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Received: 20 December 2018 Revised: 2 July 2019 Accepted: 22 July 2019

DOI: 10.1002/ddr.21587

OVERVIEW

Natural products and their derivatives as multifunctional


ligands against Alzheimer's disease

Pooja Patil1,2 | Ashima Thakur1 | Abha Sharma1 | Swaran Jeet Singh Flora1

1
Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Abstract
Research (NIPER) Raebareli, Lucknow, Uttar Alzheimer's disease (AD), a complex neurodegenerative disorder causing multiple cellular
Pradesh, India
2 changes including impaired cholinergic system, beta-amyloid (βA) aggregation, tau hyper-
Department of Pharmacology & Toxicology,
National Institute of Pharmaceutical Education phosphorylation, metal dyshomeostasis, neuroinflammation, and many other pathways
and Research (NIPER) Raebareli, Lucknow,
are involved in the pathogenesis of the disease. However, the exact cause of the disease
Uttar Pradesh, India
is not known. Natural products such as flavonoids, alkaloids, resveratrol, and curcumin
Correspondence
have multifunctional properties, and have drawn the attention of the researchers because
Abha Sharma and Swaran Jeet Singh Flora,
Department of Medicinal Chemistry and these molecules are capable of interacting concurrently with the multiple targets of AD.
Department of Pharmacology & Toxicology,
Therefore, natural products and their derivatives with proven efficacy could be used in
National Institute of Pharmaceutical Education
and Research (NIPER) Raebareli, Lucknow the management of the neurodegenerative disorders. This review focuses on the natural
Campus, Sarojini Nagar, Lucknow 226 002,
product based multitarget directed ligands like tacrine-coumarin, tacrine-huperzine A,
UP, India.
Email: sjsflora@hotmail.com; harmine-isoxazoline, berberine-thiophenyl, galantamine-indole, pyridoxine-resveratrol,
abha.sharma@niperraebareli.edu.in
donepezil-curcumin and their mode of action.

KEYWORDS
Alzheimer's, alkaloid, flavonoid, multitarget ligand

1 | I N T RO D UC T I O N formation of an extracellular accumulation of senile plaques and intra-


cellular neurofibrillary tangles. There are no medications for the cure
Alzheimer's disease (AD) was discovered by Dr. Alois Alzheimer in and halting the progression of AD. Existing drugs only temporarily
1906, which is an age-related progressive, chronic, and irreversible relieve symptoms by either inhibiting the enzyme acetylcholinesterase
neurodegenerative disease. In AD, cortex and hippocampus are or antagonize N-methyl-D-aspartate receptor. Consequently, treat-
affected, which leads to progressive memory loss, cognitive and lan- ment fails and eventually cognitive function of the patient deterio-
guage impairment that usually starts slowly and gets worse over time. rates (Van der Mussele et al., 2014). However, the development of
The common early symptom is short-term memory loss and with the more efficacious therapies for AD is challenging because of complex
progression of the disease, some other problems are visible including etiology. Many newly designed molecules have entered clinical trials
disorientation, lack of self-care, lose the ability to communicate, but their failure has made researchers to reexamine the etiology of
behavioral issues, mood swings, and motivational loss. In the final AD. The multifaceted nature of AD suggests for synthesizing
stage of the disease, condition of the patient gets worse, withdraws multifunctional molecules which are capable of interacting with multi-
himself/herself from the family and society and eventually leads to ple targets. In this direction, designing multitarget directing ligands
paralysis and death (Alzheimer's Association, 2017). The actual cause (MTDLs) has gained attention for the development of novel molecules
of AD is not clearly understood. However, causes could be genetic, against AD. Using the MTDL strategy, a variety of hybrid compounds
history of head injuries, depression, or hypertension that facilitates targeting more than one pathway involved in AD pathogenesis has
pathogenesis (Li et al., 2017; Van der Mussele et al., 2014). Early been reported (Savelieff et al., 2018). This review highlights some
symptoms of AD are considered as the early signs of normal aging. recent advances in development of natural products based MTDLs as
The apparent changes observed in AD patient's brain are the promising drug candidates for the treatment of AD.

Drug Dev Res. 2019;1–19. wileyonlinelibrary.com/journal/ddr © 2019 Wiley Periodicals, Inc. 1


2 PATIL ET AL.

2 | PATHOPHYSIOLOGY formation of insoluble βA peptide via cleavage of APP is one of the


causative factors implicated in AD pathogenesis.
Several hypotheses have been put forward that explain the AD
pathology, nevertheless the exact pathophysiology is poorly under-
2.3 | Tau hypothesis
stood and it remains complex (Cummings, Lee, Ritter, & Zhong, 2018).
A few of the proposed hypotheses are as follows. Tau protein (τ) is a phosphoprotein, which exists in six isoforms con-
sisting of amino acids 352–441 with 38 phosphorylation sites. Brain
tau protein comprises projection and the microtubule-binding domain.
2.1 | Cholinergic hypothesis
Moreover, the projection domain is further divided into two regions:
Cholinergic neurotransmission plays an important role in the cognitive the proline-rich region and acidic residues rich amino-terminal region.
function, cortical plasticity, regulating the sleep–wake cycle, controlling The microtubule binding domain is also divided into two regions:
cerebral blood flow, and cortical activity. Studies have shown that the tubulin-binding region and the acidic carboxy-terminal region
cholinergic system is also involved in learning and memory, and, (Cummings et al., 2018). Tau protein is a highly soluble neuronal
therefore, impairment in the cholinergic system may lead to the microtubule-associated protein (MAP). Phosphorylated tau protein
loss of memory. Neuronal loss in the basal forebrain and in the hippo- interacts with tubulin to stabilize axonal microtubule assembly and is
campus region is significant in AD (Birks & Harvey, 2006; responsible for intracellular trafficking (Jakob-Roetne & Jacobsen,
Francis, Palmer, Snape, & Wilcock, 1999). The acetylcholine (ACh)
2009). Abnormal hyperphosphorylation of tau occurs by kinases such
released within the synapses during cholinergic neurotransmission.
as cyclin-dependent kinase-5 (Cdk5), glycogen synthase kinase-3β
Two enzymes-acetylcholinesterase (AChE) and butyrylcholinesterase
(GSK-3β), Ca2+/calmodulin activated protein kinase II, casein kinase I
(BuChE) are involved in hydrolysis of acetylcholine which lead to the
and dual specificity tyrosine phosphorylation regulated kinase 1A
signal termination. Unaltered or increased BuChE activity has been
(DYRK1A). The abnormal phosphorylation of tau results in the conver-
found in certain AD patients. AChE is also associated with the forma-
sion of normal tau into paired helical filament tau (PHF-tau) and neu-
tion of neurotoxic βA fibril that is, AChE induced βA aggregation leads
rofibrillary tangles (NFTs). Destabilization of microtubule by
to the progression of AD (Jiang, Gao, & Turdu, 2017). Therefore, the
hyperphosphorylated tau finally causes nerve cell death. Compared to
inhibition of AChE and BuChE is considered as a promising strategy for
the normal brain, the level of hyperphosphorylated tau in the brain of
the treatment of AD (Jiang et al., 2017).
a AD patient was three to four times higher (Savelieff et al., 2018).

2.2 | Amyloid hypothesis


2.4 | Neuroinflammation
β-amyloid precursor protein (APP) is a type I transmembrane
Increased levels of microglia and astrocytes lead to chronic neu-
sialoglycoprotein encoded by a single gene present on 19 exons con-
roinflammation due to the release of proinflammatory cytokines, like
taining chromosome 21. APP exists in three isoforms—APP695,
interleukin-1β, tumor necrosis factor α (TNF-α), and interferon-γ
APP751, and APP770. The main functions of APP are helping in neu-
which affects the brain tissues and these were detected in AD
rite outgrowth, modulation of synaptic plasticity, helps in cell adhe-
patients. Reactive oxygen species (ROS) which can stimulate
sion, and stabilizing intracellular calcium level. The soluble form of
APP shows both neurotrophic and neuroprotective properties γ-secretase activity that cleave APP to form a βA peptide (Savelieff

(Villaflores, Chen, Chen, Yeh, & Wu, 2012). The processing of APP et al., 2018). Thus, anti-inflammatory approaches have been used for

comprises two pathways—nonamyloidogenic and amyloidogenic. The the development of novel molecules which can be used for the treat-

primary pathway produces soluble βA peptide and C-terminal frag- ment and prevention of AD (Qu, Mossine, Cui, Sun, & Gu, 2016).

ment α via cleavage by enzyme α-secretase at Lys16 of the APP.


Then, cleavage of C-terminal fragment α by γ-secretase generates
2.5 | Biometal dyshomeostasis
nonamyloidogenic peptide p3. The APP cleavage by β secretase pro-
duces soluble βA peptides and C-terminal fragment β. The latter is Metals like copper, iron, and zinc play a crucial role in the biologically
cleaved by γ-secretase at multiple sites and produces βA monomers, indispensable processes, by providing stability to protein structures, in
which consists of amino acids in the range of 38–43. Self-assembly of metabolism, act as a catalyst and in cellular signal communication
the βA monomers into the neurotoxic oligomers followed by the for- (Kepp, 2012). Stimulation of free radical formation via the Fenton
mation of fibrillary aggregates initiates a neuronal dysfunction, leading reaction mainly caused by the redox active metals, especially Fe2+ and
to dementia (Lin et al., 2011). The aggregated oligomers further result Cu2+ may lead to increase in oxidation of DNA, proteins, and lipids
in the formation of senile plaques, a characteristic of AD. An increase (Deibel, Ehmann, & Markesbery, 1996; Faller, Hureau, & Berthoumieu,
in the levels of the βA42 peptide was observed in AD patients. Further, 2013). Therefore, dysregulation of biometals leads to a rise in oxida-
genetic studies specify that genes like APOE, PSEN1, and PSEN2 tive stress in a neurodegenerative disease like AD that's why metal
influence βA pathology (Tanzi & Bertram, 2005). Therefore, the chelators could help in the prevention of AD progression.
PATIL ET AL. 3

2.6 | Oxidative stress 2.10 | Monoamine oxidases


ROS includes superoxide anion radical, hydroxyl radical, peroxide, Monoamine oxidases exist in two isoforms (MAO-A and MAO-B) and
hydrogen peroxide hydroxide ion, singlet hydroperoxyl. Endogenously are present on the outer membrane of mitochondria, and are respon-
in the human body, ROS is generated during oxygen metabolism and sible for deamination of melatonin, serotonin, epinephrine, and nor-
cellular signaling. In normal condition, the innate antioxidant system epinephrine which results in the formation of H2O2 and ammonia as
regulates ROS balance (Chen & Zhong, 2014). However, in pathologi- byproducts. The formation of H2O2 may lead to oxidative stress
cal conditions an imbalance between the production and removal of (Bortolato, Chen, & Shih, 2008). Another report has suggested that
ROS occurs, resulting in elevated ROS levels (Sayre, Perry, & Smith, there is a relationship between MAO-B, γ-secretase, and Aβ in neu-
2007). Reports indicate that brain oxidative stress is one of the initial rons (Schedin-Weiss et al., 2017). Therefore, the development of

changes detected in AD pathogenesis, that may play a role in the pro- MAOs inhibitors could be a promising strategy to combat AD.

gression of the disease (Bonda et al., 2011; Greenough, Camakaris, &


Bush, 2013). Particularly, the brain uses more oxygen than other tis- 3 | CURRENT AD THERAPY
sues and undergoes mitochondrial respiration, which increases the
chances to ROS exposure. ROS play a critical role in the accumulation To date, there is no curative or preventive therapy for AD. Five medi-
and deposition of βA as well as protein oxidation, protein nitration, cations have been approved by US Food and Drug Administration
glycoxidation, and lipid peroxidation in AD (Cheignon et al., 2018; Sul- (FDA) for management of AD-tacrine, rivastigmine, donepezil, and
tana & Butterfield, 2008). galantamine are acetylcholinesterase inhibitors (AChEI), while
memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist
(Figure 1). The first FDA approved AChE inhibitor was tacrine which
2.7 | Insulin-degrading enzyme has been banned due to its hepatotoxic effects. It has been found that

Type 2 diabetes (T2D) and brain insulin resistance are considered a in AD there is a reduction in the activity of cholinergic neurons.

risk factor for AD. Studies have shown a relationship between insulin- AChEIs increases the synaptic concentration of ACh by reducing the
rate of hydrolysis of the ACh. Donepezil is approved for the treatment
degrading enzyme (IDE) with βA deposition and tau hyperphos-
of mild to moderate stages of AD (Ansari & Khodagholi, 2013; Cum-
phorylation. Insulin and βA are the two competing substrates of IDE,
mings et al., 2018). Currently AD patients are treated with AChEs
involved in the pathogenesis of AD. Furthermore, the clearance of βA in
inhibitors and NMDA antagonists which alleviate some of the symp-
the brain is associated with an IDE. Therefore, development of IDE acti-
toms of AD (Silva, Reis, Teixeira, & Borges, 2014). Due to the lack of
vators could be one of the possible drugable target in AD (Matioli &
curative efficacy of current AD drugs and complex pathophysiology of
Nitrini, 2015; Pivovarova, Höhn, Grune, Pfeiffer, & Rudovich, 2016;
AD, there is a need for developing new therapeutic agents to
Rom et al., 2019).
treat AD.

2.8 | Homocysteine 4 | N A T U R A L P R O DU C T S
Homocysteine (HCy) is a nonproteinogenic homologue of cysteine,
Epidemiological studies have shown that intake of certain dietary
derived after demethylation of methionine. HCy acts on the glutamate
components reduces the risk of AD, that encourages a researcher to
NMDA receptors leading to glutamate excitotoxicity and resulting in
explore the effects of plant extracts and isolated active constituents
excessive calcium influx, which further leads to neurotoxicity and
(Grant, 2016). On the other hand, a comprehensives study on physico-
finally neuronal death. Elevated levels of HCy are also associated with
chemical and medicinal properties of natural products revealed that
oxidative stress, apoptosis, βA aggregation, and tau protein hyper-
these possess drug-like properties, could cross biological membranes
phosphorylation (Zhuo et al., 2010; Zhuo, Wang, & Praticò, 2011).
and were capable of interfering in protein–protein interactions
(Newman & Cragg, 2016; Williams, Stone, Hauck, & Rahman, 1989).
Natural products are considered as “secondary metabolites” of plants
2.9 | Phosphodiesterases
and usually have molecular weight less than 3,000 Da. A number of
Phosphodiesterases (PDEs) are a class of enzymes which play a role in compounds isolated from various parts of the plant such as roots, rhi-
the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic zome, leaves, and seeds have the ability to prevent the formation of
guanosine monophosphate (cGMP). These monophosphates are the toxic plaques, and enhance the cholinergic signaling (Ansari &
involved in synaptic plasticity and in the regulation of intracellular sig- Khodagholi, 2013; Bui & Nguyen, 2017). Dietary components with
naling cascades. Particularly, changes in expression of PDE4, PDE7, antioxidant properties have the ability to reduce oxidative stress in
and PDE8 are associated with AD (Rabal et al., 2016). Moreover, a the brain. Therefore, the plant products possess multiple pharmaco-
study suggested a link between cAMP-dependent protein kinases and logical activities and have attracted the attention of the scientific
tau protein phosphorylation (J. Shi et al., 2011). community to use these products in the development of molecules
4 PATIL ET AL.

F I G U R E 1 Chemical structures of FDA-approved drugs for AD. (a) Donepezil; (b) Galantamine; (c) Rivastigmine; (d) Tacrine; (e) Memantine.
AD, Alzheimer's disease; FDA, US Food and Drug Administration

for the treatment of various diseases (Silva et al., 2014; Williams, Sor- inhibits AChE with an IC50 of 695.9 nM. One of the derivatives 1c
ribas, & Howes, 2011). showed a binding affinity for NR2B (Ki of 2.9 μM) with neuro-
protective activity (Simoni et al., 2012). Furthermore, novel dual site
binding hybrid of galantamine and indole moiety were synthesized
4.1 | Alkaloids
and docked on the rhAChE. The derivatives 1d–f showed the highest
Alkaloids, a class of nitrogenous organic compounds are predomi- AChE inhibitory activity with IC50 values 0.011 μM, 0.012 μM, and
nantly present in certain families of flowering plants. Some plant spe- 0.015 μM, respectively (Figure 2). In galantamine-indole derivatives,
cies contain only a few kinds of alkaloids, while species like the galantamine moiety interact with the CAS and the indole part
Solanaceae, Papaveraceae, Amaryllidaceae, and Ranunculaceae are binds to the aromatic residues in peripheral anionic site, and these
rich in alkaloids (Ansari & Khodagholi, 2013; Ng, Or, & Ip, 2015). Some derivatives act as dual site binder to the rhAChE enzyme (Atanasova
amphibians like poison dart frog, rodents like new world beaver, and a et al., 2015).
fungus such as ergot also produce alkaloids. Two US FDA approved
AChEIs (Rivastigmine and Galantamine) are alkaloids (Ng et al., 2015;
4.1.2 | Huperzines
Silva et al., 2014; Williams et al., 2011).
Huperzine A and B are lycopodium alkaloids extracted from the Chi-
nese medicinal herb, Huperiza serrata (club moss). This Chinese folk
4.1.1 | Galantamine
medicine was used for the treatment of swelling, confusion, schizo-
Galantamine is an isoquinoline alkaloid isolated from the flowers and phrenia, fever, and strain. Huperzine A is a specific, potent, and
bulbs of Galanthus caucasicus (Caucasian snowdrop), Galanthus reversible inhibitor of AChE and BuChE with IC50 of 0.82 nM and
sworonowii (Voronov's snowdrop), Leucojum aestivum (snowflake), and 74.43 nM, respectively (Table 1, 2a) (Bai et al., 2000; Liu et al., 1986).
Lycoris including Lycoris radiate (red spider lily), belong to family Huperzine B is also a reversible inhibitor of AChE with IC50 of
Amaryllidaceae (Harvey, 1995). Galantamine increases ACh levels in 14.3 μM (Table 1, 2b) and exhibits a higher efficacy (Shi et al., 2009).
the synaptic cleft by competitive inhibition of AChE, and also acts as Therefore, Huperzine A and B are widely used as natural moieties
an allosteric modulator of nicotinic acetylcholine receptor (nAChRs) for designing more potent AChEIs. Novel tight-binding AChE inhibi-
(Heinrich & Teoh, 2004; Woodruff-Pak, Vogel, & Wenk, 2001). Sev- tors comprising carbo-bicyclo substructure of Huperzine A and
eral derivatives of galantamine were synthesized by linking them with 4-aminoquinoline substructure (from tacrine) with various substitu-
memantine with linkers of different lengths and compositions. These ents have been proposed as promising AChE inhibitors (Table 1, 2c
were evaluated as AChE inhibitors, NMDAR binders, and also for and 2d) (Camps et al., 2000). Tacrine–Huperzine A hybrid (Huprines)
selectivity toward the 2B subunit (NR2B) of NMDAR. It was found are more potent than (−)-huperzine A and tacrine alone (up to
that derivative 1a inhibits AChE with an IC50 of 0.52 nM. Derivative 13-folds and 25-folds, respectively). Among the substituted deriva-
1b act as a NMDAR antagonist with a Ki value of 2.32 μM, and also tives, the most active derivatives containing chlorine at position 3 and
PATIL ET AL. 5

FIGURE 2 Galantamine based molecules for AD. AD, Alzheimer's disease

position 9 with either methyl or ethyl group (Camps et al., 2000). A interactions with the PAS of AChE thus acting as a dual site inhibitor.
series of heterodimers comprising dimethoxyindanone of donepezil Among the substituted derivatives, compound 2m exhibits potent
and pyridone of huperzine A are bonded by a varying length of methy- inhibitory activity against hAChE, hBuChE, BACE-1 (with IC50 values
lene linker, have been reported as promising AChE inhibitors with 2.39 nM, 513 nM, 80 nM, respectively) along with 43% inhibition of
potential interest for treating AD. The compound 2e with a tetram- Aβ42 aggregation at 10 μM, therefore, compound 2m could be a prom-
ethylene linker was found as the most potent AChE inhibitor with ising disease modifying anti-Alzheimer's drug candidate (Viayna
IC50 of 9 nM (Hu et al., 2013). Novel huperzine A and imine deriva- et al., 2014).
tives (Table 1 compounds 2f, 2g, 2h, and 2i) with additional small
substituted aromatic ring show effective inhibition of hAChE in the
4.1.3 | Berberine
nanomolar range. The aromatic ring of Huperzine A derivatives shows
the π-π stacking with amino acid residues of AChE. The derivatives 2f, Berberine is a benzylisoquinoline alkaloid usually found in roots, rhi-
2g, 2h, and 2i were approximately 865-fold, 1,065-fold, 477-fold, and zomes, stems, and bark of plants such as Berberis spp., Coptis chinensis,
517-fold more active than the parent Huperzine A, respectively (Yan Hydrastis canadensis, and Phellodendron amurense. It has potent antiox-
et al., 2009). idant, anti-inflammatory, antitumor, and antimicrobial effects, along
Furthermore, novel Huperzine B derivatives were rationally with cardioprotective and neuroprotective properties (Imanshahidi &
designed, in which 16 positions of Huperzine B moiety are connected Hosseinzadeh, 2008; Jung et al., 2009; Küpeli, Koş ar, Yeş ilada, &
through a tether chain with the terminal aromatic ring, that favors inter- Baş er, 2002). Berberine inhibits both AChE (IC50 of 0.37) and BuChE
action with the PAS. The derivatives 2j and 2k are more potent AChE (IC50 of 18.21 μM), but is more selective for AChE. Additionally, ber-
inhibitors (480 to 1,360-fold) and also potent BuChE inhibitors (370 to berine has antagonistic activity against NMDA receptor (particularly
1,560-fold) than the parent Huperzine B (Shi et al., 2009). Additionally, NR1), and also blocks the voltage-dependent potassium current, lead-
the compound 2k also possesses neuroprotective property against ing to neuroprotection. Therefore, berberine enhances cholinergic
H2O2 induced cytotoxicity in PC12 cells. The novel dual site binding stimulation and improves cognitive impairment in AD (Durairajan
bis-huperzine B derivative 2l, is found to be the most potent AChE et al., 2012; Kulkarni & Dhir, 2010). Novel dual site binding derivatives
inhibitor (3,900-fold) than parent huperzine B. In compound 2l, the long of triazole and berberine moiety were synthesized and docked on
tether contains two positively charged nitrogen atoms that could inter- TcAChE (Torpedo californica acetylcholinesterase). One of the deriva-
act via hydrogen bond or cation-π interaction with the active site of tives, 3c, in which the 4-position of triazole ring was substituted with
AChE (Feng et al., 2005). Novel multitarget rhein-huprin hybrids have diisopropylamino, inhibits AChE with IC50 of 0.044 μM. In derivative
been designed in which hydroxyanthraquinone system of rhein are 3d, the 4-position of the triazole ring substituted with butyl inhibits
attached through diverse linkers to a unit of huprin Y. The huprin Y 79% βA aggregation at 20 μM (A. Shi, Huang, Lu, He, & Li, 2011). Fur-
interacts with CAS while the aromatic rings of rhein create π-π stacking thermore, berberine-thiophenyl hybrids were synthesized in which
6 PATIL ET AL.

TABLE 1 Naturally occurring huperzine A, B, and their derivatives as cholinesterase inhibitors

IC50 (nM) Ref.

Compound Structure R and X hAChE hBuChE TcAChE


2a. - 0.82 74.43 11.4 Bai, Tang, and He (2000), Liu et al.
(−)-Huperzine A H
N O

NH2
H

2b H - 14,300 214,000 nd. Liu et al. (1986)


N O
Huperzine B

N H

2c. rac – 2c R R – CH3 0.78 ± 0.02 236 ± 44 nd. Camps et al. (2000)

N Cl

NH2

(−) – 2c 0.03 ± 0.10 247 ± 18 Hu, Zhang, Chandrashankra,


Ip, and Ip (2013)
(+) – 2c 23 ± 18 153 ± 31
2d. rac – 2d R – CH2CH3 0.75 ± 0.06 15.8 ± 2.4
(−) – 2d 0.32 ± 0.09 159 ± 10
(+) – 2d 23.1 ± 2.3 58.3 ± 5.9
2e. (RS,S) H - 9±1 na. nd.
N O
O
O
CH2 NH
O 4

2f R1,R2,R4 – H 31 nd. 0.0246 Yan et al. (2009)


R2 R1 R3 – OCH3
N
R3 CH NH

R4 O

2g R1, R3 – H 29 0.02
R2,R4 – OCH3
2h R2,R4 – H 84 0.0446
R1,R3 – OCH3
2i R1,R2,R4 – H 22 0.0412
R3 – CN
2j CH3 CH3 X R–F nd. nd. 29.7 Shi et al. (2009)
N CH3 N R X – CH
10
H
N O

N H

2k R–H 10.5
X–N
2l - nd. nd. 4.93 ± 0.23 Feng et al. (2005)
2m OH O OH - 2.39 513 - Viayna et al. (2014)

NH O
9
NH Cl

N
PATIL ET AL. 7

FIGURE 3 Berberine based design of multitarget molecules for AD. AD, Alzheimer's disease

FIGURE 4 Harmine modified multifunctional molecules

FIGURE 5 Structural modification of aporphine alkaloids

the oxygen or NH group of the berberine derivatives was replaced 4.1.4 | Harmine
with a sulfur atom, resulting in enhancement of antioxidant proper-
Harmine belongs to the β-carboline alkaloid family, isolated from the
ties. Among the hybrids, compound 3a berberine was coupled with o-
South American vine Banisteriopsis caapi and structurally consists of a
methylthiophenyl by an ethylene spacer, and was found to be a
potent inhibitor of AChE (IC50 of 0.077) than BuChE (IC50 of indole and a pyridine core (He et al., 2015; Tahtouh et al., 2012). Harmine

1.360 μM). 3b derivative of berberine with o-chlorothiophenyl was has antifungal, antimicrobial, antiplasmodial, antioxidative properties,
found not only as a potent AChE inhibitor (IC50 of 0.042 μM) but also and inhibitor of DYRK1A (He et al., 2015; Smith, Medda, Gokhale,
as a potent BuChE inhibitor (IC50 of 0.662) (Figure 3). These hybrids Dunckley, & Hulme, 2012; Ting et al., 2013). Additionally, Harmine 4a is
also inhibit βA aggregation and have antioxidant properties also a more potent inhibitor of tau protein hyperphosphorylation and
(Su et al., 2013). also inhibits the DYRK1A-catalyzed direct phosphorylation of tau at
8 PATIL ET AL.

TABLE 2 Effect of polyphenols on the various pathological pathways involve in AD

Polyphenol class Example and source Influence on AD Reference


Phenolic acids Gallic acid (tea, clove, grapes, Prevents the production of βA in AD mice by Hong, Jeong, and Jun
strawberries) antioxidation and improves cognition in AD rat and (2012), Nerurkar et al.
suppresses apoptosis. (2011)
Caffeic acid (tea, coffee, red Inhibits AChE and βA aggregation; improves memory Chao et al. (2012)
wine, eucalyptus bark) deficits in the mouse model by enhancing choline
acetyltransferase (CAT) and superoxide dismutase
(SOD) activity; promotes antioxidant activity by
inhibition of lipid peroxidation. Inhibit production of
nitric oxide.
Curcumin (turmeric) Inhibits lipid peroxidation and AChE, enhance Ahmed, Enam, and Gilani
cognition, GSH and glial fibrillary acidic protein (2010), Ahmed and
(GFAP) and inhibit βA aggregation in a mouse model; Gilani (2009), Wang
modulates NMDA receptor. et al. (2013)
Flavones Apigenin (celery) Suppresses MAPK signaling in neuroblastoma cell line Zhao, Wang, Liu, et al.
“SH-SY5Y.” Prevents oxidative stress and inhibits (2013), Zhao, Wang,
self and Cu2+ induced βA aggregation. Cause Wang, and Fa (2013)
improvement in learning and memory in APP/PS1
double transgenic AD mice.
Luteolin (celery, thyme, Inhibits ChE's and β-secretase, prevents βA formation Choi et al. (2014), Xu et al.
green peppers, and and down regulates APP expression. Reduces Aβ (2014), Zheng, Yuan, Li,
chamomile tea) aggregation, tau hyperphosphorylation, Wu, and Huang (2015)
inflammatory mediators, GSK-3 activation,
suppresses neuronal apoptosis by reducing
intracellular ROS generation, increases SOD activity.
Isoflavones Genistein (soybeans) Inhibits NF-κB, JNK, and ERK signaling pathways in rat Qian et al. (2015), Zeng,
against H2O2-induced cellular damage. Inhibits βA Chen, and Zhao (2004),
aggregation. Zhao et al. (2014)
Flavonols Quercetin (tea, onions, Inhibits βA aggregation, tau hyperphosphorylation, Li et al. (2015),
apples, berries) increases the activity of adenosine Sabogal-Guáqueta et al.
monophosphate-activated protein kinase resulting in (2015), Zhang, Su, Wang,
the enhancement of cognition in transgenic AD mice Zhu, and Li (2014)
model. Scavenges ROS and enhances SOD activity
indicating antioxidant activity.
Kampferol (tea, leek, tomato) In mice inhibits βA plaques and reverses βA-induced Ono et al. (2003)
impaired performance.
Flavanones Naringenin (Centella asiatica, AChE inhibitory activity, prevents βA toxicity and Heo, Kim, Shin, et al.
citrus fruits) antioxidant activity. (2004), Heo, Kim, Lee,
et al. (2004)
Chalcones Butein (Chinese lacquer tree) Inhibits neuroinflammatory mediators and enhances Lee and Jeong (2016)
GSH thus providing neuroprotection against
oxidative stress.
Phloridzin (apple) Induces ROS scavenging activity and enhances SOD. Bhullar and Rupasinghe
(2013), Ghumatkar et al.
(2018)
Flavanols (monomer) Catechin, Epicatechin, Acts as an antioxidant, memory enhancer, a metal Lee et al. (2009), Mandel,
Gallocatechin, chelator, has anti-inflammatory and Amit, Kalfon,
Epigallocatechin gallate antiamyloidogenic activities by increasing Reznichenko, Weinreb,
(chocolate, bitter melon, α-secretase, and decreasing β and γ-secretase. and Youdim (2008),
green tea) Mandel, Amit, Kalfon,
Reznichenko, and
Youdim (2008), Mandel,
Amit, Weinreb,
Reznichenko, and
Youdim (2008)
Stilbenes In βA25-35 induced mice significantly improves
cognition while increasing ChAT, antioxidant
(Continues)
PATIL ET AL. 9

TABLE 2 (Continued)

Polyphenol class Example and source Influence on AD Reference


Reservatrol and Piceatannol properties, inhibits βA aggregation, reduces toxicity Kim, Lee, Kim, and Lee
(red wine, raps, peanuts, and suppresses cellular apoptosis. (2008), Ruan et al.
and cranberry) (2009)

Flavanols (polymer) Tannic acid, Suppresses oxidative stress; inhibit tau aggregation; Vepsäläinen et al. (2013)
Proanthocyanidins enhance learning and cognition in mice.
(persimmon, cinnamon,
grape, blueberry,
blackcurrant)

FIGURE 6 Classification of flavonoids and their chemical structures

Ser396 with IC50 of 700 nM. In addition, harmol 4b and 9-ethylharmine telomerase cholinesterase, and βA aggregation, along with antioxidant
4c gave improved IC50 values of 90 nM and 400 nM, respectively. capacity, immunoregulation, and antitumor activity (Himeno et al., 2011;
Harmine inhibits AChE with an IC50 of 9.0 μM (Smith et al., 2012). A Tang et al., 2007). The position of a nitrogen atom in the pharmacophore
series of harmine-isoxazoline derivatives were synthesized, out of which only distinguishes between oxoaporphine and oxoisoaporphine alkaloids
the phenyl substituted derivative 4d has good AChE inhibitory activity that is, oxoaporphine commonly known as 1-azabenzanthrone while
but it is less potent than harmine 4a (Figure 4) (Filali, Bouajila, Znati, oxoisoaporphine is known as 6-azabenzanthrone. The synthetic
Bousejra-El Garah, & Ben Jannet, 2015).
oxoisoaporphine derivatives are potent AChE inhibitors (5a, 5b with IC50
of 4.8 × 10−4 ± 0.8 at 10−4 μM and 2.62 × 10−3 ± 0.2 at 10−3 μM,
respectively) (Tang et al., 2009). The synthetic oxoaporphine derivatives
4.1.5 | Aporphine alkaloids
5c and 5d (IC50 of 0.35 μM and 0.11 μM, respectively) are twofold to
Aporphine alkaloids have a tetrahydroisoquinoline substructure and threefold less potent AChE inhibitors than oxoisoaporphine derivatives.
belong to the isoquinoline class of alkaloids. They are isolated from the The molecular modeling study depicts that the 1-azabenzanthrone moi-
rhizome of Chinese medicinal herb, Menispermum dauricum (Tang et al., ety of the oxoisoaporphine alkaloids could bind to Trp279 residue of PAS
2007, 2009). Aporphine alkaloids, such as oxoisoaporphine and of AChE by π-π stacking interaction. The water solubility and selectivity
oxoaporphine show diverse biological properties for example inhibit of oxoisoaporphine alkaloid toward AChE were greatly improved by
10 PATIL ET AL.

FIGURE 7 Designing multifunctional molecules based on the molecular scaffold of (a) flavones; (b) isoflavones; (c) flavanones

introducing amines or ammonium groups as a spacer (Tang et al., 2009). selectivity ratio (1,850-fold). The synthesized cationic compounds 5f
A new series of oxoisoaporphine-tacrine hybrid connected via an and 5g with quaternary nitrogen as the basic side chain showed higher
amino alkyl tether were synthesized. Among hybrids, 5e was found AChE inhibitory activity at 1.06 nM and 1.08 nM, respectively, as com-
31-fold more potent eeAChE inhibitor (IC50 value 3.4 nM) than tacrine, pared with the corresponding nonquaternary nitrogen compounds 5h
and also displayed activity against EqBuChE with IC50 of 110 nM. All and 5i with AChE inhibitory effect of 6.18 nM and 2.47 nM, respec-
the new derivatives exhibited the βA antiaggregating activity; potent tively (Figure 5) (Tang et al., 2007). Yang et al. (2012) reported isolation
inhibitor of the self-induced βA aggregation at 10 μM (35.5–85.8%) and of aporphine alkaloids, namely, N-methylasimilobine, nuciferine, and
also inhibit AChE-induced βA aggregation at 100 μM (Tang et al., nornuciferine from Nelumbo nucifera and tested them against AChE
2011). A series of oxoisoaporphine derivatives linked to a diverse basic inhibition. N-methylasimilobine showed 50% inhibition of AChE at con-
side chain at 9-position were synthesized and evaluated for AChE inhi- centrations of 1.5 ± 0.2 μg ml−1 in reversible and noncompetitive
bition, all the derivatives showed IC50 values in the nanomolar range. mode. Eight derivatives of nuciferine were synthesized by dealkylation
The compound 5f with pyrrolidine as the basic side chain, exhibited (at oxygen and nitrogen), and ring aromatization reactions.
potent AChE inhibition (IC50 of 1.06 nM) and also had the highest 1,2-Dihydroxyaporphine and dehydronuciferine derivatives were
PATIL ET AL. 11

FIGURE 8 Chalcones based multifunctional molecules

found AChE inhibitors with an IC50 of 28 and 25 μg/ml, respectively structural features of the C ring (Figure 6) (Panche, Diwan, & Chandra,
(Yang et al., 2014). 2016; Savelieff et al., 2018).

5.1 | Flavones
5 | FLAVONOIDS
Flavones are mainly present in leaves, flowers, and fruits, and show
inhibitory effect on advanced glycation end products (AGEs) and also
Flavonoids are group of polyphenolic phytonutrients, found in almost
anti-inflammatory, antioxidant, and neuroprotective activities. A series
all fruits, flowers, seeds, and vegetables. They are more common in
of analogs of flavones acts as promising anti-Alzheimer agents have
higher plants being abundant in families like Polygonaceae, Rutaceae,
been reported (Cruz et al., 2017; F. Li et al., 2017; Li, Wang, Hu, &
Leguminosae, Umbelliferae, and Compositae (Ansari & Khodagholi,
Kong, 2013; Luo et al., 2013; Panche et al., 2016; Shen et al., 2009;
2013; Savelieff et al., 2018). Due to their polyphenolic nature, they
Sheng, Lin, Zhang, Chol, & Huang, 2009; Singh, Kaur, Singh, & Silakari,
have the ability to scavenge free radicals, hydrogen peroxide, and
2017; Singh & Silakari, 2016). Figure 7 shows a few derivatives based
superoxide radical and therefore are neuroprotective (Bui & Nguyen,
on flavones scaffold.
2017; Silva et al., 2014). Free radical scavenging property of polyphe-
nols varies with the number and position of the hydroxyl groups.
Table 2 includes the effect of polyphenols on various causative factors 5.2 | Isoflavones
of AD. Therefore, a novel series of flavonoid derivatives were devel- Isoflavonoids are commonly found in leguminous plants, for example,
oped because of their antioxidant properties (Silva et al., 2014). soybeans, also isolated from microbes. They act as precursors for the
Flavonoids can be subdivided into different subgroups depending synthesis of phytoalexins during plant–microbe interactions. A series
on the position of B ring on carbon of the C ring, and the degree of of isoflavone analogs has been evaluated for their inhibitory activities
unsaturation and oxidation of the C ring. Isoflavones are those com- against AChE and MAO-B (Figure 7) (Feng, Li, Xia, & Wu, 2017; Liu
pounds in which the B ring is attached in position 3 of the C ring that et al., 2017).
is, 3-phenylchromen-4-one structure. In the case of neoflavonoids, B
ring is attached in position 4 of C ring that is, 4-phenylcoumarine
5.3 | Flavanones
structure. While in case of the following subgroups: flavones, flavo-
nols, flavanones, flavan-3-ol or flavanols or catechins and chalcones, Flavanones (e.g., hesperetin) are another important subgroup of flavo-
the B ring is attached to position 2 of C ring; only differs in the noids, found in all citrus fruits such as oranges, lemons, and grapes.
12 PATIL ET AL.

FIGURE 9 Coumarin based MTDL. MTDL, multitarget directing ligands

They possess free radical scavenging properties, and also anti-inflam- biological activities. The molecular modeling studies show that it binds
matory, blood lipid-lowering, and cholesterol-lowering properties. with PAS of AChE and acts as a potent inhibitor of AChE and also
Therefore, the use of flavanones for the synthesis of MTDL has inhibits the βA aggregation (Sheng et al., 2009). A new series of the
increased (Sheng et al., 2009). tacrine-coumarin hybrid is reported in which both scaffolds were
linked by a piperazine-based alkyl spacer (Figure 9). The derivative
10a has potent inhibitory activity against EeAChE (IC50 of 0.092 μM)
5.4 | Chalcones
and moderate for EqBuChE (IC50 of 0.234 μM), βA antiaggregation
Chalcones are one of the subgroups of flavonoids, known as open- properties (67.8% inhibition at 20 μM) and also has Cu2+ and Fe2+
chain flavonoids because of the absence of ring C of the basic flavo- metal chelating ability due to its amide linkage (Xie, Wang, Li, Yang, &
noid skeleton structure (Figure 6). They are present in major amounts Kong, 2013). Further, the coumarin moiety linked with thiourea, (com-
in tomatoes, pears, strawberries, bearberries, and certain wheat prod- pound 10b) was found the most potent AChE inhibitor with IC50 value
ucts. Chalcones and their derivatives (Figure 8) have generated inter- of 0.04 μM (Saeed et al., 2015). In coumarin based MTDL derivatives
est in researchers as anti-Alzheimer's agents because of the large (10c and 10d), the 6- and 7-positions of coumarin are linked with alkyl
number of biological benefits they provide (Duan, Liu, Fan, Zhang, & spacer of different lengths with terminal diethyl amino group which
Wang, 2014; Fosso, LeVine, Green, Tsodikov, & Garneau-Tsodikova, leads to human AChE inhibition at nanomolar concentration (IC50 of
2015; Liu et al., 2014; Sheng et al., 2009; Xiao et al., 2017). 11.7 nM and 12.9 nM, respectively) along with significant inhibitory
activity toward βA42 self-aggregation around 60% and promising neu-
roprotective behavior, which makes this compounds a potential
5.5 | Neoflavonoids
disease-modifying agent (Saeed et al., 2015). Further, when coumarin
Neoflavonoids are characterized by the presence of a keto group at is attached to the dithiocarbamate moiety, then compound 10e shows
2 and phenyl group at 4 position of C ring (Figure 6). Coumarin is a the best inhibitory activity toward hAChE (IC50 of 0.027 μM) and also
neoflavonoid mainly found in many plants and has a broad range of acts as a βA antiaggregator (40.19% at 25 μM) (Jiang et al., 2018).
PATIL ET AL. 13

FIGURE 10 Multifunctional molecules designed based on the molecular scaffold of resveratrol

Kinetic and molecular modeling studies suggest that compound 10e diverse biological activities such as the anticancer, anti-inflammatory,
was a mixed-type inhibitor; indicating that it could interact with CAS and neuroprotective properties (Ansari & Khodagholi, 2013; Kovacic,
as well as PAS of AChE. Metal chelation study shows that 10e deriv- Weston, & Development, 2017). Resveratrol is an anti-AD agent due
ative selectively chelates Fe 3+
ion (Jiang et al., 2018). Furthermore, to its antioxidant, βA antiaggregation inhibitory, and radical scaveng-
the novel hybrids of N-benzyl pyridinium moiety with coumarin ing activities (Sharma, Pachauri & Flora, 2018; Li et al., 2012; Tu et al.,
were synthesized in which compound 10f showed potent inhibitory 2015; Wang, Ning, Niu, Liu, & Yao, 2015). The stilbene structure of
activity toward eeAChE (IC50 value 37.3 nM), a selective and com- the compound is responsible for its MAO inhibitory activity (Bui &
petitive inhibitor of hMAO-B (IC50 value 1.57 μM) and potent inhibi- Nguyen, 2017; Li et al., 2012). Recently, a series of pyridoxine-
tor of βA aggregation (62.1% at 20 μM). Kinetic and molecular resveratrol derivatives (Figure 10) were established as potent inhibi-
modeling studies show that derivative 10f was a mixed-type inhibi- tors of cholinesterase and also act as an antioxidant and possess metal

tor which interacts simultaneously with CAS and PAS of AChE (Lan chelating properties. The compounds 11a and 11b had a piperidine

et al., 2017). Similarly, N-benzylpiperidine moiety of donepezil has (11a) and diethylamine (11b) substituent, act as potent AChE inhibi-

been reported to combine with coumarin with varying lengths of the tors with IC50 values of 2.11 μM and 1.56 μM, respectively. Derivative

spacer. The compound 10g showed potent inhibitory activity for 11c had morpholine substituent acts as a potent MAO-B inhibitor
with an IC50 value of 2.68 μM. All derivatives exhibited good antioxi-
hAChE (IC50 value 1.37 μM) and selectively inhibited hMAO-B (IC50
dant activity with values of 1.52–2.63 of Trolox eq* at 50 μM. The
of 2.62 μM) and also was nontoxic to SH-SY5Y neuroblastoma cells
compound 6c in which 3- and 4-hydroxy are not free that is, protec-
(Xie et al., 2016). Coumarin-pargyline hybrid 10h selectively inhibits
ted with isopropylidene, was a weaker antioxidant than that of com-
hMAO-B (IC50 value 0027 μM) and is a moderate inhibitor of βA
pounds 11a and 11b. This shows that free hydroxy groups may
aggregation (54% at 25 μM) and caused low toxicity to PC12 cells
contribute toward the antioxidant activity (X. Yang et al., 2017). A
(H.-L. Yang et al., 2017). A series of the novel coumarin-thiazole
series of deferiprone-resveratrol hybrids shows antioxidant activity,
hybrid was synthesized in which the linker between the N-alkyl
causes inhibition of self-induced βA1-42 aggregation, and also has
chains and heterocyclic core is the acetamide moiety. Among this
metal chelating ability due to the incorporation of 3-hydroxypyridine-
series, compound 10i is a potent mixed-type inhibitor of AChE (IC50
4-one as a chelating moiety into the structure of resveratrol. Com-
value 43 nM) (Sonmez et al., 2017).
pounds 11d and 11e, had greater antioxidant properties than Trolox,
and similar pFe(III)** values than deferiprone (Xu, Zhang, Sheng, &
6 | RESVERATROL Ma, 2017). Furthermore, compounds 11d and 11e act as a potent
inhibitor of βA1-42 aggregation (65.30% and 58.43%, respectively)
Resveratrol (3,5,40 -trihydroxystilbene) is a type of natural polyphenol than resveratrol or curcumin due to the introduction of electron
mainly found in foods like peanuts, grapes, red wine, berries and has donating groups such as alkoxy (11d) or hydroxyl (11e) at the
14 PATIL ET AL.

FIGURE 11 Curcumin based multitarget molecules as anti-Alzheimer agents

4 position of the benzene ring of resveratrol. Further, resveratrol- moderately inhibits 31.2% βA42 aggregation at 50 μM, as well has low
clioquinol hybrid and imine-resveratrol analogs act as multifunctional neurotoxicity (Jeřábek et al., 2017).
compounds with metal chelating ability, antioxidant activity and are
inhibitors of both self induced and Cu2+-induced βA aggregation.
Imine-resveratrol hybrid (11f) is a significant inhibitor of self-induced 7 | C U R CU M I N
βA aggregation (64.6% at 20 μM) and it reduced Cu2+ induced aggre-
gation (68.1% at 50 μM) (Li, Wang, & Kong, 2014). As a continuation Curcumin is isolated from the plant Curcuma longa (turmeric) and
of this study, compounds 11g and 11h were found to be potent inhib- belongs to the family Zingiberaceae. Chemically, curcumin is a
itors of self-induced βA aggregation with IC50 values 7.56 μM and diarylheptanoid, also known as diferuloylmethane (Bui & Nguyen,
6.51 μM and also showed antioxidant property (ORAC-FL values are 2017; Silva et al., 2014). Structurally curcumin is an α,β-unsaturated
4.72 and 4.70, respectively) (Lu et al., 2013). In a new series of carbonyl compound with attached planar aromatic ring (Elmegeed,
8-hydroxyquinoline-resveratrol derivatives, (E)-5-(4-hydroxystyryl) Ahmed, Hashash, Abd-Elhalim, & El-Kady, 2015). It possesses a broad
quinoline-8-ol (11i) shows better inhibitory activity against self- range of pharmacological activities including anti-inflammatory, anti-
induced βA aggregation (IC50 value 8.50 μM) and Cu2+-induced βA cancer, antimicrobial, antioxidant, and wound healing effect (Williams
aggregation (Puksasook et al., 2017). Further, a novel series of stilbene et al., 2011). It also exhibits activity against neurological diseases
derivatives, compound 11j, exhibited moderate cholinesterase inhibi- including AD, Parkinson's disease, multiple sclerosis, epilepsy, schizo-
tion activity (AChE, IC50 value 6.55 μM; BuChE, IC50 value 8.04 μM), phrenia, and depression. Curcumin has the ability to inhibit βA aggre-
caused better inhibition of βA42 aggregation (57.78% at 20 μM) and gation (Yanagisawa, Ibrahim, et al., 2015). Due to its wide range of
also caused inhibition of monoamine oxidase (MAO-A, IC50 of pharmacological activities, various curcumin analogs (Figure 11) have
17.58 μM; MAO-B, IC50 12.19 μM), and therefore could be consid- been synthesized and evaluated. The curcumin analogs exhibit inhibi-
ered as a potent anti-AD agent (Pan, Wang, Xie, Li, & Kong, 2014). tory activities against AChE, Tau, βA1-42 aggregation, β-secretase
The tacrine-resveratrol hybrid was synthesized (compound 11k), cleaving enzyme (BACE1) and also some of them have the ability to
which was a potent inhibitor of AChE with IC50 value 8.8 μM, while it scavenge the free radicals and also chelates metal ions (Chen et al.,
PATIL ET AL. 15

2011; Fang, Gou, Liu, Cao, & Cheng, 2014; Konno et al., 2014; Okuda Docking, design, synthesis and acetylcholinesterase inhibitory activity.
et al., 2016; Yan et al., 2017; Yanagisawa, Taguchi, et al., 2015). Biorganic and Medicinal Chemistry, 23(17), 5382–5389.
Bai, D., Tang, X., & He, X. J. C. M. C. (2000). Huperzine A, a potential thera-
peutic agent for treatment of Alzheimer's disease. Current Medicinal
Chemistry, 7(3), 355–374.
8 | CONCLUSION AND FUTURE
Bhullar, K. S., & Rupasinghe, H. (2013). Polyphenols: Multipotent thera-
DIRECTIONS peutic agents in neurodegenerative diseases. Oxidative Medicine and
Cellular Longevity, 891748, 1–18.
Alzheimer's disease is a major health problem of elderly people and Birks, J., & Harvey, R. J. (2006). Donepezil for dementia due to Alzheimer's
many reports indicate that the number of affected population will disease. Cochrane Database of Systematic Reviews, 6, CD001190.
Bonda, D. J., Lee, H.-G., Blair, J. A., Zhu, X., Perry, G., & Smith, M. A. J. M.
increase in coming years. The current drug regimen is not effective in
(2011). Role of metal dyshomeostasis in Alzheimer's disease.
curing the disease. Many natural compounds alone and their combina- Metallomics, 3(3), 267–270.
tion with other drugs are used in AD patients to improve memory and Bortolato, M., Chen, K., & Shih, J. C. (2008). Monoamine oxidase inactiva-
tion: From pathophysiology to therapeutics. Advanced Drug Delivery
cognition. The major limitations associated with natural products are
Reviews, 60(13–14), 1527–1533.
low bioavailability and less clinical efficacy which restrict delivery to Bui, T. T., & Nguyen, T. H. J. (2017). Natural product for the treatment of
the target for exerting their pharmacological effect. Therefore, efforts Alzheimer's disease. Journal of Basic Clinical Physiology Pharmacology,
have been taken to design novel molecules based on natural tem- 28(5), 413–423.
Camps, P., El Achab, R., Morral, J., Muñoz-Torrero, D., Badia, A.,
plates, particularly to develop MTDL for combating multifactorial
Baños, J. E., … Luque, F. J. (2000). New tacrine− huperzine A hybrids
disease and eliminating drawbacks of natural products which is the (huprines): Highly potent tight-binding acetylcholinesterase inhibitors
need of present drug development process. Research shows that nat- of interest for the treatment of Alzheimer's disease. Journal of Medici-
ural products like curcumin, resveratrol, alkaloids, flavonoids, and nal Chemistry, 43(24), 4657–4666.
Chao, X., He, X., Yang, Y., Zhou, X., Jin, M., Liu, S., … Pi, R. (2012). Design,
their derivatives could be useful in alleviating the symptoms of
synthesis and pharmacological evaluation of novel tacrine–caffeic acid
AD. Because of the multifactorial nature of the disease, the molecules hybrids as multi-targeted compounds against Alzheimer's disease.
have been designed on multitarget strategy. Therefore, molecules Bioorganic & Medicinal Chemistry Letters, 22(20), 6498–6502.
capable of modulating multiple targets such as acetylcholinesterase, Cheignon, C., Tomas, M., Bonnefont-Rousselot, D., Faller, P., Hureau, C., &
Collin, F. (2018). Oxidative stress and the amyloid beta peptide in
βA aggregation, tau hyperphosphorylation, metal dyshomeostasis, oxi-
Alzheimer's disease. Redox Biology, 14, 450–464.
dative stress, and many more are needed to slow the progression of Chen, S.-Y., Chen, Y., Li, Y.-P., Chen, S.-H., Tan, J.-H., Ou, T.-M., …
the disease or have the potential to cure AD. Huang, Z. S. (2011). Design, synthesis, and biological evaluation of cur-
cumin analogues as multifunctional agents for the treatment of
Alzheimer's disease. Biorganic and Medicinal Chemistry, 19(18),
ACKNOWLEDGMENT 5596–5604.
Chen, Z., & Zhong, C. (2014). Oxidative stress in Alzheimer's disease. Neu-
The authors Pooja Patil and Ashima Thakur are thankful to Depart- roscience Bulletin, 30(2), 271–281.
ment of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Gov- Choi, J. S., Islam, M. N., Ali, M. Y., Kim, Y. M., Park, H. J., Sohn, H. S., &
Jung, H. A. (2014). The effects of C-glycosylation of luteolin on its
ernment of India for granting fellowship. Communication number is
antioxidant, anti-Alzheimer's disease, anti-diabetic, and anti-
NIPER-R/Communication/066. inflammatory activities. Archives of Pharmacal Research, 37(10),
1354–1363.
Cruz, I., Puthongking, P., Cravo, S., Palmeira, A., Cidade, H., Pinto, M., &
ORCID Sousa, E. J. (2017). Xanthone and flavone derivatives as dual agents
with acetylcholinesterase inhibition and antioxidant activity as poten-
Abha Sharma https://orcid.org/0000-0002-4401-0513 tial anti-Alzheimer agents. Journal of Chemistry, 8587260, 1–16.
Cummings, J., Lee, G., Ritter, A., & Zhong, K. (2018). Alzheimer's disease
drug development pipeline: 2018. Alzheimer's & Dementia: Translational
RE FE R ENC E Research & Clinical Interventions, 4, 195–214.
Deibel, M., Ehmann, W., & Markesbery, W. J. (1996). Copper, iron, and zinc
Ahmed, T., Enam, S., & Gilani, A. (2010). Curcuminoids enhance memory in imbalances in severely degenerated brain regions in Alzheimer's dis-
an amyloid-infused rat model of Alzheimer's disease. Neuroscience, ease: Possible relation to oxidative stress. Journal of the Neurological
169(3), 1296–1306. Sciences, 143(1–2), 137–142.
Ahmed, T., & Gilani, A.-H. (2009). Inhibitory effect of curcuminoids on ace- Duan, K., Liu, H., Fan, H., Zhang, J., & Wang, Q. J. (2014). Synthesis and
tylcholinesterase activity and attenuation of scopolamine-induced anticholinesterase inhibitory activity of Mannich base derivatives of
amnesia may explain medicinal use of turmeric in Alzheimer's disease. flavonoids. Journal of Chemical Research, 38(7), 443–446.
Pharmacology Biochemistry and Behavior, 91(4), 554–559. Durairajan, S. S. K., Liu, L.-F., Lu, J.-H., Chen, L.-L., Yuan, Q., Chung, S. K., …
Ansari, N., & Khodagholi, F. (2013). Natural products as promising drug Li, M. (2012). Berberine ameliorates β-amyloid pathology, gliosis, and
candidates for the treatment of Alzheimer's disease: Molecular mecha- cognitive impairment in an Alzheimer's disease transgenic mouse
nism aspect. Current Neuropharmacology, 11(4), 414–429. model. Neurobiology of Aging, 33(12), 2903–2919.
Association, A.S. (2017). Alzheimer's disease facts and figures. Alzheimer's & Elmegeed, G. A., Ahmed, H. H., Hashash, M. A., Abd-Elhalim, M. M., & El-
Dementia, 13(4), 325–373. Kady, D. S. (2015). Synthesis of novel steroidal curcumin derivatives as
Atanasova, M., Stavrakov, G., Philipova, I., Zheleva, D., Yordanov, N., & anti-Alzheimer's disease candidates: Evidences-based on in vivo study.
Doytchinova, I. (2015). Galantamine derivatives with indole moiety: Steroids, 101, 78–89.
16 PATIL ET AL.

Faller, P., Hureau, C., & Berthoumieu, O. (2013). Role of metal ions in the Imanshahidi, M., & Hosseinzadeh, H. (2008). Pharmacological and thera-
self-assembly of the Alzheimer's amyloid-β peptide. Inorganic Chemis- peutic effects of Berberis vulgaris and its active constituent, berberine.
try, 52(21), 12193–12206. Phytotherapy Research, 22(8), 999–1012.
Fang, L., Gou, S., Liu, X., Cao, F., & Cheng, L. J. (2014). Design, synthesis Jakob-Roetne, R., & Jacobsen, H. (2009). Alzheimer's disease: From pathol-
and anti-Alzheimer properties of dimethylaminomethyl-substituted ogy to therapeutic approaches. Angewandte Chemie International Edi-
curcumin derivatives. Biorganic and Medicinal Chemictry Letters, 24(1), tion, 48(17), 3030–3059.
40–43. Jeřábek, J., Uliassi, E., Guidotti, L., Korábecný, J., Soukup, O., Sepsova, V.,
Feng, B., Li, X., Xia, J., & Wu, S. J. (2017). Discovery of novel isoflavone … Bolognesi, M. L. (2017). Tacrine-resveratrol fused hybrids as multi-
derivatives as AChE/BuChE dual-targeted inhibitors: Synthesis, biolog- target-directed ligands against Alzheimer's disease. European Journal of
ical evaluation and molecular modelling. Journal of Enzyme Inhibition Medicinal Chemistry, 127, 250–262.
and Medicinal Chemistry, 32(1), 968–977. Jiang, N., Huang, Q., Liu, J., Liang, N., Li, Q., Li, Q., & Xie, S.-S. J. (2018).
Feng, S., Wang, Z., He, X., Zheng, S., Xia, Y., Jiang, H., … Bai, D. J. (2005). Design, synthesis and biological evaluation of new coumarin-
Bis-huperzine B: Highly potent and selective acetylcholinesterase dithiocarbamate hybrids as multifunctional agents for the treatment of
inhibitors. Journal of Medicinal Chemistry, 48(3), 655–657. Alzheimer's disease. European Journal of Medicinal Chemistry, 146,
Filali, I., Bouajila, J., Znati, M., Bousejra-El Garah, F., & Ben Jannet, H. J. 287–298.
(2015). Synthesis of new isoxazoline derivatives from harmine and Jiang, Y., Gao, H., & Turdu, G. (2017). Traditional Chinese medicinal herbs
evaluation of their anti-Alzheimer, anti-cancer and anti-inflammatory as potential AChE inhibitors for anti-Alzheimer's disease: A review.
activities. Journal of Enzyme Inhibition and Medicinal Chemistry, 30(3), Bioorganic Chemistry, 75, 50–61.
371–376. Jung, H. A., Min, B.-S., Yokozawa, T., Lee, J.-H., Kim, Y. S., & Choi, J. S.
Fosso, M. Y., LeVine, H., 3rd, Green, K. D., Tsodikov, O. V., & Garneau- (2009). Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma
Tsodikova, S. (2015). Effects of structural modifications on the metal alkaloids. Biological and Pharmaceutical Bulletin, 32(8), 1433–1438.
binding, anti-amyloid activity, and cholinesterase inhibitory activity of Kepp, K. P. (2012). Bioinorganic chemistry of Alzheimer's disease. Chemical
chalcones. Organic and Biomolecular Chemistry, 13(36), 9418–9426. Reviews, 112(10), 5193–5239.
Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999). The cholin- Kim, H. J., Lee, K. W., Kim, M.-S., & Lee, H. J. (2008). Piceatannol attenu-
ergic hypothesis of Alzheimer's disease: A review of progress. Journal ates hydrogen-peroxide-and peroxynitrite-induced apoptosis of PC12
of Neurology, Neurosurgery & Psychiatry, 66(2), 137–147. cells by blocking down-regulation of Bcl-XL and activation of JNK. The
Ghumatkar, P. J., Patil, S. P., Peshattiwar, V., Vijaykumar, T., Dighe, V., Journal of Nutritional Biochemistry, 19(7), 459–466.
Vanage, G., & Sathaye, S. (2018). The modulatory role of phloretin in Konno, H., Endo, H., Ise, S., Miyazaki, K., Aoki, H., Sanjoh, A., … Akaji, K.
Aβ 25–35 induced sporadic Alzheimer's disease in rat model. Naunyn- (2014). Synthesis and evaluation of curcumin derivatives toward an
Schmiedeberg's Archives of Pharmacology, 392, 1–13. inhibitor of beta-site amyloid precursor protein cleaving enzyme 1.
Grant, W. B. (2016). Using multicountry ecological and observational stud- Biorganic and Medicinal Chemistry Letters, 24(2), 685–690.
ies to determine dietary risk factors for Alzheimer's disease. Journal of Kovacic, P., Weston, W. J. N. A. i. D. D., & Development. (2017). Phenolic
the American College of Nutrition, 35(5), 476–489. antioxidants as drugs for Alzheimer's disease: Oxidative stress and
Greenough, M. A., Camakaris, J., & Bush, A. I. (2013). Metal selectivity, 2(5), 555598.
dyshomeostasis and oxidative stress in Alzheimer's disease. Neuro- Kulkarni, S., & Dhir, A. (2010). Berberine: A plant alkaloid with therapeutic
chemistry International, 62(5), 540–555. potential for central nervous system disorders. Phytotherapy Research,
Harvey, A. L. (1995). The pharmacology of galanthamine and its analogues. 24(3), 317–324.
Pharmacology and Therapeutics, 68(1), 113–128. Küpeli, E., Koş ar, M., Yeş ilada, E., & Baş er, K. H. C. J. (2002). A compara-
He, D., Wu, H., Wei, Y., Liu, W., Huang, F., Shi, H., … Wang, C. (2015). tive study on the anti-inflammatory, antinociceptive and antipyretic
Effects of harmine, an acetylcholinesterase inhibitor, on spatial learn- effects of isoquinoline alkaloids from the roots of Turkish Berberis
ing and memory of APP/PS1 transgenic mice and scopolamine- species. Life Sciences, 72(6), 645–657.
induced memory impairment mice. European Journal of Pharmacology, Lan, J.-S., Ding, Y., Liu, Y., Kang, P., Hou, J.-W., Zhang, X.-Y., … Zhang, T. J.
768, 96–107. (2017). Design, synthesis and biological evaluation of novel coumarin-
Heinrich, M., & Teoh, H. L. (2004). Galanthamine from snowdrop—The N-benzyl pyridinium hybrids as multi-target agents for the treatment
development of a modern drug against Alzheimer's disease from local of Alzheimer's disease. European Journal of Medicinal Chemistry, 139,
Caucasian knowledge. Journal of Ethnopharmacology, 92(2–3), 48–59.
147–162. Lee, D. S., & Jeong, G. S. (2016). Butein provides neuroprotective and anti-
Heo, H. J., Kim, D.-O., Shin, S. C., Kim, M. J., Kim, B. G., & Shin, D.-H. neuroinflammatory effects through Nrf2/ARE-dependent haem
(2004). Effect of antioxidant flavanone, naringenin, from Citrus junos oxygenase 1 expression by activating the PI3K/Akt pathway. British
on neuroprotection. Journal of Agricultural and Food Chemistry, 52(6), Journal of Pharmacology, 173(19), 2894–2909.
1520–1525. Lee, J. W., Lee, Y. K., Ban, J. O., Ha, T. Y., Yun, Y. P., Han, S. B., …
Heo, H. J., Kim, M.-J., Lee, J.-M., Choi, S. J., Cho, H.-Y., Hong, B., … Hong, J. T. (2009). Green tea (-)-epigallocatechin-3-gallate inhibits
Shin, D. H. (2004). Naringenin from Citrus junos has an inhibitory β-amyloid-induced cognitive dysfunction through modification of
effect on acetylcholinesterase and a mitigating effect on amnesia. secretase activity via inhibition of ERK and NF-κ B pathways in mice.
Dementia and Geriatric Cognitive Disorders, 17(3), 151–157. The Journal of Nutrition, 139(10), 1987–1993.
Himeno, E., Ohyagi, Y., Ma, L., Nakamura, N., Miyoshi, K., Sakae, N., … Li, D.-D., Han, R.-M., Liang, R., Chen, C.-H., Lai, W., Zhang, J.-P., &
Kira, J. (2011). Apomorphine treatment in Alzheimer mice promoting Skibsted, L. H. (2012). Hydroxyl radical reaction with trans-resveratrol:
amyloid-β degradation. Annals of Neurology, 69(2), 248–256. Initial carbon radical adduct formation followed by rearrangement to
Hong, S.-Y., Jeong, W.-S., & Jun, M. (2012). Protective effects of the key phenoxyl radical. Journal of Physical Chemistry B, 116(24), 7154–7161.
compounds isolated from Corni fructus against β-amyloid-induced Li, F., Wu, J.-J., Wang, J., Yang, X.-L., Cai, P., Liu, Q.-H., … Wang, X. B.
neurotoxicity in PC12 cells. Molecules, 17(9), 10831–10845. (2017). Synthesis and pharmacological evaluation of novel chromone
Hu, Y., Zhang, J., Chandrashankra, O., Ip, F. C., & Ip, N. Y. (2013). Design, derivatives as balanced multifunctional agents against Alzheimer's dis-
synthesis and evaluation of novel heterodimers of donepezil and ease. Biorganic and Medicinal Chemistry, 25(14), 3815–3826.
huperzine fragments as acetylcholinesterase inhibitors. Biorganic and Li, R.-S., Wang, X.-B., Hu, X.-J., & Kong, L.-Y. J. (2013). Design, synthesis
Medicinal Chemistry, 21(3), 676–683. and evaluation of flavonoid derivatives as potential multifunctional
PATIL ET AL. 17

acetylcholinesterase inhibitors against Alzheimer's disease. Biorganic Okuda, M., Hijikuro, I., Fujita, Y., Teruya, T., Kawakami, H., Takahashi, T., &
and Medicinal Chemistry Letters, 23(9), 2636–2641. Sugimoto, H. (2016). Design and synthesis of curcumin derivatives as
Li, S.-Y., Wang, X.-B., & Kong, L.-Y. J. (2014). Design, synthesis and biologi- tau and amyloid β dual aggregation inhibitors. Biorganic and Medicinal
cal evaluation of imine resveratrol derivatives as multi-targeted agents Chemistry Letters, 26(20), 5024–5028.
against Alzheimer's disease. European Journal of Medicinal Chemistry, Ono, K., Yoshiike, Y., Takashima, A., Hasegawa, K., Naiki, H., & Yamada, M.
71, 36–45. (2003). Potent anti-amyloidogenic and fibril-destabilizing effects of
Li, Y., Li, Y., Li, X., Zhang, S., Zhao, J., Zhu, X., & Tian, G. (2017). Head injury polyphenols in vitro: Implications for the prevention and therapeutics
as a risk factor for dementia and Alzheimer's disease: A systematic of Alzheimer's disease. Journal of Neurochemistry, 87(1), 172–181.
review and meta-analysis of 32 observational studies. PLoS One, 12(1), Pan, L.-F., Wang, X.-B., Xie, S.-S., Li, S.-Y., & Kong, L.-Y. (2014). Multi-
e0169650. target-directed resveratrol derivatives: Anti-cholinesterases, anti-
Li, Y., Zhou, S., Li, J., Sun, Y., Hasimu, H., Liu, R., & Zhang, T. (2015). Quer- β-amyloid aggregation and monoamine oxidase inhibition properties
cetin protects human brain microvascular endothelial cells from fibril- against Alzheimer's disease. Medicinal Chemistry Communications, 5(5),
lar β-amyloid1–40-induced toxicity. Acta Pharmaceutica Sinica B, 5(1), 609–616.
47–54. Panche, A., Diwan, A., & Chandra, S. (2016). Flavonoids: An overview. Jour-
Lin, A. J., Koike, M. A., Green, K. N., Kim, J. G., Mazhar, A., Rice, T. B., … nal of Nutritional Science, 5, e47.
Tromberg, B. J. (2011). Spatial frequency domain imaging of intrinsic Pivovarova, O., Höhn, A., Grune, T., Pfeiffer, A. F., & Rudovich, N. (2016).
optical property contrast in a mouse model of Alzheimer's disease. Insulin-degrading enzyme: New therapeutic target for diabetes and
Annals of Biomedical Engineering, 39(4), 1349–1357. Alzheimer's disease? Annals of Medicine, 48(8), 614–624.
Liu, H. R., Liu, X. J., Fan, H. Q., Tang, J. J., Gao, X. H., & Liu, W. K. (2014). Puksasook, T., Kimura, S., Tadtong, S., Jiaranaikulwanitch, J.,
Design, synthesis and pharmacological evaluation of chalcone deriva- Pratuangdejkul, J., Kitphati, W., … Nukoolkarn, V. (2017).
tives as acetylcholinesterase inhibitors. Bioorganic & Medicinal Chemis- Semisynthesis and biological evaluation of prenylated resveratrol
try, 22(21), 6124–6133. derivatives as multi-targeted agents for Alzheimer's disease. Journal of
Liu, J.-S., Zhu, Y.-L., Yu, C.-M., Zhou, Y.-Z., Han, Y.-Y., Wu, F.-W., & Qi, B.- Medicinal Chemistry, 71(4), 665–682.
F. (1986). The structures of huperzine A and B, two new alkaloids Qian, Y., Cao, L., Guan, T., Chen, L., Xin, H., Li, Y., … Yu, D. (2015). Protec-
exhibiting marked anticholinesterase activity. Canadian Journal of tion by genistein on cortical neurons against oxidative stress injury via
Chemistry, 64(4), 837–839. inhibition of NF-kappaB, JNK and ERK signaling pathway. Pharmaceu-
Liu, Q.-H., Wu, J.-J., Li, F., Cai, P., Yang, X.-L., Kong, L.-Y., & Wang, X.-B. tical Biology, 53(8), 1124–1132.
J. M. (2017). Synthesis and pharmacological evaluation of multi- Qu, Z., Mossine, V. V., Cui, J., Sun, G. Y., & Gu, Z. (2016). Protective effects
functional homoisoflavonoid derivatives as potent inhibitors of mono- of AGE and its components on neuroinflammation and neu-
amine oxidase B and cholinesterase for the treatment of Alzheimer's rodegeneration. Neuromolecular Medicine, 18(3), 474–482.
disease. Medicinal Chemistry Communications, 8(7), 1459–1467. Rabal, O., Sánchez-Arias, J. A., Cuadrado-Tejedor, M., de Miguel, I., Pérez-
Lu, C., Guo, Y., Yan, J., Luo, Z., Luo, H.-B., Yan, M., … Li, X. J. (2013). González, M., García-Barroso, C., … Oyarzabal, J. (2016). Design, syn-
Design, synthesis, and evaluation of multitarget-directed resveratrol thesis, and biological evaluation of first-in-class dual acting histone
derivatives for the treatment of Alzheimer's disease. Journal of Medici- deacetylases (HDACs) and phosphodiesterase 5 (PDE5) inhibitors for
nal Chemistry, 56(14), 5843–5859. the treatment of Alzheimer's disease. Journal of Medicinal Chemistry,
Luo, W., Su, Y.-B., Hong, C., Tian, R.-G., Su, L.-P., Wang, Y.-Q., … 59(19), 8967–9004.
Wang, C. J. (2013). Design, synthesis and evaluation of novel Rom, S., Zuluaga-Ramirez, V., Gajghate, S., Seliga, A., Winfield, M.,
4-dimethylamine flavonoid derivatives as potential multi-functional Heldt, N. A., … Persidsky, Y. (2019). Hyperglycemia-driven neu-
anti-Alzheimer agents. Biorganic and Medicinal Chemistry, 21(23), roinflammation compromises BBB leading to memory loss in both dia-
7275–7282. betes mellitus (DM) type 1 and type 2 mouse models. Molecular
Mandel, S. A., Amit, T., Kalfon, L., Reznichenko, L., Weinreb, O., & Neurobiology, 56(3), 1883–1896.
Youdim, M. B. (2008). Cell signaling pathways and iron chelation in the Ruan, C.-J., Si, J.-Y., Zhang, L., Chen, D.-H., Du, G.-H., & Sun, L. (2009).
neurorestorative activity of green tea polyphenols: Special reference Protective effect of stilbenes containing extract-fraction from Cajanus
to epigallocatechin gallate (EGCG). Journal of Alzheimer's Disease, 15(2), cajan L. on Aβ25–35-induced cognitive deficits in mice. Neuroscience
211–222. Letters, 467(2), 159–163.
Mandel, S. A., Amit, T., Kalfon, L., Reznichenko, L., & Youdim, M. B. (2008). Sabogal-Guáqueta, A. M., Munoz-Manco, J. I., Ramírez-Pineda, J. R.,
Targeting multiple neurodegenerative diseases etiologies with Lamprea-Rodriguez, M., Osorio, E., & Cardona-Gómez, G. P. (2015).
multimodal-acting green tea catechins. The Journal of Nutrition, 138(8), The flavonoid quercetin ameliorates Alzheimer's disease pathology
1578S–1583S. and protects cognitive and emotional function in aged triple transgenic
Mandel, S. A., Amit, T., Weinreb, O., Reznichenko, L., & Youdim, M. B. Alzheimer's disease model mice. Neuropharmacology, 93, 134–145.
(2008). Simultaneous manipulation of multiple brain targets by green Saeed, A., Zaib, S., Ashraf, S., Iftikhar, J., Muddassar, M., Zhang, K. Y., &
tea catechins: A potential neuroprotective strategy for Alzheimer and Iqbal, J. (2015). Synthesis, cholinesterase inhibition and molecular
Parkinson diseases. CNS Neuroscience & Therapeutics, 14(4), 352–365. modelling studies of coumarin linked thiourea derivatives. Biorganic
Matioli, M. N. P., & Nitrini, R. (2015). Mechanisms linking brain insulin Chemistry, 63, 58–63.
resistance to Alzheimer's disease. Dementia & Neuropsychologia, 9(2), Savelieff, M. G., Nam, G., Kang, J., Lee, H. J., Lee, M., & Lim, M. H. (2018).
96–102. Development of multifunctional molecules as potential therapeutic
Nerurkar, P. V., Johns, L. M., Buesa, L. M., Kipyakwai, G., Volper, E., candidates for alzheimer's disease, parkinson's disease, and
Sato, R., … Nerurkar, V. R. (2011). Momordica charantia (bitter melon) amyotrophic lateral sclerosis in the last decade. Chemical Reviews, 119
attenuates high-fat diet-associated oxidative stress and neu- (2), 1221–1322.
roinflammation. Journal of Neuroinflammation, 8(1), 64. Sayre, L. M., Perry, G., & Smith, M. A. (2007). Oxidative stress and neuro-
Newman, D. J., & Cragg, G. M. (2016). Natural products as sources of new toxicity. Chemical Research in Toxicology, 21(1), 172–188.
drugs from 1981 to 2014. Journal of Natural Products, 79(3), 629–661. Schedin-Weiss, S., Inoue, M., Hromadkova, L., Teranishi, Y.,
Ng, Y. P., Or, T. C. T., & Ip, N. Y. (2015). Plant alkaloids as drug leads for Yamamoto, N. G., Wiehager, B., … Tjernberg, L. O. (2017). Monoamine
Alzheimer's disease. Neurochemistry International, 89, 260–270. oxidase B is elevated in Alzheimer disease neurons, is associated with
18 PATIL ET AL.

γ-secretase and regulates neuronal amyloid β-peptide levels. class of selective acetylcholinesterase inhibitors. Biorganic and Medici-
Alzheimer's Research & Therapy, 9(1), 57. nal Chemistry Letters, 17(13), 3765–3768.
Sharma, A., Pachauri, V., & Flora, S. J. S. (2018). Advances in multi- Tang, H., Wei, Y.-B., Zhang, C., Ning, F.-X., Qiao, W., Huang, S.-L., …
functional ligands and need for metal-related pharmacology for the Gu, L. Q. (2009). Synthesis, biological evaluation and molecular model-
management of Alzheimer disease. Frontiers in Pharmacology, 9, ing of oxoisoaporphine and oxoaporphine derivatives as new dual
1247. inhibitors of acetylcholinesterase/butyrylcholinesterase. European
Shen, Y., Zhang, J., Sheng, R., Dong, X., He, Q., & Yang, B. (2009). Synthesis Journal of Medicinal Chemistry, 44(6), 2523–2532.
and biological evaluation of novel flavonoid derivatives as dual binding Tang, H., Zhao, L.-Z., Zhao, H.-T., Huang, S.-L., Zhong, S.-M., Qin, J.-K., …
acetylcholinesterase inhibitors. Journal of Enzyme Inhibition and Medici- Liang, H. (2011). Hybrids of oxoisoaporphine-tacrine congeners: Novel
nal Chemistry, 24(2), 372–380. acetylcholinesterase and acetylcholinesterase-induced β-amyloid
Sheng, R., Lin, X., Zhang, J., Chol, K. S., & Huang, W. (2009). Design, syn- aggregation inhibitors. European Journal of Medicinal Chemistry, 46(10),
thesis and evaluation of flavonoid derivatives as potent AChE inhibi- 4970–4979.
tors. Biorganic and Medicinal Chemistry, 17(18), 6692–6698. Tanzi, R. E., & Bertram, L. (2005). Twenty years of the Alzheimer's disease
Shi, A., Huang, L., Lu, C., He, F., & Li, X. J. (2011). Synthesis, biological eval- amyloid hypothesis: A genetic perspective. Cell, 120(4), 545–555.
uation and molecular modeling of novel triazole-containing berberine Ting, Z., Ke-min, D., Lei, Z., Xue-mei, C., Chang-Hong, W., & Zheng-
derivatives as acetylcholinesterase and β-amyloid aggregation inhibi- Tao, W. (2013). Acetylcholinesterase and butyrylcholinesterase inhibi-
tors. Biorganic and Medicinal Chemistry, 19(7), 2298–2305. tory activities of β-carboline and quinoline alkaloids derivatives from
Shi, J., Qian, W., Yin, X., Iqbal, K., Grundke-Iqbal, I., Gu, X., … Liu, F. (2011). the plants of genus Peganum. Journal of Chemistry, 6, Article ID
Cyclic AMP-dependent protein kinase regulates the alternative splic- 717232.
ing of tau exon 10: A mechanism involved in tau pathology of Tu, L.-H., Young, L. M., Wong, A. G., Ashcroft, A. E., Radford, S. E., &
alzheimer disease. Journal of Biological Chemistry, 286(16), Raleigh, D. P. (2015). Mutational analysis of the ability of resveratrol
14639–14648. to inhibit amyloid formation by islet amyloid polypeptide: Critical eval-
Shi, Y.-F., Zhang, H.-Y., Wang, W., Fu, Y., Xia, Y., Tang, X.-C., … He, X. C. uation of the importance of aromatic–inhibitor and histidine–inhibitor
(2009). Novel 16-substituted bifunctional derivatives of huperzine B: interactions. Biochemistry, 54(3), 666–676.
Multifunctional cholinesterase inhibitors. Acta Pharmacologica Sinica, Van der Mussele, S., Fransen, E., Struyfs, H., Luyckx, J., Mariën, P.,
30(8), 1195. Saerens, J., … Engelborghs, S. (2014). Depression in mild cognitive
Silva, T., Reis, J., Teixeira, J., & Borges, F. (2014). Alzheimer's disease, impairment is associated with progression to Alzheimer's disease: A
enzyme targets and drug discovery struggles: From natural products to longitudinal study. Journal of Alzheimer's Disease, 42(4), 1239–1250.
drug prototypes. Ageing Research Reviews, 15, 116–145. Vepsäläinen, S., Koivisto, H., Pekkarinen, E., Mäkinen, P., Dobson, G.,
Simoni, E., Daniele, S., Bottegoni, G., Pizzirani, D., Trincavelli, M. L., McDougall, G. J., … Hiltunen, M. (2013). Anthocyanin-enriched bil-
Goldoni, L., … Cavalli, A. (2012). Combining galantamine and berry and blackcurrant extracts modulate amyloid precursor protein
memantine in multitargeted, new chemical entities potentially useful processing and alleviate behavioral abnormalities in the APP/PS1
in Alzheimer's disease. Journal of Medicinal Chemistry, 55(22), mouse model of Alzheimer's disease. The Journal of Nutritional Bio-
9708–9721. chemistry, 24(1), 360–370.
Singh, M., Kaur, M., Singh, N., & Silakari, O. J. (2017). Exploration of multi- Viayna, E., Sola, I., Bartolini, M., De Simone, A., Tapia-Rojas, C.,
target potential of chromen-4-one based compounds in Alzheimer's Serrano, F. G., … Muñoz-Torrero, D. (2014). Synthesis and multitarget
disease: Design, synthesis and biological evaluations. Bioorganic and biological profiling of a novel family of rhein derivatives as disease-
Medicinal Chemistry, 25(24), 6273–6285. modifying anti-Alzheimer agents. Journal of Medicinal Chemistry, 57(6),
Singh, M., & Silakari, O. J. R. A. (2016). Design, synthesis and biological eval- 2549–2567.
uation of novel 2-phenyl-1-benzopyran-4-one derivatives as potential Villaflores, O. B., Chen, Y.-J., Chen, C.-P., Yeh, J.-M., & Wu, T.-Y. (2012).
poly-functional anti-Alzheimer's agents, 6(110), 108411–108422. Curcuminoids and resveratrol as anti-Alzheimer agents. Taiwanese
Smith, B., Medda, F., Gokhale, V., Dunckley, T., & Hulme, C. J. (2012). Journal of Obstetrics and Gynecology, 51(4), 515–525.
Recent advances in the design, synthesis, and biological evaluation of Wang, Q., Ning, L., Niu, Y., Liu, H., & Yao, X. J. T. (2015). Molecular mecha-
selective DYRK1A inhibitors: A new avenue for a disease modifying nism of the inhibition and remodeling of human islet amyloid polypep-
treatment of Alzheimer's? ACS Chemical Neuroscience, 3(11), 857–872. tide (hIAPP1–37) oligomer by resveratrol from molecular dynamics
Sonmez, F., Zengin Kurt, B., Gazioglu, I., Basile, L., Dag, A., Cappello, V., … simulation. Journal of Physical Chemistry B, 119(1), 15–24.
Guccione, S. (2017). Design, synthesis and docking study of novel cou- Wang, Y., Yin, H., Wang, L., Shuboy, A., Lou, J., Han, B., Zhang, Li,
marin ligands as potential selective acetylcholinesterase inhibitors. J. (2013). Curcumin as a potential treatment for Alzheimer's disease: A
Journal of Enzyme Inhibition and Medicinal Chemistry, 32(1), 285–297. study of the effects of curcumin on hippocampal expression of glial
Su, T., Xie, S., Wei, H., Yan, J., Huang, L., & Li, X. J. (2013). Synthesis and bio- fibrillary acidic protein. The American Journal of Chinese Medicine, 41
logical evaluation of berberine–thiophenyl hybrids as multi-functional (01), 59–70.
agents: Inhibition of acetylcholinesterase, butyrylcholinesterase, and Aβ Williams, D. H., Stone, M. J., Hauck, P. R., & Rahman, S. K. (1989). Why are
aggregation and antioxidant activity. Biorganic and Medicinal Chemistry, secondary metabolites (natural products) biosynthesized? Journal of
21(18), 5830–5840. Natural Products, 52(6), 1189–1208.
Sultana, R., & Butterfield, D. A. (2008). Redox proteomics studies of in vivo Williams, P., Sorribas, A., & Howes, M. J. (2011). Natural products as a
amyloid beta-peptide animal models of Alzheimer's disease: Insight source of Alzheimer's drug leads. Natural Product Reports, 28(1),
into the role of oxidative stress. PROTEOMICS–Clinical Applications, 2 48–77.
(5), 685–696. Woodruff-Pak, D. S., Vogel, R. W., & Wenk, G. L. (2001). Galantamine:
Tahtouh, T., Elkins, J. M., Filippakopoulos, P., Soundararajan, M., Burgy, G., Effect on nicotinic receptor binding, acetylcholinesterase inhibition,
Durieu, E., … Meijer, L. J. (2012). Selectivity, cocrystal structures, and and learning. Proceedings of the National Academy of Sciences of the
neuroprotective properties of leucettines, a family of protein kinase United States of America, 98(4), 2089–2094.
inhibitors derived from the marine sponge alkaloid leucettamine B. Xiao, G., Li, Y., Qiang, X., Xu, R., Zheng, Y., Cao, Z., … Deng, Y. (2017). Design,
Journal of Medicinal Chemistry, 55(21), 9312–9330. synthesis and biological evaluation of 40 -aminochalcone-rivastigmine
Tang, H., Ning, F.-X., Wei, Y.-B., Huang, S.-L., Huang, Z.-S., Chan, A. S., & hybrids as multifunctional agents for the treatment of Alzheimer's dis-
Gu, L. Q. (2007). Derivatives of oxoisoaporphine alkaloids: A novel ease. Biorganic and Medicinal Chemistry, 25(3), 1030–1041.
PATIL ET AL. 19

Xie, S.-S., Lan, J.-S., Wang, X., Wang, Z.-M., Jiang, N., Li, F., … Kong, L. Y. inhibitor and the primary investigation for structure–activity correla-
(2016). Design, synthesis and biological evaluation of novel donepezil– tions. Natural Product Research, 26(5), 387–392.
coumarin hybrids as multi-target agents for the treatment of Alzheimer's Yang, Z., Song, Z., Xue, W., Sheng, J., Shu, Z., Shi, Y., … Yao, X. (2014). Syn-
disease. Biorganic and Medicinal Chemistry, 24(7), 1528–1539. thesis and structure–activity relationship of nuciferine derivatives as
Xie, S.-S., Wang, X.-B., Li, J.-Y., Yang, L., & Kong, L.-Y. J. E. (2013). Design, potential acetylcholinesterase inhibitors. Medicinal Chemistry Research,
synthesis and evaluation of novel tacrine–coumarin hybrids as 23(6), 3178–3186.
multifunctional cholinesterase inhibitors against Alzheimer's disease. Zeng, H., Chen, Q., & Zhao, B. (2004). Genistein ameliorates β-amyloid
European Journal of Medicinal Chemistry, 64, 540–553. peptide (25–35)-induced hippocampal neuronal apoptosis. Free Radical
Xu, J., Wang, H., Ding, K., Zhang, L., Wang, C., Li, T., … Lu, X. (2014). Biology and Medicine, 36(2), 180–188.
Luteolin provides neuroprotection in models of traumatic brain injury Zhang, T., Su, J., Wang, K., Zhu, T., & Li, X. (2014). Ursolic acid reduces oxi-
via the Nrf2–ARE pathway. Free Radical Biology and Medicine, 71, dative stress to alleviate early brain injury following experimental sub-
186–195. arachnoid hemorrhage. Neuroscience Letters, 579, 12–17.
Xu, P., Zhang, M., Sheng, R., & Ma, Y. J. (2017). Synthesis and biological Zhao, L., Wang, J.-L., Liu, R., Li, X.-X., Li, J.-F., & Zhang, L. (2013). Neuro-
evaluation of deferiprone-resveratrol hybrids as antioxidants, Aβ1–42 protective, anti-amyloidogenic and neurotrophic effects of apigenin in
aggregation inhibitors and metal-chelating agents for Alzheimer's dis- an Alzheimer's disease mouse model. Molecules, 18(8), 9949–9965.
ease. European Journal of Medicinal Chemistry, 127, 174–186. Zhao, L., Wang, J.-L., Wang, Y.-R., & Fa, X.-Z. (2013). Apigenin attenuates
Yan, J., Hu, J., Liu, A., He, L., Li, X., & Wei, H. J. (2017). Design, synthesis, copper-mediated β-amyloid neurotoxicity through antioxidation, mito-
and evaluation of multitarget-directed ligands against Alzheimer's dis- chondrion protection and MAPK signal inactivation in an AD cell
ease based on the fusion of donepezil and curcumin. Bioorganic & model. Brain Research, 1492, 33–45.
Medicinal Chemistry, 25(12), 2946–2955. Zhao, X., Yuan, L., Yu, H., Xi, Y., Ma, W., Zhou, X., … Xiao, R. (2014). Genis-
Yan, J., Sun, L., Wu, G., Yi, P., Yang, F., Zhou, L., … Qiu, M. (2009). Rational design tein inhibited amyloid-β induced inflammatory damage in C6 glial cells.
and synthesis of highly potent anti-acetylcholinesterase activity huperzine Archives of Medical Research, 45(2), 152–157.
A derivatives. Biorganic and Medicinal Chemistry, 17(19), 6937–6941. Zheng, N., Yuan, P., Li, C., Wu, J., & Huang, J. (2015). Luteolin reduces
Yanagisawa, D., Ibrahim, N. F., Taguchi, H., Morikawa, S., Hirao, K., BACE1 expression through NF-κB and estrogen receptor mediated
Shirai, N., … Tooyama, I. (2015). Curcumin derivative with the substitu- pathways in HEK293 and SH-SY5Y cells. Journal of Alzheimer's Disease,
tion at C-4 position, but not curcumin, is effective against amyloid 45(2), 659–671.
pathology in APP/PS1 mice. Neurobiology of Aging, 36(1), 201–210. Zhuo, J.-M., Portugal, G. S., Kruger, W. D., Wang, H., Gould, T. J., &
Yanagisawa, D., Taguchi, H., Morikawa, S., Kato, T., Hirao, K., Shirai, N., & Praticò, D. (2010). Diet-induced hyperhomocysteinemia increases
Tooyama, I. (2015). Novel curcumin derivatives as potent inhibitors of amyloid-β formation and deposition in a mouse model of Alzheimer's
amyloid β aggregation. Biochemistry and Biophysics Reports, 4, 357–368. disease. Current Alzheimer Research, 7(2), 140–149.
Yang, H.-L., Cai, P., Liu, Q.-H., Yang, X.-L., Li, F., Wang, J., … Kong, L.-Y. Zhuo, J.-M., Wang, H., & Praticò, D. (2011). Is hyperhomocysteinemia an
(2017). Design, synthesis and evaluation of coumarin-pargyline hybrids Alzheimer's disease (AD) risk factor, an AD marker, or neither? Trends
as novel dual inhibitors of monoamine oxidases and amyloid-β aggre- in Pharmacological Sciences, 32(9), 562–571.
gation for the treatment of Alzheimer's disease. European Journal of
Medicinal Chemistry, 138, 715–728.
Yang, X., Qiang, X., Li, Y., Luo, L., Xu, R., Zheng, Y., … Deng, Y. (2017). Pyri-
doxine-resveratrol hybrids Mannich base derivatives as novel dual How to cite this article: Patil P, Thakur A, Sharma A,
inhibitors of AChE and MAO-B with antioxidant and metal-chelating Flora SJS. Natural products and their derivatives as
properties for the treatment of Alzheimer's disease. Biorganic Chemis-
multifunctional ligands against Alzheimer's disease. Drug Dev
try, 71, 305–314.
Yang, Z.-D., Zhang, X., Du, J., Ma, Z.-J., Guo, F., Li, S., & Yao, X.-J. (2012). An Res. 2019;1–19. https://doi.org/10.1002/ddr.21587
aporphine alkaloid from Nelumbo nucifera as an acetylcholinesterase

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