 35]. Thus, inhibition of BChE in addition to AChE may provide therapeutic benefit not only in AD. In addition, selective BChE inhibitors do not exhibit the adverse cholinergic effects that are characteristic of AChE inhibitors.