Cholinergic Phamacology Seminar Paper

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Current Neuropharmacology, 2021, 19, 1323-1344 1323
RESEARCH ARTICLE
Therapeutic Potential of Multifunctional Derivatives of Cholinesterase In-

hibitors
Maja Przybyłowska1, Krystyna Dzierzbicka1, Szymon Kowalski2, Klaudia Chmielewska1 and
Iwona Inkielewicz-Stepniak3,*
1
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland; 2Depart-
ment of Medicinal Chemistry, Medical University of Gdansk, Gdansk, Poland; 3Department of Pharmaceutical Patho-
physiology, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
Abstract: The aim of this work is to review tacrine analogues from the last three years, which
were not included in the latest review work, donepezil and galantamine hybrids from 2015 and ri-
vastigmine derivatives from 2014. In this account, we summarize the efforts toward the develop-
ARTICLE HISTORY
ment and characterization of non-toxic inhibitors of cholinesterases based on mentioned drugs with
Received: August 20, 2020 various interesting additional properties such as antioxidant, decreasing β-amyloid plaque aggrega-
Revised: October 07, 2020 tion, nitric oxide production, pro-inflammatory cytokines release, monoamine oxidase-B activity,
Accepted: November 29, 2020
cytotoxicity and oxidative stress in vitro and in animal model that classify these hybrids as poten-
DOI: tial multifunctional therapeutic agents for Alzheimer’s disease. Moreover, herein, we have de-
10.2174/1570159X19666201218103434 scribed the cholinergic hypothesis, mechanisms of neurodegeneration and current pharmacotherapy
of Alzheimer’s disease based on the restoration of cholinergic function through blocking enzymes
that break down acetylcholine.
Keywords: Tacrine, donepezil, galantamine, rivastigmine, multifunctional cholinesterase inhibitors, alzheimer’s disease.
1. INTRODUCTION being responsible for diverse brain activity. Cholinergic neu-

rotransmission is involved in a number of psychic processes,
1.1. The Cholinergic Hypothesis and Therapy of including walking and sleep, learning, memory, stress re-
Alzheimer’s Disease sponse, and affectivity [10, 11]. Furthermore, its impact on
In the mid-1970s, studies based on a brain autopsy of pa- other neurotransmitters greatly expands the scope of the ac-
tients with Alzheimer’s disease (AD) revealed a significant tivity. For instance, stimulation of M1/M5 receptors releases
deficit of the choline acetyltransferase (ChAT) in the limbic neurotransmitter, dopamine, from striatal synaptosomes
system and cerebral cortex, which is responsible for the [12]. Moreover, nAChRs stimulate the release of glutamate,
acetylcholine (ACh) synthesis [1-3]. In a further study, it has gamma-aminobutyric acid (GABA), norepinephrine or sero-
been determined that the nucleus basalis of Meynert in the tonin [13]. Many studies have shown that the cholinergic le-
basal forebrain, which is the source of cortical cholinergic in- sion in Alzheimer's disease is associated with nicotinic and
nervation, undergoes neurodegeneration in Alzheimer’s dis- muscarinic receptor changes. Nordberg and Winblad [14]
ease [4, 5]. The aforementioned studies, as well as the de- have determined a decrease in postsynaptic nicotinc recep-
monstration that cholinergic antagonists impair memory [6], tors on cortical neurons. Mash et al. [15] have shown a de-
crease in M2 receptors (mostly presynaptic) in the cerebral
formed the basis for the cholinergic hypothesis of
cortex, however, the level of M1 receptors remained
Alzheimer’s Disease.
unchanged. On the other hand, it has been suggested that
ACh is a major neurotransmitter in the brain, with activi- M1 receptors may be dysfunctional in the cerebral cortex
ty through the cortex, basal forebrain and basal ganglia [7]. [16]. Interestingly, the gene expression level of α7 nicotinc
Cholinergic projection neurons are found in nuclei such as receptor is increased in Alzheimer’s disease patients com-
the medial habenula, the pedunculopontine and laterodorsal pared to healthy controls, however, its impact on pathogene-
tegmental areas [8]. ACh acts through two classes of recep- sis remains to be elucidated [17]. Current pharmacotherapy
tors: ionotropic nicotinic receptors (nAChRs) and is based on the restoration of cholinergic function through
metabotropic muscarinic receptors (M1-M5) [9]. They are lo- blocking enzymes that break down acetylcholine. Suppres-
cated both pre- and postsynaptically throughout the brain, sion of acetylcholine breakdown by cholinesterase inhibitors
sustains ACh activity at cholinergic synapses. Tacrine was
the first cholinesterases inhibitor [both acetylcholinesterase
* Address correspondence to this author at the Department of Pharmaceuti-
cal Pathophysiology, Faculty of Pharmacy, Medical University of Gdansk,
(AChE) and butyrylcholinesterase (BChE)] approved by the
Debinki 7, 80-211, Gdansk, Poland; Tel/Fax: +48-58-349-1516, FDA for the treatment of Alzheimer's disease [18]. Tacrine
+48-58-349-1517; E-mail: iwona.inkielewicz-stepniak@gumed.edu.pl was shown to have efficacy in mild to moderately impaired
1570-159X/21 $65.00+.00 © 2021 Bentham Science Publishers

1324 Current Neuropharmacology, 2021, Vol. 19, No. 8 Przybyłowska et al.
Alzheimer's patients, however, it did not affect the ultimate Although the current therapy of AD is based on the inhi-
course of the disease [19]. Moreover, tacrine exhibited signi- bition of cholinesterase, clinical limitations of its use should
ficant hepatotoxicity (in approximately 25% of patients) and be mentioned. Serious side effects of tacrine are hepatotoxic-
quite low bioavailability after oral administration (about ity, nausea, vomiting, loss of appetite, diarrhoea and clumsi-
17%) [19]. For the above reasons, the use of tacrine was ness. A limitation of use is also its short half-life, which re-
limited soon after its inception in therapeutic application quires multiple application by each patient [33]. Side effects
[20]. that occur with rivastigmine are nausea, vomiting, diarrhea,
anorexia, weight loss and abdominal pain. Some neurologi-
However, tacrine structure is still widely used in medici- cal side effects are possible as well like headache, and syn-
nal chemistry for designing hybrid or multitarget com- copes [34]. Also, a donepezil revealed some lack of toler-
pounds without toxic side effects [21, 22]. Medicines cur- ance in patients manifested by dizziness, gastrointestinal
rently used in AD therapy include three cholinesterase inhibi- symptoms (for example a nausea, vomiting, or constipation),
tors: donepezil, rivastigmine and galantamine [23]. Chemi- insomnia, fatigue, sinus bradycardia and toxic effect toward
cal structures of tacrine, donepezil, rivastigmine and galan- the liver [35]. Any side effect of galantamine has not been
tamine are given in (Fig. 1). In 1996, donepezil was approved. Its use is well tolerated and safe [36].
proved for mild to moderate AD therapy as a non-competi-
tive, rapidly reversible acetylcholinesterase (AChE) inhibi- Unfortunately, there are also some limitations of cho-
tor [24]. Rivastigmine is another drug, which was approved linesterase inhibitor studies. Many investigations of neuro-
in 2000 for AD treatment [25]. Galantamine was approved pathology and cognitive impairment in multiple species
in 2001 as a competitive, rapidly reversible potent AChE in- have shown that Alzheimer's disease is a uniquely human
hibitor [26]. Rivastigmine (the same as tacrine) is a non-com- disease [37]. Therefore, commonly used experimental ani-
petitive, pseudo-irreversible inhibitor of both AChE and mal models contribute to a very poor success rate of AD clin-
BChE [25]. BChE regulates extracellular acetylcholine con- ical trials, which can be partially explained by the premature
centration and is mainly located on glial cells, whereas translation of successful pathology reduction in transgenic
AChE plays a major role in cholinergic transmission and is mice to humans [37]. Furthermore, the complexity of path-
located in pre- and postsynaptic membranes [27]. The activi- omechanisms of Alzheimer disease, and its incomplete un-
derstanding, makes it difficult to develop an effective thera-
ty of AChE rapidly declines with the death of cholinergic
peutic strategy [38-40].
neurons, with a simultaneous increase in the role of BChE
role in the regulation of cholinergic transmission [27]. There- The aim of this work is to review tacrine analogues from
fore, inhibition of both enzymes is a significant treatment 2017, donepezil and galantamine from 2015, as well as ri-
benefit for rivastigmine. However, donepezil also not only vastigmine derivatives from the last six years, taking into ac-
acts at the neurotransmitter level, it inhibits various aspects count their potential multifunctional activity against AD un-
of glutamate-induced excitotoxicity, induces a neuroprotec- der in vitro and in vivo condition.
tive isoform of AChE as well as reduces early expression of
inflammatory cytokines and oxidative stress effects [28]. 1.2. Other Mechanisms of Neurodegeneration in
Furthermore, some recent studies indicate that treatment Alzheimer's Disease
based on the promotion of cholinergic function may also Unfortunately, the current pharmacotherapeutic ap-
have more durable beneficial biological effects. It has been proach based on cholinesterase inhibitors has positive results
shown that the use of donepezil is associated with substan- only for a short period of time, usually 1-3 years, and is not
tially less regional cortical thinning and basal forebrain atro- able to completely arrest the progression of the disease [41].
phy over time [29, 30]. Moreover, study on the same popula- This is due to the multifaceted, progressive and interactive
tion has found a 45% reduction in the rate of hippocampal at- pathophysiology of AD. Besides, impairment of cholinergic
rophy after one-year donepezil treatment [31]. In another neurotransmission, AD pathology includes an aggregation of
study, after 18 months of treatment with donepezil and galan- β-amyloid that leads to tau protein hyperphosphorylation, ex-
tamine, a decrease in regional cerebral blood flow in the pari- cess production of nitric oxide (NO) and reactive oxygen
etal cortex as well as an increase in the frontal and limbic species (ROS), microglia and astrocyte activation and ulti-
cortices has been observed [32]. mately to neurotoxicity and cognitive dysfunction [42].
Fig. (1). Chemical structures of tacrine, donepezil, rivastigmine and galantamine.

Multifunctional Cholinesterase Inhibitors Current Neuropharmacology, 2021, Vol. 19, No. 8 1325
However, the complete mechanism of AD pathogenesis is transgenic AD model exhibit mitigated hippocampal mi-
still unclear, which has a major impact on the failure of clini- croglial activation, reduced plaque deposition and improved
cal trials in AD treatment. Therefore, the development of performance of incognitive tasks [60]. Cyclooxygenase 2
multi-target drugs to inhibit multiple factors involved in AD (COX-2) is upregulated in many inflammatory disorders
seems to be a promising therapeutic approach. [61]; however, it is not clear in the case of AD. Increased
Senile plaques are one of the neuropathological AD hall- levels of COX-2 mRNA and protein staining in AD tissue
marks present extracellularly [43]. They consist mainly of have been detected [62, 63]. On the other hand, a decreased
amyloid-β protein (Aβ), which is produced from its precur- COX-2 expression has been found particularly in the late
sor called amyloid precursor protein (APP) [44]. APP is cut stage AD [64, 65]. In the case of COX-1, which is promi-
by β- and γ-secretases forming Aβ, which is mainly generat- nently expressed by microglia in human brain [66], contribu-
ed from neurons, however, γ-secretase-dependent cleave oc- tion in neuroinflammation in AD has also not been estab-
curs in several cell types, and generates heterogeneity in Aβ, lished. Nevertheless, 5-lipoxygenase (5-LOX), producing
mainly producing Aβ40 and Aβ42 [44]. Aβ42 is the predomi- pro-inflammatory leukotrienes, as well as, COX enzymes, is
considered to be potential novel targets for AD therapy [67].
nant species deposited in AD brains as well as the most tox-
The family of phosphodiesterase-4 (PDE4) enzymes regulat-
ic one [45]. According to the Amyloid Cascade Hypothesis,
ing cyclic adenosine monophosphate (cAMP) signalling in
the accumulation of Aβ plaques in the brain of AD patients
neurons and glial cells represents another underexploited
leads to a number of secondary pathological changes, includ-
therapeutic targets [68]. PDE4B (subtype of PDE4) is in-
ing altered ionic homeostasis, inflammation (microglial and
duced in macrophages, monocytes, and microglial cells by
astrocytic activation), accumulation of the hyperphosphory-
inflammatory stimulators including Aβ [69] and represents a
lated tau protein forming neurofibrillary tangles (NFTs), sy-
novel therapeutic target, which may reduce neuroinflamma-
naptic degeneration and neuronal cell death [46].
tion in AD [68].
Oxidative stress is a condition of imbalance between re-
Monoamine oxidase (MAO) is one of the main enzymes,
active oxygen species (ROS) production and antioxidant de-
which catabolize catecholamines and serotonin and is wide-
fences, resulting in excessive accumulation of ROS [47]. It
ly distributed in the central nervous system in 2 main iso-
has been suggested that oxidative imbalance may play an im-
forms: A and B [70]. It has been determined that both A and
portant role in the initiation and progression of Alzheimer’s
B forms of MAO are altered in Alzheimer’s disease [71];
Diseases [48]. It has been determined that the accumulation
however, the mechanism by which they affect AD pathogen-
of Aβ increases oxidative stress and leads to mitochondrial
esis is not fully understood. A recent study has shown that
dysfunction and energy failure [49]. Moreover, Aβ-induced
oxidative imbalance may increase the levels of the products MAO-B levels are increased in astrocytes as well as in pyra-
related to lipid peroxidation, protein oxidation and DNA/R- midal neurons in the AD brain [72]. Moreover, the study al-
NA oxidation [50]. It has been found that decreased levels so suggested that MAO-B regulates Aβ production in neu-
of antioxidants (uric acid, vitamin C and E) or antioxidant rons via γ-secretase [72]. It has been shown that MAO-B in-
enzymes (e.g. superoxide dismutase, catalase) in patients hibitor may be a useful and reliable tool for the treatment of
with AD [51]. Besides, disturbances in metal levels, such as AD patients improving their cognitive functions and reduc-
iron, zinc, and copper have been identified in AD patients ing behavioral alterations, without frequent or severe side ef-
[52]. There is evidence to support that these alterations lead fects [73].
to neuronal death through enhancing the ROS production, af- Some metals like iron or copper play a significant role in
fecting cellular redox homeostasis (the depletion of glu- human health, because they have an impact on the proper
tathione), disruption of mitochondrial function as well as in- course of the homeostasis process. Their excess or deficien-
ducing intracellular free calcium, which is part of a sig- cyis essential for an occurrence of several commonly known
nalling pathway [53, 54]. Metal ions may also accelerate pro- neurodegenerative disorders like AD. Hence, metal chelat-
tein aggregation and their high micromolar concentrations ing activity is valuable and desirable property during search-
are found in amyloid plaques [55]. Moreover, overproduc- ing for AD efficient treatment therapy [46]. Multitarget ther-
tion of the nitric oxide (NO) inducing by Aβ (through the ac- apeutic strategies for AD are summarized in (Fig. 2).
tivation of microglia) also contributes to the production of
highly reactive oxidative species and secondary components 2. MULTIFUNCTIONAL DERIVATIVES OF
of nitroxidative stress [56]. TACRINE, DONEPEZIL, GALANTAMINE AND RI-
VASTIGMINE
Many studies have shown that neuroinflammation plays
a fundamental role in the progression of Alzheimer's disease In the work published in 2019 [74], authors described
[57]. Chronically activated microglia release many proin- new multifunctional tacrine derivatives. This article presents
flammatory and toxic products, including cytokines, reactive the latest analogues, which were synthesized and investigat-
oxygen species and nitric oxide [58]. One of the more impor- ed in a span of the last three years. Moreover, herein we de-
tant proinflammatory cytokines in AD is tumour necrosis scribed donepezil and galantamine hybrids which were re-
factor α (TNF-α), which plays both the initiation and regula- ported in the last five years, as well as rivastigmine deriva-
tion role of the cytokine cascade during inflammation [59]. tives from the last six years. All structures showing multi-
Mice lacking TNFR1 (TNF-α receptor) crossed with the functional properties were included in Table (1).
Table 1. Structures of tacrine, donepezil and rivastigmine derivatives and their biological activities.
S.
Structure Additional Functions References
No.
1 Antioxidant activity, protective properties against the injury caused by H2O2 [81]
2a-d: excellent metal chelating properties. 2a,b: inhibitory potency against

2 [82]
AChE-induced Aβ aggregation
Promising in vivo AChE inhibition

3 [83]
profile
Inhibitory potency against PAS and AChE-induced Aβ aggregation, ability to

4 [84]
induce S-phase post-treatment
Inhibitory potency against Aβ self-aggregation at the level of 47% at 20 µM,

5 [85]
antioxidant properties towards PC12 cells from CoCl2-damage
Neuroprotective activity towards SH-SY5Y cells against rotenone plus oli-

6 [86]
gomycin-A or okadaic acid
7 7b,c,f: neuroprotective activity on SH-SY5Y cell line [88]

S.
No.
Antioxidant properties, inhibition of Aβ1-42 aggregation, neuroprotection of SH-

8 [89]
SY5Y in the presence of H2O2
Inhibition of self-/Cu-induced Aβ aggregation, radical scavenging capacity and

9 metal chelating properties (Fe, Cu, Zn), neuroprotection in SH-SY5Y cells [96]
treated with Aβ1-42 ascorbate/iron stressors
Inhibition of Aβ self-aggregation amelioration, the impairment of memory in

10 [97]
mice models treated with scopolamine in the Morris water maze test
11 Inhibition of Aβ aggregation [100]
12 Antioxidant activity and neuroprotection against Aβ1-40 in SH-SY5Y cells [101]
Improvement of cognitive and locomotor activity in a mouse model with AD

in the step-through test and open field test, an increase of the amount of H2S in
13 hippocampus, decrease mRNA expression of the proinflammatory cytokines, [108]
TNF-α, IL-6, and IL-1β and increase synapse-associated in the hippocampus of
tested mice
Inhibition of Aβ42 self-aggregation, neuroprotection in rats neurons in a serum

14 [111]
and K+ deprivation model
S.
No.
15 Ability to cross the BBB in vitro [120]
Inhibition of hMAO A, and MAO-B,

16 [127]
strong antioxidant properties
17 Strong antioxidant effect with the oxygen radical absorbance capacity [129]
Inhibition of MAO-B and

Aβ1−42 aggregation, antioxidant effect, ability to chelat Cu2+ ions, to protect
PC12 cells from oxidative stress caused by H2O2, rotenone, and oligomycin-A,
18 to protect BV-2 cells from LPS-Stimulated Inflammation, improvement of cog- [130]
nition and spatial memory against scopolamine-induced acute memory deficit,
D-galactose (D-gal) and AlCl3 induced chronic oxidative stress in mice model
without acute toxicity and hepatotoxicity, ability to cross the BBB in vitro
Inhibitory activity against hMAO-B, self-induced and hAChE-induced Aβ ag-

gregation, antioxidant properties, the neuroprotective effects on PC12 cells
treated with H2O2 and against LPS-stimulated inflammation on BV-2 cells, abil-
19 [131]
ity to cross the BBB in vitro, good liver metabolic stability in RLM, dose-de-
pendently reversed scopolamine-induced memory deficit in mice model but
without acute toxicity
Anti-inflammatory properties in vivo in mice model, antioxidant activity in

20 SH-SY5Y cell line and ability to chelate Cu2+ and Fe2+ ions, protection of SH- [132]
SY5Y cells against the late neuronal death caused by Aβ1-42 oligomers
ADME profile in silico, anti-inflammatory and neuroprotective activity against

21 AβO-induced neuroinflammation and neurodegeneration in vitro in THP-1 [135]
cells and in vivo in mice model
S.
No.
Inhibitory activity against BACE1 and Aβ1−42 aggregation,

22 [139]
neuroprotective properties against Aβ1−42-induced damage in SH-SY5Y cells
Inhibitory activity against Aβ self-aggregation and Cu2+-induced Aβ aggrega-

23 [141]
tion, ability to protect SH-SY5Y cells from the Aβ-induced toxicity
24 Inhibitory potency against MAO-B, ability to cross the BBB in vitro [143]
Selective Cu2+ chelator in a 1:1 ratio, ability to cross the BBB in vitro, activity
25 [144]
against MAO-B
26 Inhibition of PDE9A [153]
Ability to inhibit self-induced and Cu2+-induced Aβ1-42 aggregation, inhibitory

27 activity against MAO-B, antioxidative properties, ability to chelate metals and [154]
to cross the BBB in vitro
S.
No.
28 Prevention from ROS in SH-SY5Y cell line [155]
Anti-inflammatory and antioxidant activity in BV-2 cells, the induction of pro-

29 teins expression (i.e. GSH) involved in the antioxidant defense in SH-SY5Y [156]
cell line, a decrease of ROS levels and NO-release in BV-2 cells
Antioxidative activity, selective metal chelator and neuroprotector against

30 H2O2-induced PC12 cell injury, ability to pass the BBB in vitro, relevant neuro- [157]
protective effects in scopolamine-induced cognitive impairment in mice model
31a-c: pleiotropic activities

31d-f: protection from the self-mediated Aβ aggregation,
31 [158]
31e,f: neuroprotective effect in HT22 cells against glutamate-índuced neuronal
death
Prevention of Aβ self-aggregation in TEM observation, ABTS+ scavenging,

32 [159]
and ability to chelat Cu2+ ions
Prevention of Aβ self-aggregation, protection of HT22 cells from glutamate

33 [160]
and H2O2 induced cell death, scavenging free radicals and Cu2 ions chelation
Antioxidant activity, neuroprotection of H2O2- induced PC12 cells and Aβ1-42-

induced SH-SY5Y cells, hepatoprotection of H2O2- induced LO2 cells, selec-
34 tive metal chelator, activity against Cu2+/hAChE/self-induced Aβ1-42 aggrega- [161]
tion, disaggregation of Cu2+-induced Aβ1-42 aggregation, ability to pass the BBB
in vitro
Fig. (2). Therapeutic strategies of multifunctional compounds for Alzheimer's disease. (A higher resolution / colour version of this figure is
available in the electronic copy of the article).
2.1. Tacrine Analogues Wang et al. [81] synthesized a series of hybrids of

tacrine and deferasirox as potential multifunctional drugs
It has been proven that introduction of chlorine atom to
used in AD treatment. The most derivatives in the series
the structure of tacrine and its derivatives has an effect on
were potent inhibitors of AChE from bovine serum
the increase of anti-cholinesterase activity and decrease in
(bAChE) metal ions chelators. The most effective com-
hepatotoxicity [75, 76]. Ragab et al. [77] designed, synthe- pound, 1, showed in addition an antioxidant activity, low cy-
sized and biologically evaluated a series of new 4- totoxicity and protective properties against the injury caused
(chlorophenyl)tetrahydroquinoline derivatives. The results by H2O2. Type of inhibition, based on molecular modeling,
of the biological investigation showed that all analogues had
for all of compounds, was mixed with the ability to bind to
equivalent or much higher activity against cholinesterase
the catalytic anionic site (CAS) and the periphelar anionic
and were less hepatotoxic than referenced drug tacrine.
site (PAS) of Torpedo californica variant of AChE (T-
Moreover, in silico drug-likeness of the obtained derivatives cAChE).
were predicted and their practical logP was estimated, show-
ing the ability of all of them to be promising hits/leads. In ad- Tacrine-isatin Schiff base hybrids displayed potent activi-
dition, the docking study was performed for the most potent ty against AChE and BChE with the selectivity for AChE
cholinesterase inhibitor in the series, showing its binding over BChE. The most potent inhibitors of AChE were deriva-
mode is similar to that representing by tacrine. tives 2a-c with IC50 values of 0.42 nM, 0.62 nM, 0.95 nM, re-
spectively. They were 92-, 62- and 41-fold stronger than ref-
The first step against the main toxic effects of nerve erenced tacrine (IC50 = 38.72 nM). The most active deriva-
agents is simultaneous administration of anticholinergic
tive against BChE was 2d with an IC50 value of 0.11 nM,
agents and oxime reactivators, such as pralidoxime (2-
PAM), which can reactivate inhibited AChE [78, 79]. 2- which was 56 times stronger than tacrine (IC50 = 6.21 nM).
PAM is not active against every nerve agent, thus there is a All compounds in the series showed excellent metal chelat-
need to look for more efficient compound. Novel series of ing properties. Moreover, 2a,b were good inhibitors of
tacrine-pyridinium hybrid reactivators linked by carbon AChE-induced amyloid-beta (Aβ) aggregation. Studies of ki-
chain were designed, synthesized and tested for their netic and molecular modeling exhibited mixed-type inhibi-
eeAChE inhibitory activity. The highest obtained results for tion for 2a [82].
AChE activity were 95%, 92% and 90% and 1 μM concen- El-Malah et al. [83] designed and synthesized new
trations of the oximes [80]. thienopyridine-tacrine analogues as potential cholinesterase
inhibitors. Obtained derivatives have been evaluated for activity against AChE with IC50 values in the range of
their in vivo brain AChE inhibitory activity. For the most 0.06-0.27 nM. Studies carried out on SH-SY5Y (neuroblasto-
promising compounds, in vitro AChE inhibition was investi- ma cell line) cells treated with Aβ1-42 peptides revealed neuro-
gated. The most potent in the series was hybrid 3 with an protective activity against Aβ-induced cell toxicity for three
IC50 value of 172 nM. compounds: 7b,c,f, whereas 7c was the most potent. Results
An example of bivalent reversible inhibitor of AChE is were expressed as the percentage of SH-SY5Y untreated
5-amino-N1,N3-bis(2-(1,2,3,4-tetrahydroacridin-9-ylami- cells and for mentioned compounds were p < 0.05.
no)ethyl)isophthalamide compound 4. It was designed using A promising strategy in the treatment of Alzheimer’s dis-
molecular modeling and showed high affinity and ability to ease is the combination of vanillina and tacrine. Because of
bind to CAS and PAS. The synthesis included using 9- the various biological properties of vanillin, e.g: antioxidant
alkyl(1,2,3,4-tetrahydroacridine) pharmacophore with ap- activity, Aβ-amyloid inhibitory activity and capacity to in-
pended functionality. Biological evaluation revealed high inhibit AChE, it is used to obtain multi-target-directed ligands
hibition of AChE and BChE with IC50 values of 0.54 ± 0.06 (MTDL). Antioxidant properties of novel series of tacrine-
nM and 32.49 ± 1.2 nM, respectively (the value of selectivi- vaniline hybrids were tested by Scipioni et al. [89] using
ty ratio was 60.16 toward AChE). Moreover, compound 4 DPPH assay, achieving IC50 value of 19.5 µM, as well as
was able to inhibit PAS and aggregation of Aβ induced by FRAP and ORAC tests with results up to 1.54 and 6.4
AChE. Rat hippocampal neuron studies showed low cytotox- Trolox equivalents, respectively. The kinetic studies re-
ic effect and ability to induce S-phase post-treatment. There- vealed inhibition of AChE at µM range. Moreover, com-
fore, a further detailed evaluation of this derivative as a po- pound 8 inhibited Aβ1-42 amyloid similar to referenced curcu-
tential drug for AD treatment is proposed [84]. min. The investigation of neuroprotection for derivative men-
Li et al. [85] synthesized a series of novel tacrine-pheno- tion above at 1 µM proved it to protect cells of SH-SY5Y in
lic acid dihybrids and tacrine-phenolic acid-ligustrazine tri- the presence of hydrogen peroxide at 400 µM.
hybrids and evaluated them towards cholinesterase inhibito- Medrasi et al. [90] synthesized new pyrrolotacrines in
ry activity. The most interesting in the series was compound Friedländer-type of reaction and investigated their ability to
5, which inhibited eeAChE, hAChE, eqBChE and hBChE inhibit AChE. All compounds in the series showed potent or
with IC50 values of 3.9 nM, 65.2 nM; 24.3 nM and 48.8 nM, moderate anti-AChE activity with IC50 value of 0.2 µM for
respectively. It was stronger towards AChE (mixed-type du- the most potent derivative. Interestingly, the replacement of
al site inhibitor) and simultaneously weaker against BChE a fused cyclohexane ring by a fused cyclopenatne ring didn’t
than referenced drug tacrine. It was not hepatotoxic and ex- have an impact on the improvement of AChE inhibition. Fur-
hibited inhibition of Aβ self-aggregation at a level of 47% at thermore, the effect of the presence of chlorine atom on ame-
20 µM, antioxidant properties towards PC12 cells from lioration cholinesterase inhibitory, which is observed by
CoCl2-damage, which makes it a promising multifunctional some authors is not observed in results reported by Medrasi
drug for patients with AD. et al. [91-93].
Quinoxalines are compounds showing anti-neuroinflam- Deferiprone is well known metal chelating drug, which
mation, antitumoral, antomycobacterial and antifungal prop- binds to iron in a 3:1 ratio; thus it decreases the content of
erties. Therefore, a series of novel quinoxalinetacrines were this element in the body of animals and humas [94]. Some re-
synthesized and their biological activity was investigated. search proved that it attenuated the increase in AChE activi-
Derivative 6 showed lower activity against AChE and BChE ty and decreased Aβ and iron deposition, as well as neuro-
with IC50 values of 22.0 ± 1.3 μM and 6.79 ± 0.33 μM, re- protective and memory enhancing effects for deferiprone in
spectively, but it was selective toward BChE. Furthermore, rats treated with scopolamine which might be attributed to
this compound exhibited lower hepatotoxicity than tacrine its iron chelating action and anti-oxidative effect [95]. A
and neuroprotective activity against rotenone plus oli- combination of tacrine and deferiprone provides good AChE
gomycin-A or okadaic acid [86]. inhibitory activity, inhibition of self-/Cu-induced Aβ aggre-
Also, a series of tacrine analogues containing pyranopy- gation, radical scavenging capacity and metal chelating prop-
razole moiety were synthesized. These derivatives were in- erties (Fe, Cu, Zn). Chand et al. [96] synthesized a series of
vestigated for their AChE and BChE inhibition. Most com- tacrine-deferiprone hybrids. Besides advantages mentioned
pounds in the obtained group showed high activity against above, obtained analogues are characterized by neuroprotec-
AChE with IC50 values for the two strongest analogues of tion in SH-SY5Y cells treated with Aβ1-42 ascorbate/iron
0.044 µM and 0.058 µM [87]. stressors (9a and 9b). The best results displayed derivatives
with chloro-substitution, containing 2-hydroxypropyl linkers
Due to multifunctional nature of AD, it is important to with IC50 values in the range of 0.64-1.01 µM. One can in-
design structures that could display multi-target-directed
clude them in the potential of leading compounds in the
role. Example of this approach was described by Rajeshwari
search for effective therapy in Alzheimer’s disease treat-
et al. [88]. Six selected hybrids containing two pharma-
ment.
cophores: tacrine and 2-phenylbenzothiazole exhibited,
based on molecular studies, the ability to bind to CAS and Also, compound 10 is a promising multifunctional an-
PAS of AChE. All compounds in the series proved excellent ti-Alzheimer’s disease candidate. It was the most active in
the series of tacrine-ferulic acid hybrids with IC50 against of Alzheimer's disease in experimental models by targeting
eeAChE and BChE of 37.02 nM and 101.4 nM, respective- multiple pathophysiological mechanisms [107]. H2S also has
ly. Moreover it didn’t show relevant hepatotoxicity and it neuroprotective, hepatoprotective, and anti-inflammatory
was able to inhibit Aβ self-aggregation by 65.49% at 25µM properties. From that perspective, the hybrids of H2S-donors
and ameliorated the impairment of memory in mice models and tacrine could be efficient strategy in Alzheimer’s dis-
treated with scopolamine in the Morris water maze test [97]. ease treatment. An example of this approach is the connec-
Ökten et al. [98] designed and bioevaluated three disub- tion of tacrine and H2S-releasing moieties (ACS81) to give
stituted six or seven hydrocycle membered tacrine deriva- compound 13. Authors reported that this hybrid, besides ex-
tives. Substitutents were bromine atom or silyl. All of ob- cellent AChE inhibition, improved cognitive and locomotor
tained compounds effectively inhibited four enzymes: activity in a mouse model with AD in the step-through test
AChE, BChE, Carbonic anhydrase isoenzymes I and II (h- and open field test, respectively. Moreover, it induced the in-
CA I and II) with IC50 values of 30.26 ± 6.71–117.54 ± crease in the amount of H2S in hippocampus, decreased mR-
42.22 nM, 22.45 ± 5.81–77.41 ± 4.02 nM, 57. 28 ± 22.16– NA expression of the proinflammatory cytokines, TNF-α,
213.41 ± 82.75 nM and 46.95 ± 11.32–274.94 ± 62.15 nM, re- IL-6, and IL-1β and increased synapse-associated in the hip-
spectively. pocampus of tested mice. Regarding the fact, tacrine was
withdrawn from use due to its hepatotoxicity, it is important
Also a series of eleven tacrine-1,2,3-triazole hybrids that obtained results for compound 13 showed its safety for
were synthesized through Cu(i)-catalyzed alkyne-azide 1,3- the liver. Without a doubt, this hybrid is a promising candi-
dipolar cycloaddition (CuAAC) reaction as potential drugs date against AD [108].
using in Alzheimer’s disease treatment. The most potent
compound inhibited eeAChE and BChE in micromolar Gniazdowska et al. [109] designed and synthesized a
range, which gave slightly lower result than the referenced group of radioconjugates – tacrine derivatives labeled with
tacrine. Molecular docking studies revealed it can bind to technetium-99m and gallium-68, which are potential diag-
both, CAS and PAS sites [99]. nostic radiopharmaceuticals. Authors tested lipophilicity, sta-
bility in the presence of an excess of standard amino acids
Cheng et al. [100] designed and synthesized a series of
cysteine or histidine, human serum and in cerebrospinal
brominated phenylacetic acid-tacrine derivatives and evaluat-
fluid. Based on investigation of lipophilicity, Gniazdowska
ed their AChE and BChE inhibitory activity, capacity to in-
et al. selected for molecular docking and biodistribution
hibit self-induced and AChE-induced Aβ aggregation and he-
studies, as well as cholinesterases inhibition assays only two
patotoxic effect. Among all, compound 11 exhibited the
compounds, but both of them were good BChE and AChE in-
highest AChE/BChE inhibition, lack of hepatotoxicity in
hibitors. Unfortunately, they showed the ability to cross the
comparison to referenced drugs tacrine and donepezil, as
blood-brain barrier into the brains of rats, but in insufficient
well as inhibition of mentioned above Aβ aggregation.
level, which may be due to insufficient lipophilicity related
Multitarget small molecules (MTSM) are able to interact to used hydrophilic chelators (Hynic and DOTA). Enhanced
simultaneously with the different enzymatic systems or re- utility of PET and SPECT imaging for both conjugates may
ceptors playing important role in the pathology of AD, thus be reached after some modifications in administration proce-
MTSM are one of the most promising approaches in search- dure like change into the central nervous system injection or
ing for new anti-AD drugs. A novel series of tacrine and ko- by insertion though the catheter (for PET) and proper adjust-
jic acid hybrids, which are MTSM, were synthesized and ment of detection system for applied activity dose (for SPEC-
their biological activity was evaluated. The most active com- T).
pound in the series, 12, proved to be less hepatotoxic than
tacrine and selective inhibitor of hAChE with IC50 value of BChE, besides AChE, plays an important role in AD. In
the central nervous system, it is mainly present in glial cells
4.52 µM. Moreover it exhibited antioxidant activity and neu-
and neurons, and it regulates extracellular acetylcholine con-
roprotection against Aβ1-40 at 3 µM and 10 µM concentra-
centration. With the decrease of AChE activity which occurs
tions in SH-SY5Y cells [101]. with the death of cholinergic neurons, the role of BChE in
Next interesting group of tacrine analogues are tacrine- cholinergic transmission increases [110]. Due to this fact, a
H2S donor hybrids (THS). Hydrogen sulfide (H2S) is an en- series of tacrine-phenolic heterodimers were designed and
dogenous signaling gasotransmitter molecule. It is produced synthesized as potent BChE inhibitors using in Alzheimer’s
in the liver, as well as in brain by cystathionine betasyn- disease treatment [111]. A series includes different modifica-
thase, 3-mercaptopyruvate-sulfurtransferase, cysteine amino- tions of the nature (imino, amino, ether), various length of
transferase and cystathionine γ-lyase [102]. The role of H2S the linker, as well as number and position of the substituents
in brain is regulation of synaptic activity of neurons and glia on the aromatic ring. All of them proved to be strong BChE
by increasing the intracellular calcium ions, as well as it acts inhibitors from the nanomolar to subnanomolar range. The
significant function in the development of long-term potenti- most active was compound 14 and it showed IC50 value of
ation [103, 104]. The decrease of level of H2S promotes the 0.52 nM against human BChE, what was 85-fold more ac-
progression of depression and it plays relevant role in the de- tive than referenced drug tacrine. What is important for mul-
velopment of learning and memory deficits [105, 106]. tifunctional nature of AD, this compound can inhibit the self-
Some studies also proved that it slows down the progression -aggregation of Aβ42 with lack of neurotoxicity up to 5 mM,
low hepatotoxicity and stability under physiological condi- Phosphodiesterase 4 (PDE4) is the primary cAMP-specif-
tions. Moreover, it exhibited neuroprotection in rats neurons ic hydrolase which is involved in the process of memory con-
in a serum and K+ deprivation model. solidation and a PDE4D inhibitor can affect the hippocam-
pus and dependent on it memory tasks [121, 122]. Pan et al.
Lopes et al. [112] designed, synthesized and evaluated
[123] designed, synthesized and bioevaluated a novel series
cholinesterase inhibitory activity of tacrine and carbohy-
of tacrine-pyrazolo[3,4-b]pyridine hybrids as potential cho-
drate-based moieties hybrids as potential agents against AD.
linesterase and phosphodiesterase 4D (PDE4D) inhibitors.
The synthesis was based on the reaction between tacrine and
The inhibitory activity depended on the length of carbon
the appropriate sugar-based tosylates according to the mech-
chain between tacrine and pyrazolo[3,4-b]pyridine. The
anism of nucleophilic substitution. Most of the D-xylose ana-
most active compounds in the series inhibited AChE with
logues showed potent AChE and BChE inhibitory activity
IC50 value of 0.125 µM, as well as it showed a desired bal-
with IC50 values of 2.2 nM and 4.93 nM, respectively, for
ance of AChE and BChE and PDE4D inhibition activities,
the most active compound. Most hybrids in the series were
with IC50 values of 0.449 and 0.271 μM, respectively.
selective for AChE over BChE (the highest IC50 ratio that
was noticed was 7.6). Only two derivatives showed selectivi- Also, a novel series of phosphorus and thiophosphorus
ty for BChE. Mostly, described derivatives showed a lack of tacrine analogues was designed and synthesized in reaction
hepatotoxicity according to ProTox-II. Furthermore, on the between appropriate chlorophosphates or chlorothiophos-
basis of molecular modeling studies, it was found that de- phates and N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-
signed hybrids are able to interact with the entire binding diamine. Their inhibitory activity and modeling studies were
cavity and the main contribution of the linker is to enable investigated. Two compounds in the series proved to be
the most favorable positioning of the two moieties with more active than tacrine, whereas the most active was 3-
CAS, PAS, and hydrophobic pocket to provide optimal inter- times stronger than referenced drug. All of the synthesized
actions with the binding cavity. derivatives proved to be less toxic against SH-SY5Y cell
line than tacrine [110].
Cheng et al. [113] designed and synthesized a series of
dual AChE and BChE inhibitors for AD treatment by con- 2.2. Donepezil Analogues
necting tacrine with indole-3-acetic acid (IAA). Some com-
pounds in the series exhibited dual inhibitory activity in Łozińska et al. [124] synthesized a novel series of
nanomolar range. Based on molecular modeling analysis for donepezil-melatonin hybrids as selective inhibitors of
these derivatives, the capacity to bind to catalytic active site BChE. The synthesis was based on coupling reaction of alky-
and peripheral anionic site of cholinesterase was found. The lamine-substituted N-benzylpiperidine derivatives and with
preliminary SAR analysis suggested the optimal length of di- a carbonate analogue of N-acetylserotonin. The modification
aminoalkyl linker between tacrine and IAA is six atoms of of the linker between two main moieties has been carried
carbon. out by introduction of carbamate bond connected to the aro-
matic system of the melatonin. It led to improvement of the
M1 muscarinic acetylcholine receptors (M1 mAChRs) affinity toward BChE, as it was observed in the case of
play important, selective role for verbal memory mech- tacrine and melatonin derivatives [125].
anisms [114, 115]. Stimulation of them is able to improve
cognitive deficit and M1 agonists can advance verbal memo- Also, a novel series of donepezil-hydrazinonicotinamide
ry, enhance cholinergic transmission, as well as have an im- hybrids was synthesized and bioevaluated. All of the ob-
pact on amyloid precursor protein (APP) processing, what in tained compounds revealed a higher affinity to AChE in
results prevents Aβ-aggregation and slows the progression comparison to BChE, higher selectivity toward AChE than
of Alzheimer’s disease [116-119]. The series of tacrine-ben- to BChE and they were less active against AChE and more
zyl quinolone carboxylic acid (tacrine-BQCA) derivatives active against BChE than referenced drug donepezil [126].
was synthesized and their hAChE/hBChE inhibitory activity
was evaluated. The indirect aim was increase of cholinergic Next interesting group of donepezil derivatives are hy-
transmission by inhibiting of cholinesterase and the direct brids of donepezil, chromone and melatonin as potential mul-
aim was supporting cholinergic transmission via M1 tifunctional drugs against AD. The most promising com-
mAChR activation. The series consisted of three groups of pound in the series, 16, exhibited potent hBChE inhibition
compounds that differed in tacrine moiety (7-methoxy- with IC50 values of 11.90 ± 0.05 nM, but also a moderate in-
tacrine, 6-chlorotacrine or unsubsituted tacrine). After the inhibition of hAChE, human monoamine oxidase A (hMAO
troduction of BQCA, a positive modulator of M1 muscarinic A), and monoamine oxidase B (MAO-B) with IC50 of 1.73 ±
acetylcholine receptors the impact on M1 mAChRs was in- 0.34 µM, 2.78 ± 0.12 µM, 21.29 ± 3.85 µM, respectively.
vestigated via Fluo-4 NW assay on the Chinese hamster This analogue revealed also strong antioxidant properties
ovarian (CHO-M1WT2) cell line. All of the derivatives in (3.04 TE) [127]. It should be mentioned, it is a selective
the series were potent hAChE and hBChE inhibitors with ac- BChE inhibitor, what is significant in the case of patients
tivity in micromolar and nanomolar range. Unfortunately, with moderate to severe forms of AD [128].
the agonist effect towards M1 mAChRs, which should be
provide by introduction of BQCA moiety wasn’t revealed. Benchekroun et al. [129] a novel series of donepezil and
Investigation of permeation BBB in vitro was positive for ferulic acid derivatives as potential multitarget anti-AD
compounds 15a,b [120]. agents. All of the obtained compounds were characterized
by strong antioxidant effect with the oxygen radical absor- showed non-competitive mechanism of inhibition that can
bance capacity values in the range 4.80–8.71 TE, what is bind to PAS of AChE.
much higher than results observed for referenced melatonin Several studies suggest that Aβ deposits and neurofibril-
and ferulic acid. One of the most active hybrids, selective lary tangles provide cause neuroinflammation, which con-
against eqBChE with strong antioxidant properties proved to tribute to early and late stage of the AD neurodegeneration
be compound 17. [133, 134]. Therefore, drugs designed to treat the different
Donepezil – trolox hybrids were designed, synthesized neuroinflammations are needed. Dias Viegas et al. [135] re-
and bioevaluated as multifunctional drugs for AD treatment. ported synthesis and biological evaluation of a series of N-
They exhibited moderate to good inhibition of hAChE and benzyl-piperidine-arylacylhydrazone derivatives as
MAO-B with IC50 values of 0.54 μM and 4.3 μM, respective- donepezil hybrids, that can possess anti-inflammatory prop-
ly, for the most active compound in the series, 18. More- erties, as well as can be active against neurodegeneration in
over, it showed Aβ1−42 inhibitory activity, great antioxidant patients brains with AD. Two compounds in the series, 21a
effect (IC50 = 41.33 μM by DPPH method, 1.72 and 1.79 TE and 21b, were good AChE inhibitors, exhibited the best
by ABTS and ORAC methods) and ability to chelat Cu
2+ ADME (Absorption, Distribution, Metabolism, Excretion)
ions. It did not show significant toxicity in HepG2, PC12, profile in silico, anti-inflammatory and neuroprotective activ-
and BV-2 cells (murine microglia cell line), as well as it is ity against AβO-induced neuroinflammation and neurode-
able to protect cells from oxidative stress caused by H2O2, generation in vitro in THP-1 cells (human acute monocytic
leukemia cell line) and in vivo in mice model. They inhibit-
rotenone, and oligomycin-A. Furthermore, oral administra-
ed tumor necrosis factor alpha (TNF-α), which is secreted
tion of this analogue improved cognition and spatial memo-
by activated microglia cells and as a result it makes a pro-
ry against scopolamine-induced acute memory deficit, D-
gression of AD. It suggests, they could prevent he signal
galactose (D-gal) and AlCl3 induced chronic oxidative stress
transduction pathway mediated by TNF type 1 receptor (TN-
in mice model without acute toxicity and hepatotoxicity FR1) at brain level, what is important regarding the fact that
[130]. This derivative revealed ability to cross BBB in vitro. TNFR1 also is involved in cognitive decline [136, 137]. Al-
A promising strategy in searching for new drugs for AD so, they showed inhibitory activity against cyclooxyge-
is represented by a novel series of donepezil – butylated hy- nase-1 and -2 (COX-1 and COX-2, respectively), which
droxytoluene (BHT) hybrids. Most of the compounds display significant role in the mechanisms of CNS inflamma-
played moderate to good inhibition of AChE/MAO-B and tion [138].
excellent antioxidant activities. The most active in the series Next interesting group are deoxyvasicinone-donepezil
was compound 19 and it proved to be a multifunctional hybrids. They exhibited from moderate to excellent inhibito-
agent with cholinergic, antioxidant and neuroprotective activ- ry activity against hAChE, BACE1, and Aβ1−42 aggregation.
ity. It inhibited eeAChE and hAChE with IC50 values of Among all, compounds 22a and 22b revealed low cytotoxici-
0.075 μM and 0.75 μM, respectively. Moreover, it exhibited ty and neuroprotective properties against Aβ1−42-induced da-
inhibitory activity against hMAO-B with IC50 value of mage in SH-SY5Y cells. Derivative 22a inhibited hAChE,
7.4 μM, ability to inhibit self-induced and hAChE-induced BACE1 and Aβ1−42 aggregation with IC50 values of 56.14
Aβ aggregation, antioxidant properties with IC50 value of nM, 0.834 µM and 13.26 µM, respectively. In the same in-
71.7 μM using DPPH method, as well as 0.82 and 1.62 TE vestigation, the results obtained for compound 22b are 3.29
by ABTS method and ORAC method, respectively. Also, nM, 0.129 µM and 9.26 µM, respectively. Moreover, these
the neuroprotective effects on PC12 cells treated with H2O2 compounds should be able to penetrate the blood-brain barri-
and against Lipopolysaccharides (LPS)-stimulated inflamma- er [139].
tion on BV-2 cells were tested. In addition, compound 19
could cross BBB in vitro and showed good liver metabolic Valencia et al. [140] described neurogenic and neuropro-
stability in RLM (rat liver microsomes) and the passive avoi- tective hybrids by connecting flavonoid-related structures
dance test showed for this derivative dose-dependently rev- and a donepezil fragment to obtain new 4-chromone- and 4-
ersed scopolamine-induced memory deficit in mice model quinolone – N-benzylpiperidine hybrids (DFHs). They ex-
but without acute toxicity [131]. hibited nanomolar affinities for the sigma-1 receptor (σ1R).
Also, they inhibited hAChE, 5-lipoxygenase (5-LOX),
Dias et al. [132] designed, synthesized and evaluated bio- MAO-A and MAO-B. Based on kinetic studies, the new
logical activity of novel series of feruloyl – donepezil hy- DFHs can bind with the two main sites of the AChE gorge
brids as potential multifunctional drugs using in AD. The (CAS and PAS). Hybrids derived from 4-chromone series in-
most active analogue in the series was compound 20. It inhibited hAChE with IC50 value in the range from the nano-
hibited eeAChE with IC50 value of 0.46 µM. Moreover, it molar to the low micromolar. What is interesting, deriva-
proved its multifunctional profile in the investigation of an- tives from 4-oxo-1Hquinoline series were not as potent
ti-inflammatory properties in vivo in mice model, antioxi- hAChE inhibitors as 4-chromone analogues. It may be
dant activity in SH-SY5Y cell line and ability to chelat Cu2+ caused by existence of a tautomeric equilibrium in the aza-
and Fe2+ ions. Also, a neuroprotection studies revealed it heterocycle what can impede the interaction with the en-
protected SH-SY5Y cells against the late neuronal death zyme. Moreover, most of the compounds in the series can
caused by Aβ1-42 oligomers. Molecular docking studies cross BBB, based on in vitro PAMPA-BBB model. Also,
they can scavenge free radical species and protect neuronal 2.3. Galantamine Analogues
cells against mitochondrial oxidative stress. The binding site of AChE is deep and narrow. PAS is lo-
Also, a novel series of donepezil derivatives obtained by cated at the entrance of the binding gorge and takes part in
connecting donepezil by a 1–2 methylene bridge with a sub- an interaction with Aβ, forming as a result the amyloid
stituted planar heterocyclic structure were designed, synthe- plaques. That is why blocking of PAS is important for pro-
sized and bioevaluated as potential drugs for patients with tecting from AChE-induced Aβ aggregation. Galantamine
AD. AChE inhibitory activity of obtained compounds, as it fits perfectly to the binding gorge of AChE, but unfortunate-
was anticipated, was lower in comparison to referenced ly it is too short to fully fill it, so galantamine derivatives
drug, donepezil. The reason for this was the weak binding of that can bind to both CAS and PAS are needed [145-149].
the benzylpiperazine or N-benzylpiperidine portion with the Stavrakov et al. [150] synthesized a series of galantamine
CAS of AChE. Introduction of a heterocyclic planar group and camphane hybrids as dual-site binding AChE inhibitors.
Camphane is a bulky fragment that can be located on the
contributed to a moderate inhibitory activity against Aβ self-
wide gorge entrance, what short galantamine is not able to
aggregation, while the inhibition of the Cu2+-induced Aβ ag- fill. Some compounds in the series exhibited 191- and 369-
gregation was particularly enhanced for compounds with me- times higher AChE inhibition than referenced drug galan-
tal chelation capacity. Four compounds in the series, 23a-d, tamine. Moreover, they bind to PAS of AChE, do not show
were able to protect SH-SY5Y cells from the Aβ-induced neurotoxic effect and can pass the BBB.
toxicity [141].
Chandrika et al. [142] described synthesis and biological 2.4. Rivastigmine Analogues
tests of two series of bifunctional donepezil derivatives Phosphodiestrases 9 (PDE9) are group of enzymes that
against AD. They contained 1,3- or 1,4-chalcone-donepezil can hydrolyze the intracellular second messenger cyclic
hybrids. The second group possessed higher eeAChE and ef- guanosine monophosphate (cGMP). cGMP can regulate
BChE inhibitory activity than 1,3-chalcone-donepezil hy- pleiotropic cellular functions in health and disease [151,
brids, with several exceptions. Some compounds showed bet- 152]. One of the eleven isoforms of PDE9 is phosphodi-
ter inhibition of bioAβ42 oligomer assembly in comparison esterase 9A (PDE9A). Its concentration is high in the cortex,
to donepezil, but any of them was able to dissociate pre- basal ganglia, hippocampus, and cerebellum of brain. It has
formed oligomers. Moreover, combination studies proved a been proved that the inhibition of phosphodiestrases (PDEs)
covalent linkage between chalcones and donepezil is needed increase the performance of cognition functions in animals
for the prevention of bioAβ42 oligomerization. organisms. The inhibition of PDE9A is relevant for AD, be-
cause of restoring proteins associated with memory and at-
Coumarin-donepezil hybrids were synthesized and their tenuating neuronal injuries in hippocampal area by the reduc-
biochemical properties were tested as potent ChE and tion of amount of cGMP in brain to active NO/cGMP/P-
MAO-B inhibitors. Most of the compounds displayed potent KG/CREB signaling, with simultaneous increase of brain-
inhibition of AChE, BChE and selective activity against derived neurotrophic factor (BDNF) [151]. Yu et al. [153]
MAO-B. The most active derivative in the series, 24, inhibit- as the first one designed, synthesized and evaluated biologi-
ed eeAChE, eqBChE, hAChE, hBChE and hMAO-B with cal activity of series of pyrazolopyrimidinone-rivastigmine
IC50 values of 0.87 μM, 0.93 μM, 1.37 μM, 1.98 μM and hybrids to inhibit simultaneously PDE9A and BChE. Most
2.62 μM, respectively. Cytotoxicity investigation did not re- of the analogues in the series proved to be inhibitors of both
veal toxic effect on SH-SY5Y cell line. Furthermore, molec- PDE9A and BChE. The most potent were compounds 26a
ular modeling studies proved it to be mixed-type inhibitor, and 26b and inhibited PDE9A with IC50 values of 14 nM
and 17 nM, respectively and BChE with IC50 values of 3.3
able to bind to CAS, PAS and mid-gorge site of AChE, and
μM and 0.97 μM, respectively. The results obtained for
it revealed a competitive mechanism of inhibition of MAO-
BChE proved these two derivatives to be stronger inhibitors
B. In addition it was able to penetrate BBB in vitro [143]. than referenced rivastigmine. In addition, they were not tox-
Synthesis of 2-acetylphenol-donepezil hybrids is an ic.
another approach in searching for multi-target-directed Also, a series of novel 4’-aminochalcone-revastigmine
molecules against AD. reported by Zhu et al. [144]. They hybrids were synthesized and their biological properties
evaluated their inhibitory activity against AChE, BChE, were evaluated as multitarget drugs against AD. In the
MAO-A and MAO-B. Compound 25a revealed the highest whole series, the highest multifunctional activity exhibited
inhibition of eeAChE with IC50 value of 2.9 µM and is able compound 27. It inhibited AChE with mixed type of inhibi-
to bind to CAS and PAS of AChE. In addition, it was a selec- tion with IC50 value of 4.91 µM, binding both CAS and
tive Cu2+ chelator in a 1:1 ratio and can pass the BBB in PAS. In addition, it was able to inhibit self-induced and
vitro. The most active against MAO-B was derivative 25b Cu2+-induced Aβ1-42 aggregation by 89.5% and 79.7% at 25
with IC50 value of 6.8 µM., also with ability to cross the μM, respectively, MAO-B with IC50 value of 0.29 µM. The
BBB. The structure-active-relationship indicated that the antioxidative properties of 27 were at the level of 2.83-fold
presence of O-alkylamine moiety contributed decrease poten- of Trolox. Morover, it could chelat metals and cross the
cy of hMAO-B inhibition. BBB in vitro [154].
A novel series of chalcone and tacrine derivatives were On the basis of rivastigmine and caffeic or ferulic acid, a
reported by Wang et al. [155] for AD treatment. Most of the novel group of compounds was designed, synthesized and
analogues in the series, exhibited selective hBChE inhibi- evaluated as MTDLs. The most interesting compound in the
tion. The most potent in the series was compound 28, which series was 33 and inhibited cholinesterase, prevented Aβ
inhibited hAChE and hBChE with IC50 values of 0.87µ and self-aggregation, protected HT22 cells from glutamate and
0.36 µM, respectively, what was better or similar to results H2O2 induced cell death, scavenged free radicals and chelat-
obtained for referenced rivastigmine. Due to multifunctional ed Cu2+ ions [160].
nature of AD, the series were designed as molecules with A reversible hAChE/hBChE inhibitor was an analogue
wide spectrum of biological activity. Compound 28 prevent- of apigenin and rivastigmine, compound 34, which inhibited
ed as well from reactive oxygen species (ROS) in SH-SY5Y these enzymes with IC50 values of 6.8 mM and 16.1 mM, re-
cell line, possessed low cytotoxicity and is in the required 10 spectively. Moreover, it demonstrated remarkable antioxi-
druggability ranges from in silico ADMET prediction. dant activity (ORAC = 1.3 eq), it exhibited neuroprotection
As it was mentioned above, a relevant decrease of of H2O2- induced PC12 cells and Aβ1-42- induced SH-SY5Y
amount of H2S is observed in brains of patients with AD. Al- cells, hepatoprotection of H2O2- induced LO2 (normal hu-
so, a series of rivastigmine connected with ulforaphane man hepatocytes cell line) cells and it was selective metal
(SFN) and erucin (ERN) were synthesized as H2S donors chelator. It also inhibited Cu2+-induced Aβ1-42 aggregation
with antioxidant and neuroprotective activity. Compound 29 (78.9%), hAChE-induced Aβ1-40 aggregation (73.6%) and
proved to be a new well-balanced anti-inflammatory and an- self-induced Aβ1-42 aggregation (77.9%). It could also disag-
tioxidant agent in BV-2 cells. Moreover, it could induce the gregate Cu2+-induced Aβ1-42 aggregation (64.6%) and pass
expression of proteins (i.e. GSH) involved in the antioxidant the BBB in vitro. Compound 34 was selected to in vivo
defense in SH-SY5Y cell line, decrease ROS levels and NO- studies and improved dyskinesia recovery ratio and response
release in microglia BV-2 cells what was not observed for efficiency on AlCl3-mediated AD zebrafish, and showed re-
referenced drug, rivastigmine [156]. markable neuroprotective activity against Aβ1-40-induced vas-
Another approach is synthesis and evaluation of cular injury. It also did not exhibit acute toxicity at dose up
AChE/BChE inhibitory potential, metal chelating activity to 2000 mg/kg, and could improve scopolamine-induced me-
and neuroprotection against hydrogen peroxide (H2O2)-in- mory impairment. The metabolism of 34 in vitro revealed
duced PC12 cell injury of novel scutellarein rivastigmine that 4 metabolites in rat liver microsome metabolism, 2
derivatives. The most interesting compound in the series metabolites in human liver microsome metabolism, and 4
was mixed-type inhibitor, compound 30 which inhibited metabolites in intestinal flora metabolism, which offered sup-
AChE and BChE with IC50 values of 0.57 and 22.6 µM, re- ports for the preclinical study of this derivative, what makes
spectively and could bind to both CAS and PAS. It showed it promising MTDL against AD [161].
antioxidative activity at the level of 1.3-fold of Trolox. In ad- Krátký et al. [162] reported synthesis of series of 4-
dition, it was selective metal chelator and neuroprotector chlorophenyl N-substituted carbamates 5 from isocyanates
against mentioned above H2O2-induced PC12 cell injury. and evaluated obtained compounds towards eeAChE/e-
Moreover it could pass the BBB in vitro and showed rele- qBChE inhibitory activity. They demonstrated not selective
vant neuroprotective effects in scopolamine-induced cogni- inhibition. Only some of them were more active than refer-
tive impairment in mice model [157]. enced drug, rivastigmine. Based on SAR analysis, it was
found out neither the halogenation of the salicylanilide nor
Nesi et al. [158] combined a rivastigmine with natural the presence of 2-phenylcarbamoyl moiety is required for
antioxidant moieties such as gallic acid (GA), lipoic acid the potent inhibition of AChE.
(LA) and 2-chromonecarboxylic acid (CCA) to get potential
cholinesterase inhibitors with neuroprotective activity. LA CONCLUSION
derivatives 31a-c revealed the highest BChE inhibitory activ-
ity with IC50 values in the range of 340 – 378 nM and Despite extensive knowledge of AD, the etiology and
cause of it are still not clear, which has an impact on the
pleiotropic activities. Analogues 31d-f were able to protect
lack of effective therapy that could stop the progression of
from the self-mediated Aβ aggregation with percentages
the disease. Many years of work on obtaining an active, mul-
of inhibition from 53% to 59%. Compounds 31e,f showed
tifunctional and free of side effects substance that could treat
neuroprotective effect in HT22 cells against glutamate-in-
AD has resulted in the publication of numerous scientific pa-
duced neuronal death. pers that are a source of valuable knowledge for the world of
Rivastigmine-curcumin hybrids showed high AChE/ science.
BChE inhibitory activity with sub-micromolar IC50 values. Herein, we have supplied the previous review article
The most active compound 32 was 20-times stronger (IC50 = with the latest tacrine analogues from 2017, as well as with
0.097 µM) than referenced rivastigmine and prevented the donepezil and galantamine from 2015. Moreover, we have
Aβ self-aggregation in TEM assay. In addition, the hy- reviewed rivastigmine derivatives from the last six years.
drolysate of 32 revealed potent ABTS+ scavenging and and We clearly described tacrine conjugates with e.g. de-
was able to chelat Cu2+ ions in moderate range [159]. ferasirox, pyridinium, thienopyridine, phenolic acid, vanilli-
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Therapeutic Potential of Multifunctional Derivatives of Cholinesterase In-

1. INTRODUCTION being responsible for diverse brain activity. Cholinergic neu-

1570-159X/21 $65.00+.00 © 2021 Bentham Science Publishers

Fig. (1). Chemical structures of tacrine, donepezil, rivastigmine and galantamine.

2a-d: excellent metal chelating properties. 2a,b: inhibitory potency against

Promising in vivo AChE inhibition

Inhibitory potency against PAS and AChE-induced Aβ aggregation, ability to

Inhibitory potency against Aβ self-aggregation at the level of 47% at 20 µM,

Neuroprotective activity towards SH-SY5Y cells against rotenone plus oli-

7 7b,c,f: neuroprotective activity on SH-SY5Y cell line [88]

Antioxidant properties, inhibition of Aβ1-42 aggregation, neuroprotection of SH-

Inhibition of self-/Cu-induced Aβ aggregation, radical scavenging capacity and

Inhibition of Aβ self-aggregation amelioration, the impairment of memory in

11 Inhibition of Aβ aggregation [100]

12 Antioxidant activity and neuroprotection against Aβ1-40 in SH-SY5Y cells [101]

Improvement of cognitive and locomotor activity in a mouse model with AD

Inhibition of Aβ42 self-aggregation, neuroprotection in rats neurons in a serum

15 Ability to cross the BBB in vitro [120]

Inhibition of hMAO A, and MAO-B,

Inhibition of MAO-B and

Inhibitory activity against hMAO-B, self-induced and hAChE-induced Aβ ag-

Anti-inflammatory properties in vivo in mice model, antioxidant activity in

ADME profile in silico, anti-inflammatory and neuroprotective activity against

Inhibitory activity against BACE1 and Aβ1−42 aggregation,

Inhibitory activity against Aβ self-aggregation and Cu2+-induced Aβ aggrega-

26 Inhibition of PDE9A [153]

Ability to inhibit self-induced and Cu2+-induced Aβ1-42 aggregation, inhibitory

28 Prevention from ROS in SH-SY5Y cell line [155]

Anti-inflammatory and antioxidant activity in BV-2 cells, the induction of pro-

Antioxidative activity, selective metal chelator and neuroprotector against

31a-c: pleiotropic activities

Prevention of Aβ self-aggregation in TEM observation, ABTS+ scavenging,

Prevention of Aβ self-aggregation, protection of HT22 cells from glutamate

Antioxidant activity, neuroprotection of H2O2- induced PC12 cells and Aβ1-42-

2.1. Tacrine Analogues Wang et al. [81] synthesized a series of hybrids of

na, deferiprone, or also indole-3-acetic acid. Many of them REFERENCES

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