Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common type of dementia, characterized by cognitive decline in later years of life. Among various hypotheses explaining AD pathology, the cholinergic hypothesis is one of the most studied. Though there are Food and Drug Administration (FDA) approved drugs (donepezil, galantamine, rivastigmine and tacrine) for AD treatment, their adverse effects make it urgent to develop new drugs with minimal side effects. This review focuses on the acetylcholinesterase (AChE) inhibitory potential of plant extracts and phytochemicals that could aid in preventing and mitigating AD. From the literature search, extracts of 28 species were found to have strong inhibition against AChE, with IC50 values ranging from 0.08 μg/mL to 10.0 μg/mL. The highest number of species with AChE inhibition belongs to the Amaryllidacea family, followed by Fabaceae, Lycopodiaceae, Amaranthaceae and Anacardiaceae. Several phytochemicals, including alkaloids, terpenoids and phenolics, show a multitarget approach in AD therapy, exhibiting more than one of the following activities such as inhibition of AChE, butyrylcholinesterase (BuChE), MAO-A, beta site amyloid precursor protein cleaving enzyme 1 (BACE-1), β-amyloid (Aβ) aggregation, tau phosphorylation, and an ability to cross blood-brain barrier (BBB). With a multitarget approach and minimal side effects, they could revolutionise the treatment of AD. Many phytochemicals and their derivatives are under clinical and pre-clinical trials, potentially serving as prospective therapeutic drug candidates for treating AD. This review briefly discusses the findings and advances in knowledge about plant-derived bioactive compounds as potential new drugs acting as AChE inhibitors.
Alzheimer’s disease (AD) is the most predominant type of dementia, accounting for approximately 60–80% of all cases worldwide [1–3]. Around 50 million people across the globe were living with AD as of 2020, and a twofold increase is anticipated every 20 years, exceeding 90 million by 2050 [1]. This progressive and irreversible neurodegenerative disorder primarily affects individuals over the age of 60, with a global prevalence of 4.02% and an annual incidence rate of 3.41% [2, 4]. As per the current statistics, during the COVID-19 pandemic, death cases have escalated by 16 per cent [5]. The symptoms of AD are manifested only after years of onset of the disease [6]. Early symptoms include apathy, inability to recall recent incidents or names and depression. As the condition progresses, it leads to disorientation, communication issues, poor judgement, confusion and behavioural changes. The late-stage symptoms include difficulty speaking, walking and swallowing [5].
Though the pathology of AD is not entirely acknowledged, several factors contributing to neurodegeneration have been identified so far [7–10]. One of the major pathological features of AD is the accumulation of beta-amyloid plaques in the brain, leading to nerve loss, especially in the hippocampus region, which is the site of memory, learning and emotions [11]. Increased levels of hyperphosphorylated tau proteins associated with neurofibrillary tangles are other pathological hallmarks of AD [12–14]. Patients with AD have shown reduced levels of acetylcholine (Ach) in the synapses [15]. It was not until recently that the dual roles of acetylcholinesterase (AChE), including the formation of beta-amyloid plaques in brain cells and the hydrolysis of neurotransmitters, were unveiled [11]. These diverse roles make AChE a potential target for AD treatment [11].
ACh is a neurotransmitter crucial in learning, memory and synaptic plasticity. A key indicator of AD is the depletion of ACh [15]. AChE is a key enzyme which plays a vital role in regulating nerve impulse transmission at cholinergic synapses by catalyzing the breakdown of ACh [16]. Normal neurotransmission occurs when ACh is released into the synaptic cleft from the presynaptic neuron, which then binds to the ACh receptors on the postsynaptic membrane. This initiates a relay of signals from the nerve. AChE is also present in the postsynaptic membrane and catalyzes the hydrolysis of ACh into choline and acetate to terminate the signal. The choline then re-enters the presynaptic neuron where choline-acetyl transferase combines it with acetyl-CoA to rebuild ACh [17]. In AD, the hyperactivity of AChE aggravates the breakdown of ACh, thereby disrupting cholinergic signalling and leading to cognitive decline [18]. Recent findings have highlighted the influence of AChE in beta-amyloid plaque formation, suggesting its role in the advancement of AD. This bifunctionality of AChE as a hydrolytic enzyme and promoter of amyloid aggregation makes it a crucial target in the therapeutic management of AD [19]. Studies highlight the long-term health benefits of AChE inhibitors as they are associated with slower cognitive decline and reduced mortality in older adults with dementia [20]. Recent studies have identified novel heterocyclic compounds with AChE inhibitory properties, such as coumarin-benzotriazole hybrids and carbazole derivatives. They act on both the catalytic active site and peripheral anionic site (PAS) of AChE, along with low toxicity profiles and high blood-brain barrier (BBB) permeability, offering potential leads for AD treatment [21].
Current treatment of AD is mainly based on four licensed medications that are acetylcholinesterase inhibitors (AChEIs). These include donepezil, galantamine, rivastigmine and tacrine, which prevent the breakdown of ACh and increase impulse transmission at cholinergic sites, with rivastigmine exhibiting the highest effect [15, 22, 23]. Unfortunately, these drugs have minimal bioavailability and they only offer symptomatic relief and temporary improvement in cognitive function, failing to stop or invert neurodegeneration [24]. On top of that, the continuous use of these drugs causes multiple side effects such as nausea, vomiting and gastrointestinal disorders, restricting their prolonged use [14]. Here comes the need to identify safer and more effective AChEIs targeting multiple aspects of AD pathology.
A great deal of research has been conducted in the last decade on plant-derived bioactive compounds with AChEI potential. Several plants with promising AChEI activity have been used in traditional medical systems, such as Ayurveda and traditional Chinese medicine, for their neuroprotective and memory-boosting potential [1, 25]. These plants contain various phytochemicals, including alkaloids, flavonoids, terpenoids, and many other phenolic compounds with antioxidant, anti-amyloidogenic and anti-inflammatory properties in addition to demonstrated AChEI activity [15, 26]. Studies show that plants of Amaranthaceae, Amaryllidaceae, Lycopodiaceae, Myristicaceae, Polygonaceae, Rutaceae and Valerianaceae are potential sources of AChEIs [1, 11]. This review focuses on recent research related to plant-based AChEIs and summarises the potential plants and phytochemicals with demonstrated AChEI activity.
Current AChEI drug therapies in AD
The current Food and Drug Administration (FDA) approved drugs for the treatment of AD include cholinesterase inhibitors such as donepezil, rivastigmine, galantamine and glutamate receptor antagonist memantine. These inhibitors bind to the enzyme and prevent it from hydrolyzing Ach, activating cholinergic signalling and reducing the symptoms of AD [27]. Tacrine was the first cholinesterase inhibitor drug approved by the FDA for the symptomatic relief of AD, but it is no longer in use as it causes hepatotoxicity [28]. Though these second-generation cholinesterase inhibitors are classified under the same class of medication, they belong to different chemical classes and are distinct in their pharmacological properties [29].
Rivastigmine
Rivastigmine is a phenyl-carbamate derivative (Figure 1), frequently referred to as a pseudo-irreversible cholinesterase inhibitor, as its plasma effects persist longer than expected. It is the only drug that inhibits both AChE and butyrylcholinesterase (BuChE) and it is available in both oral capsules and transdermal patches [29]. Upon absorption, it acts like ACh by binding both the anionic and esteratic sites of AChE [30]. Unlike ACh, which dissociates immediately after hydrolysis, rivastigmine gets hydrolyzed by leaving the esteratic site of AChE carbamylated for a while, inhibiting the enzyme [30]. FDA has approved a rivastigmine dosage of 4.6 mg/day of oral capsule and 9.5 mg/day of transdermal patch for mild-moderate stages of AD and 13.3 mg/day for severe stages [31, 32]. The availability of a carrier protein in the blood dramatically influences the performance of an administered drug. Being closely related to human serum albumin, bovine serum albumin is often used in conjugation with rivastigmine tartrate and has shown promising results in treating AD [33]. Rivastigmine has also exhibited a potential role in directing the amyloid precursor protein into a non-amyloidogenic pathway [34]. These benefits of rivastigmine are also associated with adverse effects. While the most frequent side effects are gastrointestinal problems such as nausea, vomiting, diarrhoea, abdominal pain, dizziness, headache, anorexia and fatigue, confusion and agitation are less common. Skin reactions are the next most common side effect seen only in transdermal patches. Though the side effects are non-lethal, an overdose of the drug in any form can be fatal [29].
Structure of current FDA-approved anti-cholinesterase drugs.
Donepezil is a piperidine-based second-generation inhibitor (Figure 1) of AChE. It consists of a benzylpiperidine moiety linked to dimethoxy indanone by the methylene group [35]. It is a selective, reversible, and non-competitive inhibitor of AChE that binds to its anionic site [36, 37]. Even though a cholinesterase inhibitor, donepezil has a more inhibitory effect on AChE than BuChE [37–39]. In addition, an increased absorption time (3–5 hours) and a long half-life of 70 hours reduce the frequency of tablet consumption. Due to its affinity to serum albumin, donepezil is easily excreted through urine [37, 39]. In vitro studies have shown the potential of deoxyvasicinone-donepezil hybrids as a multitarget drug in alleviating AD [40]. Donepezil-loaded nano drugs have displayed a dual role in inhibiting AChE and β-amyloid (Aβ)-targeting clearance [41, 42]. Despite being an AChEI used in the treatment of AD, donepezil has been reported to have several adverse effects due to elevated levels of ACh beyond the central nervous system. The side effects include cardiovascular problems such as bradycardia, QTc prolongation and a life-threatening arrhythmia, Torsades de Pointes [43]. Studies have also shown that donepezil alters sleep architecture [44], and an increase in daily dosage has induced parkinsonism [45]. Other adverse effects include nausea, vomiting, diarrhoea, anorexia, muscle cramps, fatigue, insomnia and increased gastrointestinal secretions [37, 39, 46, 47].
Galantamine
Galantamine is a heterocyclic phenanthridine derivative (Figure 1) isolated from the flowers and bulbs of Galanthus woronowi of the Amaryllidaceae family. It is the only FDA-approved alkaloid drug used for the treatment of AD [48]. Despite its relatively limited inhibitory activity, it serves efficiently as an allosteric modulator of the nicotinic ACh receptor. The selective inhibition of AChE in the central nervous system with minimal effect on the peripheral nervous system makes galantamine a preferred candidate for AD treatment. Early-stage dosage of galantamine has notably reduced oxidative stress and lowered the production of proinflammatory cytokines, resulting in enhanced cognitive function [49]. Recent studies focus on the synergistic effect of compounds. A conjugate of galantamine and memantine has shown neuroprotectivity in a dual path, inhibiting AChE and alleviating N-methyl-D-aspartate induced neurotoxicity [50]. Transdermal delivery is a more recent approach for administering galantamine-memantine conjugate, which was found effective in bypassing the hepatic first-pass metabolism [51]. Regardless of its AChEI potential, galantamine, like all other AChEIs, has several adverse effects, including gastrointestinal problems such as nausea, vomiting, diarrhoea and anorexia, which may increase with dosage [52]. Other side effects of galantamine administration include urinary retention, QT prolongation, sinus bradycardia, syncope, and delirium [52].
The reports suggest that rivastigmine is a dual inhibitor of AChE and BuChE, while galantamine and donepezil are highly selective for AChE. On comparing the efficiency and side effects, the rivastigmine transdermal patch has the upper hand, showing mild side effects compared to others, especially with gastrointestinal problems. However, the best choice always depends on the patient’s other underlying conditions. Although these are FDA-approved drugs, they still have side effects that are dose-limiting, such as gastrointestinal problems, cardiovascular complications, insomnia, anorexia, fatigue, and confusion [29, 52]. There comes the significance of safer and multifunctional plant-based drugs. There is an array of plant-derived bioactive compounds that are multifunctional and have neuroprotective, antioxidant, and anti-inflammatory properties. Reports suggest that phytochemicals such as alkaloids and terpenoids regulate multiple pathological pathways of AD, including tau protein phosphorylation, beta-amyloid plaque formation, and oxidative stress, in addition to AChE inhibition [53]. Many phytochemicals are also involved in the inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) and monoamine oxidase (MAO) [54, 55]. This suggests the potential of phytochemicals in offering a pathology-based treatment for AD rather than symptomatic relief.
Plant extracts in cholinergic neuroprotection
Since time immemorial, medicinal plants have been identified, cultivated, and used in traditional medicines. Traditional medicinal systems such as Ayurveda, Unani, Siddha, and Chinese traditional medicine all employ medicinal plants and extracts to treat numerous illnesses. According to the World Health Organization (WHO), around 80% of people across the world use herbal medicines in primary health care [56]. This points to the presence of pharmacological lead molecules in medicinal plants and their therapeutic effects. Herbal remedies are employed worldwide to treat neurological conditions, including those caused by impaired AChE activity [56]. Research has revealed the AChEI of numerous plant extracts (Table 1).
Plant extracts with AChEI activity and their IC50 value
An investigation of the bioactivity of various extracts obtained from the fruits of Horsfieldia tomentosa was conducted by Idris et al. [72]. Among the four extracts of H. tomentosa, the ethyl acetate extract exhibited the highest AChE inhibition (IC50 6.0 μg/mL) and significant antioxidant activity. It showed dual but selective inhibition of cholinesterases (BuChE IC50 32.1 μg/mL). Methanol extract, n-hexane non-soluble and n-hexane soluble fractions also exhibited significant AChEI activity (IC50 9.1 μg/mL, 13.5 μg/mL, and 21.2 μg/mL, respectively) compared to the standard eserine (IC50 27.53 μg/mL). This multipotency makes this plant a potential candidate for AD therapeutic drug discovery.
Traditionally, Sarcocephalus latifolius is a plant used in folklore medicine to treat malaria, jaundice, dysentery, hypertension, inflammation, aches and snake bites. It is also reported to have antioxidant and AChEI activities. In an experiment by Atolani et al. [89], fatty acid methyl esters from the leaves and fruits of S. latifolius were isolated by a one-step extraction and transesterification process. Although the leaves had higher extraction yield, they showed very weak AChEI activity, compared with fruit (IC50 29.14 mg/mL) and the reference, donepezil (127.70 mg/mL). Saad et al. [57] reported the AChEI potential of leaf extracts of Citharexylum spinosum. Though all extracts showed pronounced activity, the hexane-benzene fraction showed the highest inhibition (IC50 0.08 μg/mL), comparable to the reference compound donepezil (IC50 0.05 μg/mL). Other extracts such as n-butanol, hydro-alcohol (50%), chloroform, hexane and ethyl acetate fractions also showed strong inhibitory potential, with IC50 values ranging from 0.6–4.8 μg/mL, making C. spinosum an important plant in AD therapy.
Hexane and ethanolic extracts of seed and pulp/peel of Byrsonima sericea, utilized in traditional medicine of the Amazon region for the treatment of fever, skin infections, asthma, respiratory diseases and gastrointestinal problems, were evaluated for AChEI action [73]. The researchers found that hexane extract of the seed as well as ethanolic extracts of seed and pulp showed marked inhibition against AChE (IC50 6.62 μg/mL, 6.04 μg/mL, and 9.04 μg/mL, respectively), while hexane extract of pulp showed moderate (IC50 10.92 μg/mL) AChE inhibition, with reference to the standard galantamine (IC50 1.02 μg/mL).
Hypericum spp. has traditionally been used to treat mental disorders, depression, diabetes, jaundice, arthritis, and bladder complications [63]. It has been presented that hydro alcohol extract of H. perforatum reduced the ACh breakdown rate by strongly inhibiting AChE activity, with an IC50 value of 4.32 μg/mL [63]. Furthermore, acetone, chloroform, methanol and ethanol extracts of H. heterophyllum leaves significantly decreased AChE activity (IC50 11.07 μg/mL, 12.33 μg/mL, 13.99 μg/mL and 16.32 μg/mL, respectively), suggesting the presence of potential in AChEI phytochemical in Hypericum spp. [77].
Hemidesmus indicus (Apocyanaceae) is an important medicinal plant with wound-healing properties and is used against ulcers, fever, headache, eye disease, asthma, rheumatism, leucorrhoea, diarrhoea, prostatitis, neuralgia, nephritic disorders, urticaria, psoriasis, itching, and dyspepsia [68]. As part of an experiment, Penumala et al. [68] aerial parts of H. indicus were extracted with trichloromethane, 90% methanol, n-butanol and water and tested for AChEI activity. Results showed that trichloromethane and methanol extracts inhibited AChE moderately with IC50 values of 28.14 μg/mL and 48.64 μg/mL, respectively, compared to the standard galantamine (IC50 0.77 μg/mL). The other two extracts showed weak inhibition (IC50 > 100.0 μg/mL).
In a study by Ali et al. [65], whole plant extracts of Angelica decursiva were tested for anti-AChE activity in different fractions. Aqueous, butanolic, ethyl acetate, chloroform and methanolic fractions showed substantial inhibitory effects with IC50 values of 2.6 μg/mL, 6.0 μg/mL, 9.7 μg/mL, 13.7 μg/mL, 16.6 μg/mL, respectively, suggesting that it might contain bioactive compounds that can treat AD. Esenbeckia leiocarpa Engl. is an ornamental tree with a variety of secondary metabolites, including quinolinic, quinolonic and indolic alkaloids and furocoumarins, making it a therapeutically important plant. Using the Ellman colorimetric technique, Cardoso-Lopes et al. [62] tested the AChEI activity of ethanol extract, hexane and alkaloid fractions of E. leiocarpa. The alkaloidal and hexane fractions showed strong inhibition (IC50 1.6 μg/mL and 6.0 μg/mL, respectively), while ethanol extract exhibited moderate inhibition to AChE (50.7 μg/mL).
Huperzia spp. (Lycopodiaceae) have been used to treat a wide range of cognitive and neurological disorders in China for over 1,000 years [1]. A steep surge in research focusing on cholinesterase inhibitory properties of Huperzia spp. has been reported in the past decade following the isolation of the alkaloid Huperzine A from H. serrata. In a study, Armijos et al. [61] reported the strong AChEI potential of the alkaloid fraction of H. tetragona aerial parts with an IC50 value of 0.9 μg/mL. H. brevifolia and H. compacta displayed moderate activity (IC50 39.6 μg/mL and 62.4 μg/mL, respectively) compared to the standard donepezil (IC50 0.036 μg/mL). In the study by Ohba et al. [70], the alkaloid-enriched fraction of H. serrata aerial parts, whose primary component was Huperzin A, displayed an IC50 value of 5.96 μg/mL. In a similar study, Tung et al. [86] analyzed the AChEI potential of ethyl acetate fraction, buthanolic fraction and ethanolic extract of H. squarrosa. Results suggested that while ethyl acetate and butanolic fractions showed moderate AChE inhibition (IC50 23.4 μg/mL and 50.1 μg/mL, respectively), ethanolic extract showed week inhibitory potential (IC50 112.2 μg/mL). Even with the clinical evidence of the AChEI potential of Huperzin A, researchers are still focused on the pharmacological properties of Hupperzia spp. [1, 116].
Table 1 summarises screening studies on medicinal plants, including their scientific names, family, plant part, type of extract or fraction, IC50 value of AChE inhibition and positive control. This table gives an overview of the species under consideration, which are arranged in the ascending order of IC50 values of various extracts. AChEI activity of plant extracts was divided into four categories based on their IC50 values (Figure 2): strong activity (IC50< 10 μg/mL), moderate activity (10–50 μg/mL), low activity (50–100 μg/mL) and very weak activity (> 100 μg/mL). As per the abovementioned studies, 45 plant extracts (from 28 species) were found to have strong inhibition against AChE (Figure 2), with IC50 values ranging from 0.08 μg/mL for essential oil extract from the fruit peel of Myrciaria floribunda [100] and hexane-benzene fraction of Citharexylum spinosum L. leaf extract [57] to 10.0 μg/mL for the root methanolic extract of Zanthoxylum davyi Waterm. (Table 1) [60]. Moderate activity was displayed by 85 plant extracts (from 60 species; Figure 2) with IC50 values varying from 10.8 μg/mL for the total Alkaloids fraction of stem extract of Uncaria rhynchophylla (Miq.) Miq. ex Havil. [76] to 50.0 μg/mL for the aqueous extract of Salvia miltiorrhiza Bunge roots (Table 1) [69]. Forty-eight plant extracts (from 34 species) have been identified in this review with low activity, whose IC50 values vary from 50.1 μg/mL for butanolic fraction of Huperzia squarrosa (G. Forst.) Trevis. f. [86] to 100.0 μg/mL for the aqueous fraction of Persicaria hydropiper (L.) Delarbre. (Table 1) [94]. This review also assessed 27 plant extracts (from 23 species) having very weak inhibition against AChE (Figure 2), with IC50 values ranging from 100.4 μg/mL to 150.0 μg/mL (Table 1).
Chord diagram showing the AChE inhibition (4 larger arcs on the right side of the chord diagram) of various plant extracts (smaller arcs on the left side of the chord diagram). The AChE inhibition of extracts is given in terms of IC50 values such as (1) strong inhibition: IC50 < 10 µg/L; (2) moderate inhibition: IC50 10–50 µg/L; (3) low inhibition: IC50 50–100 µg/L; (4) very weak inhibition: IC50 100–150 µg/L. The chord diagram was created using RAW Graphs (rawgraphs.io).
Further analysis of the above studies suggested the importance of plant parts and solvents used in extraction. Different solvent extracts of the same plant part showed varying inhibitory concentrations, suggesting the isolation of bioactive molecules responsible for AChE inhibition in specific solvents, depending on their polarity and other factors. For instance, Suciati et al. [71] reported that ethanol extract, n-butanol and ethyl acetate fraction from roots of Rauvolfia serpentina (L.) Bth. ex Kurz presented different inhibitory concentrations. While n-butanol and ethyl acetate fractions displayed strong inhibition (IC50 5.99 μg/mL and 7.46 μg/mL, respectively), ethanol extract presented moderate inhibition (IC50 23.62 μg/mL) (Table 1). Similarly, different solvent extracts or fractions from the same plant parts of species such as Acalypha alnifolia Klein ex Willd., Aloe ferox Mill., Berberis libanotica Ehrenb. ex C.K. Schneid., Crinum bulbispermum (Burm. f.) Milne-Redh. & Schweick., Polygonum multiflorum Thunb, Pycnostachys reticulata (E.Mey.) Benth., etc., showed variable inhibitory capacity (Table 1).
Also, different plant parts extracted in the same solvent or fraction of various plant parts exhibited varying inhibitory potential against AChE, suggesting the selective production and accumulation of phytochemicals in different plant parts. For example, the methanolic extract of pulp and seeds of Annona Squamosa L. presented varying anti-AChE activity with IC50 values of 18.82 μg/mL and 22.31 μg/mL, respectively (Table 1) [83]. Similarly, ethyl acetate extract of the bulb and root of Crinum bulbispermum (Burm. f.) Milne-Redh. & Schweick exhibited significant variation in their AChEI potential. While the ethyl acetate extract of the bulb displayed notable inhibitory activity with an IC50 value of 2.1 μg/mL, that of the root showed moderate activity (IC50 39.3 μg/mL) [65].
Several plant species that produce a variety of bioactive compounds have been studied for anti-AChE activity and might be used to develop novel anti-AD medicines. Extracts from 100 species expanding in 47 plant families and 80 genera are categorized and discussed in this review (Table 1, Figure 3). Amaryllidaceae, Fabaceae, Amaranthaceae, Lycopodiaceae, Anacardiaceae, and Polygonaceae were the most common families with seven, six, five, five, five, and five species, respectively (Figure 3). Crinum bulbispermum (Burm. f.) Milne-Redh. & Schweick., Crinum jagus (J. Thomps.) Dandy, Crinum moorei Hook.f., Hippeastrum barbatum Herb, Hippeastrum hybridum, Zephyranthes carinata Herb., and Zephyranthes minuta (Kunth) D.Dietr. are the seven species of Amaryllidaceae that has presented significant AChEI activity. Most of the plant extracts from Amaryllidaceae exhibit strong to moderate inhibition, with IC50 values ranging from 2.1 μg/mL to 39.2 μg/mL (Table 1). Notably, extracts of all these plants except for H. hybridum came from their bulbs, indicating the presence of AChEI phytochemicals in the bulbs of Amaryllidaceae species. Amaryllidaceae is a monocot family comprising around 1,100 perennial bulbous, perennial plants rich in isoquinoline alkaloids, known as the Amaryllidaceae alkaloids [117]. Studies have shown that Amaryllidaceae alkaloids are responsible for the anti-AChE properties of this family [118]. Similarly, several lead molecules with AChEI potential have been identified and isolated from various plants, which are discussed further in section 4.
Number of plant genera and species per family exhibiting AChEI activity
Phytochemicals as AChEIs
Plant-based medicines have gained more popularity in recent years as an alternative to synthetic drugs in treating various illnesses. Similar is the case of AD, where phytomedicines are being intensely studied as an alternative approach for the holistic treatment of AD [119]. Herbal medicines have been used in various traditional medical systems to enhance memory and learning. Studies have shown that several phytochemicals, including flavonoids, vitamin E, vitamin C, and beta-carotene, have antioxidant properties and are known to enhance brain function by reducing oxidative stress [120]. As there is an urgent need for more efficient drugs with least or no side effects to treat AD, phytochemicals with neuroprotective activity and minimal side effects are being studied extensively to find a compound with the potential to become a multi-targeted drug that interacts with multiple targets of AD [121, 122]. This part of the review focuses on phytocompounds with AChEI activity for treating AD. Numerous phytochemicals coming under the category of alkaloids, polyphenols, flavonoids and terpenoids are reported to have AChE inhibition potential in addition to antioxidant, anti-inflammatory and neuroprotective properties [123, 124], recent studies on which are discussed here.
Alkaloids
Alkaloids are a group of low molecular weight nitrogen-containing phytochemicals derived biosynthetically from amino acids, leading to diverse chemical structures [125]. They exhibit a wide range of biological activities and are used in therapies such as pain reduction (opiate alkaloids) and chemotherapy (vinblastine, vincristine and taxane). Alkaloids are the main category of phytochemicals with AChEI potential. Galantamine extracted from the Galanthus species is the first and only FDA-approved alkaloid for treating AD. Different classes of alkaloids, including indole alkaloids, isoquinoline alkaloids, steroid alkaloids, terpenoid alkaloids and β-carboline alkaloids, have been studied for their neuroprotective role and potential in AD treatment [126].
Indole alkaloids constitute a major class of alkaloids that are derived from tryptophan and secologanin, which include compounds such as reserpine, ajmalicine, vinblastine, physostigmine and yohimbine and have therapeutic properties [127]. Physostigmine is an indole alcohol with AChEI potential isolated from Physostigma venenosum. Phenserine and tolserine are its derivatives, which also possess AChEI activity. Physostigmine is no longer used in AD treatment due to its side effects and short half-life [128, 129]. Ajmalicine and reserpine are indole alkaloids with AChEI potential, isolated from Rauwolfia serpentina Benth. Ex Karz [130]. They are also used to control blood pressure due to their antihypertensive potential [131]. Reserpine turned out to be a dual cholinesterase inhibitor of AChE and BuChE with IC50 values comparable to galantamine. Both ajmalicine and reserpine also inhibited Aβ42 fibril formation and other AD targets such as BACE-1 and MAO-B [132, 133]. Uleine is another indole alkaloid isolated from Aspidosperm ulei, and possesses high AChEI potential (IC50 0.4 µM).
Similarly, harmine and harmaline are β-carboline-type indole alkaloids isolated from Peganum harmala L. [134]. Being natural inhibitors of MAO, harmine and harmaline are used in ayahuasca, a drink used by South American people that has anxiolytic and antidepressant effects [135]. Studies have shown that these alkaloids possess AChEI potential and antioxidant, anti-inflammatory and MAO-A inhibitory properties. They also have the potential to cross the BBB [55]. They enhance cholinergic function by multiple pathways, including inhibition of AChE, limiting maleic dialdehyde production, antioxidant defence by increasing the activity of glutathione peroxidase and superoxide dismutase, reducing inflammation by suppressing TNFα, nitrous oxide and myeloperoxidases [136].
Isoquinoline alkaloids are one of the largest groups of plant alkaloids; many are potential therapeutic agents for various diseases. Protoberberine and aporphine types are the most common types of isoquinoline alkaloids [137]. Galantamine, lycorine, ungeremine, berberine, epiberberine and palmatine are some of the isoquinoline alkaloids with AChEI properties. Berberine and palmatine are protoberberine-type quaternary isoquinoline alkaloids derived from tyrosine. Both compounds are seen in Chinese memory booster herbs such as Corydalis rhizoma and Coptidis rhizome [138]. Berberine is extensively studied as a potential drug for various ailments, as it has a plethora of bioactivities such as antibacterial, antiviral, anti-inflammatory, anticancer and antihyperglycemic activity [139, 140]. Studies have shown that berberine has notable inhibitory activity against AChE (IC50: 0.5–0.7 µM) and BuChE (IC50: 30.7 µM) and also has the potential to inhibit MAO-A enzyme [138, 141, 142]. As a safe, non-toxic chemical capable of reducing AD risk factors such as diabetes and atherosclerosis, berberine can be orally administered as an anti-AD drug [143]. Pseudoberberine and pseudocoptisine are also isoquinoline alkaloids with AChEI properties [144, 145].
Palmatine is reported to be an efficient inhibitor of AChE (IC50 0.46–1.69 µM) compared to BuChE (IC50 > 100 µM) [138, 141, 146]. As per recent reports, palmatine has inhibitory potential against MAO-A [147] and can also cross the BBB, causing changes in the hippocampus and cerebellum [148]. A synergistic effect of parallel administration of berberine and palmatine was reported by [138], suggesting that the positively charged nitrogen in these alkaloids can bind to the gorge of the active site and thereby inhibit the enzyme [149].
Chelerythrine is a benzophenanthridine isoquinoline alkaloid isolated from Chelidonium majus L. that has dual cholinesterase activity against AChE (IC50 1.54 µM) and BuChE (IC50 10.34 µM) [150]. Chelerythrine is also a potential inhibitor of Aβ1–40 aggregation and deaggregation of preexisting Aβ1–40 aggregates [146]. It has also shown selective inhibition against the human MAO-A enzyme [151]. Extracts of Zanthoxylum rigidum Humb. Et Bonpl. Ex Willd yielded two alkaloids, avicine and ntidine, with dual cholinesterase inhibitory activity against AChE and BuChE. Being mixed-type inhibitors, they can bind at the catalytic and PAS of the enzymes and inhibit ChE-induced Aβ1–40 aggregates. Like chelerythrine, avicine and nitidine also showed inhibitory activity against MAO-A [152]. Groenlandicine and jatrorrhizine are also isoquinoline alkaloids isolated from Coptis chinensis Franch., which possess BACE-1 Inhibitory activity in addition to AChEI potential [153].
Amaryllidaceae alkaloids are a special class of alkaloids restricted to the family Amaryllidaceae. Galantamine is one of the most important Amaryllidaceae alkaloids isolated from Galanthus woronowii. It is an FDA-approved drug for treating AD and is a selective inhibitor of AChE compared to BuChE. The Narcissus genus gained significant attention in phytochemical and pharmaceutical research due to its wide range of alkaloidal content. Galantamine is now isolated on an industrial scale from the bulbs of Narcissus spp. [117, 154]. Ungeremine and lycorine are alkaloids with a moderate AChEI potential isolated from Narine bowdenii W. Watson and Narcissus pseudonarcissus [118]. Around 600 Amaryllidaceae alkaloids have been isolated so far, of which the Narcissus genus alone contributes more than 100 [155, 156]. Haemanthamine is yet another type of a β-crinane-type Amaryllidaceae alkaloid in many Narcissus species. Several reports reveal the AChEI activity and in vitro cytotoxic of haemanthamine against cancer cell lines such as HeLa, MCF7, HepG2, and A549 [11, 157].
Lycopodium alkaloids are another category of alkaloids found in the family Lycopodiaceae, and they possess an unusual tetracyclic ring structure. Carinatumins A and B isolate from Lycopodium carinatum Desv. ex Poir. possess notable AChEI activity with IC50 values of 4.6 µM and 7.0 µM, respectively [128, 158]. Lycojaponidine A is another lycopodium alkaloid with a high AChEI capacity similar to galantamine and hence, a potential drug for AD treatment [128]. Huperzine A is one of the highly potent and well-studied AChE inhibitor alkaloids isolated from Huperzia serrata. It is a reversible inhibitor of AChE with activity comparable to that of galantamine and physostigmine [159–161]. It has dual cholinesterase inhibitory activity but is more selective to AChE in different brain parts, including the cerebellum, cortex, hippocampus, and hypothalamus. It has increased bioavailability and can cross the BBB [159–161]. Being a mixed-type inhibitor, huperzine A also regulates amyloid beta precursor protein metabolism and inhibits Aβ aggregation, thereby reducing Aβ-associated neurotoxicity [162, 163].
Another category of alkaloids is the triterpenoid steroidal alkaloids. Several of them, including lyrcanone, hyrcamine, and buxidine, have been shown to have notable AChEI potential [127]. There are still many alkaloids yet to be studied and many to be clinically tested, which could be potential drugs for the treatment of AD and other neurodegenerative diseases.
Caffeine is a plant alkaloid found in coffee (Coffea arabica), which is a central nervous system stimulant [164]. Studies have shown that caffeine is a non-competitive inhibitor of AChE. Though its activity is moderate compared to donepezil and galantamine, it can be administered in higher doses as it is less toxic [165]. Recent research shows that habitual caffeine intake can increase cognitive response in females with AD [166]. Also, short-term intake of a combination of caffeine and caffeic acid in moderate concentration (50 mg/kg body weight) can reduce AD symptoms by lowering lipid peroxidation, increasing antioxidant status and inhibiting AChE, arginase and adenosine deaminase activity, thereby improving brain activity [167].
Polyphenols
Polyphenols are phenylpropanoid secondary metabolites produced by plants as a defence mechanism against pathogens or stress. Polyphenols are commonly classified as flavonoids and nonflavonoids. Flavonoids include flavonols, flavones, isoflavones, flavanones, anthocyanidins and chalcones, while nonflavonoids include phenolic acids (hydroxybenzoic acids, cinnamic acids) and phenolic amides [168]. Numerous studies have been published emphasizing the potential of polyphenols in suppressing the onset and advancement of several diseases [169, 170]. The interaction of phenolic compounds with active site amino acid residues of AChE is characterized by hydrogen bonding, hydrophobic interactions, and π-π stacking [171]. Moreover, the presence of multiple hydroxyl groups enhances the binding capacity of phenolic compounds and consequently, their AChEI potential [172].
Flavonoids
Flavonoids are a large class of polyphenolic secondary metabolites widely found in fruits, vegetables, herbs, and some beverages [173]. These are of interest due to their health-promoting effects, such as antioxidant, anti-inflammatory, anticancerous and antimutagenic properties, which increase their demand in pharmaceutical, neutraceutical, cosmetic and medicinal fields [174]. Many flavonoids are potential inhibitors of enzymes, such as lipoxygenase, cyclo-oxygenase, xanthine-oxidase and cholinesterases [173]. There are six major classes of flavonoids based on the position of benzoid and its modification, which include flavonols (quercetin, myricetin, kaempferol), flavones (apigenin, luteolin, chrysin), isoflavones (daidzein, genistein), flavanones (naringenin, hesperetin), anthocyanidins (cyanidin, delphinidin) and chalcones (flavokawin, cardamonin) [173].
Flavonoids are secondary metabolites that can reverse AD symptoms and improve memory and learning via multiple pathways, including AChE—choline acetyltransferase (ChAT) balancing and modulation of G protein-coupled receptor 30 (GPR30) [175, 176]. Genistein and quercetin are two flavonoids that inhibit AChE activity and enhance ChAT activity, leading to increased levels of ACh in the hippocampus and thereby improving cholinergic neurotransmission metabolites [176]. Flavonoids such as quercetin, kaempferol, luteolin and chrysin, which possess high antioxidant activity, reduce oxidative stress-induced AD by scavenging reactive oxygen species (ROS) as well as activating antioxidant enzymes such as catalase and superoxide dismutase [177–179].
In a study to find the AChEI potential of selected flavonoids, quercetin and tiliroside demonstrated remarkable AChEI potential of IC50 19.8 μM and 23.5 μM, respectively [180]. However, another study focused on leishmanicidal and AChEI activities of flavonoids isolated from the beans of Dimorphandra gardneriana revealed that rutin and quercetin displayed remarkable leishmanicidal activity and AChEI activity compared to the standard physostigmine [181]. Dzoyem and Eloff [182] reported that flavonoids isolated from Dorstenia and Polygonum species such as 2’,4’-dihydroxy-3’,6’-dimethoxychalcone, 3 6-8-diprenyleriodictyol, isobavachalcone, 4-hydroxylonchocarpin, 6-prenylapigenin showed significant AChEI activity with values ranging from 5.93–8.76 μg/mL which is comparable to the positive control eserine (IC50 4.94 μg/mL). In addition, 3 6-8-diprenyleriodictyol, isobavachalcone and 6-prenylapigenin also showed lipoxygenase inhibitory activity.
On screening a series of flavonoids for their AChEI activity, Balkis et al. [183] found that baicalein from Scutellaria baicalensis roots had the highest AChEI potential with an IC50 value of 0.61 μM as compared to positive control tacrine (IC50 25.4 μM). An investigation of the enzyme kinetics revealed that baicalein is a mixed-type inhibitor. Significant inhibitory activity was also shown by apigenin, cyanidin, chrysin, kaempferol, myricetin, quercitrin, perlargonidin, (–)-epigallocatechin gallate (EGCG), and galangin with an IC50 ranging from 3.05 μM to 19.1 μM. Other flavonoids such as baohouside 1, dephinidin and melvidin displayed relatively low inhibition with IC50 ranging from 41.1–89 μM. Sevindik et al. [184] isolated four flavonoids with remarkable cholinesterase inhibitory potential from the aerial part of Achillea millefolium. Of the four, 6-OH-luteolin 7-O-β-D-glucoside displayed the highest AChE (IC50 1.65 μM) and BChE (IC50 1.97 μM) inhibitory activity, suggesting its potential to become a novel therapeutic drug for AD treatment.
EGCG, a flavonoid in green tea, has significant AChEI activity [185]. It has also shown inhibition of tau-phosphorylation, antioxidant, anti-inflammatory and antiapoptotic properties, altogether contributing to its neuroprotective properties [185]. Naringin is a flavanone that inhibits AChE activity, neuroinflammation in stress-prone brain regions, nitric oxide-induced stress and oxidative stress [186].
Non-flavonoids
Curcumin is the prominent polyphenolic component in Curcuma longa that possesses antimicrobial, antiviral, antioxidant, anti-inflammatory and anticarcinogenic properties [187, 188]. Curcumin is used in the treatment of various diseases such as AD, psoriasis, multiple myeloma, myelodysplastic syndrome, pancreatic cancer and AIDS [188–190]. A recent in vitro study reported the AChEI potential of curcuminoids. Among curcuminoids, the highest AChEI potential was observed in bisdemethoxy curcumin (IC50 2.14 μM), followed by demethoxycurcumin (IC50 19.7 μM). Curcumin showed comparatively lower activity (IC50 51.8 μM). While bisdemethoxycurcumin showed a low inhibitory activity against BuChE (IC50 67.2 μM), curcumin and demethoxycurcumin had no inhibitory potential against the same [191]. Two studies recently reported the AChEI potential of curcumin in rat models. Wolkmer et al. [192] reported that Wistar rats fed 0.1 mL/kg body weight of curcumin daily showed inhibition of AChE and improved immunological response. In another study, Akinyemi et al. [193] reported AChE inhibition mediated memory improvement in cadmium-exposed albino rats fed with curcumin (12.5 mg/kg) for 7 days.
The dual cholinesterase inhibitory potential of resveratrol oligomers isolated from Vitis amurensis was reported by Jang et al. [194]. The resveratrol oligomers (10 μg/mL), vitisin A and heyneanol A showed inhibition against AChE, BuChE and Aβ aggregation in a dose-dependent manner. In another study, male Wistar rats treated with 10 mg/kg of resveratrol showed a remarkable AChE activity reduction [195]. Further studies showed a reduction in AChE activity in synaptomes of the cerebral cortex in 10 mg/kg resveratrol-treated diabetic rats [196]. Another therapeutic approach with pyridoxine-resveratrol hybrids showed a mixed inhibition pattern (IC50 1.56–2.11 μM) by simultaneously binding to the catalytic and PAS of AChE [197]. Both curcumin and resveratrol are promising AChE inhibitors currently under phase 3 clinical trials against AD [120].
Cinnamic acid is a polyphenolic compound found abundantly in fruits, spices and vegetables such as cinnamon (Cinnamomum cassia), grapes, citrus fruits, cocoa, celery, cruciferous vegetables and spinach [198, 199]. Numerous studies have reported its antioxidant, anticancer, anti-inflammatory and antidiabetic properties [198, 200, 201]. They can be administered orally as they are readily absorbed by the small intestine [202]. Elufioye et al. [203] reported the AChE (6.51 μg/mL) and BuChE (9.07 μg/mL) inhibitory potential of 2,3-dimethyl derivative of cinnamic acid (omifoate A), isolated from the leaves of pycnanthus angolensis (Welw.) Warb. Lan et al. [204] reported the remarkable AChEI potential (IC50 8.6 nM) of a novel cinnamic acid derivative, E)-4-(3-(3,4-dimethoxyphenyl) acrylamido)-1-(3-methylbenzyl) pyridin-1-ium bromide with over threefold higher inhibitory potential than donepezil. It also showed inhibition of Aβ aggregation, neuroprotection against amyloid-induced toxicity, and the ability to penetrate the BBB, making it a good candidate for AD therapy.
Terpenoids
Terpenes are simple hydrocarbons composed of multiple isoprene units, representing one of the largest and most diverse classes of secondary metabolites synthesized by plants [205]. Terpenoids are terpene derivatives with different functional groups. Based on the number of isoprene units that form the parent terpene, terpenoids can be classified into hemiterpenoids (one isoprene unit), monoterpenoids (two isoprene units), sesquiterpenoids (three isoprene units), diterpenoids (four isoprene units), sesterterpenoids (five isoprene units), triterpenoids (six isoprene units) and tetraterpenoids (eight isoprene units) [206, 207]. Therapeutic applications of terpenoids owe to their wide range of biological activities, such as antioxidant, anti-inflammatory, antimicrobial, anticancer, anti-hyperglycaemic, anti-cholinesterase and immunomodulatory activities [208]. For example, Taxol and artemisinin are terpene-based drugs used as anticancer and anti-malarial medications, respectively [209–211]. The anti-cholinesterase activity of terpenoids has recently gained much attention. Numerous studies have reported the AChE and BuChE inhibitory and neuroprotective potential of terpenoids.
In a study conducted by Dohi et al. [212], for screening terpenoids from commercial essential oils, 1,8-cineole (IC50 15 μg/mL) and α-pinene (IC50 22 μg/mL) showed higher AChEI activity compared to others such as estragole and limonene (IC50 > 100 μg/mL). Wojtunik-Kulesza et al. [213] reported the remarkable AChEI potential of farnesene compared to other monoterpenes tested in a Marston assay.
In an attempt to evaluate the AChEI potential of sesquiterpenoids isolated from Cynara cornigera L., Hegazy et al. [214] found that a chlorinated sesquiterpene lactone, cornigeraline A, had the highest AChEI potential (IC50 20.5 µM). Due to the presence of two hydrophobic moieties in the nucleus, it may cross the BBB [53]. Other sesquiterpenes such as sibthropine (IC50 35.8 µM), 3-hydroxy-grosheimin (IC50 30.5 µM), grosheimin (IC50 61.8 µM), solstitalin A (IC50 25.7 µM), 13-chlorosolstitialine (IC50 62.1 µM), and cynaropicrin (IC50 31.3 µM) also displayed moderate AChE inhibition [53, 214]. Alarcón et al. [215] isolated nine dihydro-β-agarofuran sesquiterpenes from the aerial parts and seeds of Maytenus disticha (Hook.f.) Urb. and Euonymus japonicus Thunb. They were all weak but selective AChE inhibitors, with IC50 values ranging from 70–381 µg/L.
Artemisinin (IC50 103.9 µM) from Artemisia annua and quinanol A (IC50 100.8 µM) from Aquilaria sinensis (Lour.) Gilg, are sesquiterpenes with moderate AChEI potential [216, 217]. In a recent study, Zardi-Bergaoui et al. [218] isolated caryophyllene-type sesquiterpenes from aerial parts of Pulicaria vulgaris Gaertn. Among them, two compounds namely, (1S,5Z,9R,11S)-12,14-dihydroxycaryophylla-2(15),5-dien-7-one and (1S,6R,9S,11R)-13,14-dihydroxycaryophyll-2(15)-en-7-one displayed higher AChEI potential (IC50 25.8 μM and 40.0 μM respectively) compared to other compounds. Another sesquiterpenoid, Megatigma-7,9-diene-1,4-epoxy-2-hydroxy-10-carboxylic acid with high AChEI potential (IC50 9.3 μM), was isolated by Liu et al. [219] from Lycopodiastrum casuarinoides (Spring) Holub.
Diterpenes such as 12-O-demethylcryptojaponol and 6α-hydroxydemethylcryptojaponol, isolated from Caryopteris mangolica Bunge, inhibited human erythrocyte AChE, with an IC50 value of 50.8 μM and 19.2 μM, respectively, suggesting their potential role in AD therapy and the importance of C6 hydroxyl group in the inhibition of AChE [220].
Tanshinones are a category of abietane-type diterpenes isolated from Salvia species, which have high permeability across the BBB. Tanshinone from the roots of Salvia glutinosa L. and Salvia yangii B.T.Drew, namely 15,16-dihydrotanshinone was found to be a moderate inhibitor of AChE (IC50 35.8 μM). While other tanshinones isolated from the same plants, such as cryptotanshinone, Miltirone, 1β-hidroxicryptotanshinone, and 1,2-didehydromiltirone are inactive inhibitors of AChE [221]. Lycocasuarinone A is another abietane-type diterpene isolated from Lycopodiastrum casuarinoides, that inhibits (IC50 26.8 μM) AChE [219].
Numerous serratene-type triterpenes were extracted from Lycopodiastrum casuarinoides, of which 26-nor-8-oxo-21-one-α-onocerin showed remarkable inhibition of AChE (IC50 1.01 μM) compared to other compounds [219]. Nguyen et al. [222] isolated twelve serratene-type terpenes from Lycopodiella cernua. Four among the twelve, namely 3β,21α-diacetoxyserratan-14β-ol (IC50 0.91 μM), 3β,21β,29-trihydroxyserrat-14-en-3β-yl p-dihydrocoumarate (IC50 1.69 μM), 3β,14α,15α,21β-tetrahydroxyserratan-24-oicacid-3β-yl-(40-methoxy-50-hydroxybenzoate) (IC50 9.98 μM), and 21β-hydroxyserrat-14-en-3,16-dione (IC50 10.67 μM) exhibited strong inhibition against AChE [208].
Ado et al. [223] revealed the AChEI potential of euscaphic acid, arjunic acid and ursolic acid isolated from the leaves of Callicarpa maingayi K & G. They exhibited IC50 values of 35.9 μM, 37.5 μM, and 21.5 μM, respectively. Similar AChEI activity was reported by Jamila et al. [224] in triterpenoids isolated from Garcinia hombroniana Pierre 2-hydroxy-3α-O-caffeoyltaraxar-14-en-28-oic acid, betulin and betulinic acid. Among the three, Pierre 2-hydroxy-3α-O-caffeoyltaraxar-14-en-28-oic acid showed the highest AChEI potential with an IC50 value of 13.5 µM, followed by betulinic acid (IC50 24.2 µM) and betulin (IC50 28.5 µM).
Trichilia lactone D5, rohituka 3 and dregeanin DM4 are three limonoids isolated from the seeds of Trichilia welwitschia. All three showed AChE inhibition at varying levels (IC50 19.13 μM, 34.15 μM, and 45.69 μM, respectively) [53]. Colocynthenin A and colocynthenin C are cucurbitane-type triterpenes isolated from the fruits of Cirtrullus colocynthis L. They possess high AChEI potentials of 2.6 μM and 3.1 μM, respectively [225].
Another AChEI triterpenoid, 3β-Hydroxy-24-nor-urs-4(23)-12-dien-28-oic acid obtained from Patrinia scabiosaefolia showed an IC50 value of 10.0 μM. In another research, Liu et al. [226] isolated three pentacyclic triterpenes from the roots and breaches of Malpighia emarginata DC such as norfriedelin A, norfriedelin B and norfriedelin C. On analysis of their AChEI potential, norfriedelin A and B showed better activity (IC50 10.3 μM and 28.7 μM, respectively) than norfriedelin C (IC50 > 50 μM). Isolation and identification of the lead molecules from plant extracts and their structure-activity relationship studies may facilitate decision-making and selection of potential phytochemicals for drug discovery to aid in AD therapy.
Conclusions
AD therapy turned out to be highly challenging due to its multifactorial etiolgy and complex pathophysiology. Despite having 3 drugs that are already approved by the FDA for AD treatment, scientists are in quest of developing anti-AD drugs with minimal toxicity and side effects. This review provides a thorough overview of various medicinal plants, their extracts and phytochemicals that could be potential AChE inhibitors. Though numerous medicinal plants have AChEI properties, some families, such as Amaryllidaceae, Fabaceae, Lycopodiaceae and Amaranthaceae, have more species with anti-AChE potential. However, a drastic variation can be seen in the AChEI activity of plant extracts regardless of the family, genus, predominant phytochemical or the extracting solvent. As per the literature review and analysis, a plethora of secondary metabolites, including alkaloids, phenolics, flavonoids and terpenoids, reportedly demonstrated cholinesterase inhibitory activity. Besides, many of them show a multitarget approach in AD therapy by inhibiting AChE, BuChE, MAO-A, BACE-1, Aβ aggregation, tau phosphorylation, and an ability to cross BBB. Most of them also possess antioxidant and anti-inflammatory properties, which are also helpful in minimising oxidative stress and inflammation mediated neurodegeneration. Certain phytochemical combinations (such as berberine and palmaline) have exhibited synergistic activity against AChE. One limiting factor here would be the limited bioavailability, which can be addressed by plant tissue culture and elicited phytochemical production. As conventional therapies only give symptomatic relief of AD, alternative therapies are being largely studied, and several phytochemicals, including curcumin, are under clinical and pre-clinical trials, which may serve as potential drug candidates for the treatment of AD. These bioactive compounds can be isolated and modified to maximise efficiency, potentially revolutionising AD therapy.
AbbreviationsAch
acetylcholine
AChE
acetylcholinesterase
AChEIs
acetylcholinesterase inhibitors
AD
Alzheimer’s disease
Aβ
β-amyloid
BACE-1
beta site amyloid precursor protein cleaving enzyme 1
BBB
blood-brain barrier
BuChE
butyrylcholinesterase
ChAT
choline acetyltransferase
EGCG
Epigallocatechin gallate
FDA
Food and Drugs Administration
GPR30
G protein-coupled receptor 30
MAO
monoamine oxidase
PAS
peripheral anionic site
DeclarationsAuthor contributions
DAV: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. DTT: Conceptualization, Writing—review & editing, Supervision. Both authors read and approved the submitted version.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent to publication
Not applicable.
Availability of data and materials
All datasets generated or analyzed during this study are included in the manuscript and references.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
SantosTCDGomesTMPintoBASCamaraALPaesAMdANaturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer’s Disease TherapyFront Pharmacol20189119210.3389/fphar.2018.0119230405413PMC6201143FiestKMRobertsJIMaxwellCJHoganDBSmithEEFrolkisAet al.The Prevalence and Incidence of Dementia Due to Alzheimer’s Disease: a Systematic Review and Meta-AnalysisCan J Neurol Sci201643S518210.1017/cjn.2016.3627307128ScheltensPBlennowKBretelerMMBStrooperBdFrisoniGBSallowaySet al.Alzheimer’s diseaseLancet20163885051710.1016/S0140-6736(15)01124-126921134PrinceMWimoAGuerchetMAliGCPrinaMWorld Alzheimer Report 2015. The Global Impact of Dementia. An Analysis of Prevalence, Incidence, Cost and TrendsAlzheimer’s Dis Int20152021 Alzheimer’s disease facts and figuresAlzheimers Dement20211732740610.1002/alz.1232833756057AbubakarMBSanusiKOUgusmanAMohamedWKamalHIbrahimNHKhooCSKumarJAlzheimer’s Disease: An Update and Insights Into PathophysiologyFront Aging Neurosci20221474240810.3389/fnagi.2022.74240835431894PMC9006951SavelieffMGLeeSLiuYLimMHUntangling amyloid-β, tau, and metals in Alzheimer’s diseaseACS Chem Biol201388566510.1021/cb400080f23506614TrippierPCLabbyKJHawkerDDMatakaJJSilvermanRBTarget- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbersJ Med Chem20135631214710.1021/jm301592623458846PMC3637880Agis-TorresASölhuberMFernandezMSanchez-MonteroJMMulti-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer’s DiseaseCurr Neuropharmacol20141223610.2174/1570159X11311666004724533013PMC3915347BlaikieLKayGLinPKTCurrent and emerging therapeutic targets of alzheimer’s disease for the design of multi-target directed ligandsMedchemcomm20191020527210.1039/c9md00337a32206241PMC7069509TaquiRDebnathMAhmedSGhoshAAdvances on plant extracts and phytocompounds with acetylcholinesterase inhibition activity for possible treatment of Alzheimer’s diseasePhytomed Plus2022210018410.1016/j.phyplu.2021.100184SutherlandGTSiebertGAKrilJJMellickGDKnowing me, knowing you: can a knowledge of risk factors for Alzheimer’s disease prove useful in understanding the pathogenesis of Parkinson’s disease?J Alzheimers Dis20112539541510.3233/JAD-2011-11002621441655SelkoeDJHardyJThe amyloid hypothesis of Alzheimer’s disease at 25 yearsEMBO Mol Med2016859560810.15252/emmm.20160621027025652PMC4888851KPPrasanthDSNBKShadaksharaMKRAhmadSFSeemaladinneRRudrapalMet al.Citronellal as a Promising Candidate for Alzheimer’s Disease Treatment: A Comprehensive Study on In Silico and In Vivo Anti-Acetylcholine Esterase ActivityMetabolites202313113310.3390/metabo1311113337999229PMC10672888MurrayAPFaraoniMBCastroMJAlzaNPCavallaroVNatural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease TherapyCurr Neuropharmacol20131138841310.2174/1570159X1131104000424381530PMC3744903AnandRGillKDMahdiAATherapeutics of Alzheimer’s disease: Past, present and futureNeuropharmacology201476275010.1016/j.neuropharm.2013.07.00423891641MasondoNAStaffordGIAremuAOMakungaNPAcetylcholinesterase inhibitors from southern African plants: An overview of ethnobotanical, pharmacological potential and phytochemical research including and beyond Alzheimer’s disease treatmentS Afr J Bot2019120396410.1016/j.sajb.2018.09.011KhanHMaryaAminSKamalMAPatelSFlavonoids as acetylcholinesterase inhibitors: Current therapeutic standing and future prospectsBiomed Pharmacother20181018607010.1016/j.biopha.2018.03.00729635895ReidGADarveshSInteraction of exogenous acetylcholinesterase and butyrylcholinesterase with amyloid-β plaques in human brain tissueChem Biol Interact202439511101210.1016/j.cbi.2024.11101238648920XuHFerreiraDLondosEEriksdotterMCholinesterase inhibitors, cognitive decline, major cardiovascular events, and mortality in dementia with Lewy bodiesAlzheimer’s Dement202319e07801710.1002/alz.078017PatelAShahDPatelYPatelSMehtaMBambharoliyaTA Review on Recent Development of Novel Heterocycles as Acetylcholinesterase Inhibitor for the Treatment of Alzheimer’s DiseaseCurr Drug Targets2023242254610.2174/138945012466622121311450036515018VecchioISorrentinoLPaolettiAMarraRArbitrioMThe State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s DiseaseJ Cent Nerv Syst Dis2021131179573521102911310.1177/1179573521102911334285627PMC8267037GaoYLiuYLiYSafety and efficacy of acetylcholinesterase inhibitors for Alzheimer’s disease: A systematic review and meta-analysisAdv Clin Exp Med20243311798710.17219/acem/17605138439609YunYMiaoYSunXSunJWangXSynthesis and biological evaluation of 2-arylbenzofuran derivatives as potential anti-Alzheimer’s disease agentsJ Enzyme Inhib Med Chem20213613465610.1080/14756366.2021.194099334134572PMC8765280HowesMJRHoughtonPJAcetylcholinesterase inhibitors of natural originInt J Biomed Pharm Sci200936786FadaeinasabMBasiriAKiaYKarimianHAliHMMurugaiyahVNew Indole Alkaloids from the Bark of Rauvolfia Reflexa and their Cholinesterase Inhibitory ActivityCell Physiol Biochem2015371997201110.1159/00043856026584298MajoloFHoffmannLFAnaWLPSAlvesCSilvaJMartinsAet al.Recent Drugs Tested in Clinical Trials for Alzheimer’s and Parkinson’s Diseases Treatment: Current Approaches in Tracking New DrugsFront Clin Drug Res: CNS Neurol Disord20241215810.2174/9789815179842124120003PratapGKShantaramMAn Alternative Approach for Anti-Alzheimer’s Compounds from Plant ExtractsPhytomedicine and Alzheimer’s Disease. CRC Press; 2020.NguyenKHoffmanHChakkamparambilBGrossbergGTEvaluation of rivastigmine in Alzheimer’s diseaseNeurodegener Dis Manag202111354810.2217/nmt-2020-005233198569PolinskyRJClinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s diseaseClin Ther1998206344710.1016/s0149-2918(98)80127-69737824HaakeANguyenKFriedmanLChakkamparambilBGrossbergGTAn update on the utility and safety of cholinesterase inhibitors for the treatment of Alzheimer’s diseaseExpert Opin Drug Saf2020191475710.1080/14740338.2020.172145631976781FarlowMRGrossbergGTSadowskyCHMengXSomogyiMA 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer’s dementiaCNS Neurosci Ther2013197455210.1111/cns.1215823924050PMC4233957ShamsiAMohammadTAnwarSAlajmiMFHussainAHassanMIet al.Probing the interaction of Rivastigmine Tartrate, an important Alzheimer’s drug, with serum albumin: Attempting treatment of Alzheimer’s diseaseInt J Biol Macromol20201485334210.1016/j.ijbiomac.2020.01.13431954794RayBMaloneyBSambamurtiKKarnatiHKNelsonPTGreigNHet al.Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s diseaseTransl Psychiatry20201047Erratum in: Transl Psychiatry. 2020;10:81. 10.1038/s41398-020-0709-x32066688PMC7026402MohsinNAAhmadMDonepezil: A review of the recent structural modifications and their impact on anti-Alzheimer activityBraz J Pharm Sci202056e1832510.1590/s2175-97902019000418325ColovićMBKrstićDZLazarević-PaštiTDBondžićAMVasićVMAcetylcholinesterase inhibitors: pharmacology and toxicologyCurr Neuropharmacol2013113153510.2174/1570159X1131103000624179466PMC3648782JelicVDarreh-ShoriTDonepezil: A Review of Pharmacological Characteristics and Role in the Management of Alzheimer DiseaseClin Med Insights: Ther20102CMT.S541010.4137/CMT.S5410SharmaKCholinesterase inhibitors as Alzheimer’s therapeutics (Review)Mol Med Rep20192014798710.3892/mmr.2019.1037431257471PMC6625431PooladgarPSakhabakhshMTaghvaASoleiman-MeigooniSDonepezil Beyond Alzheimer’s Disease? A Narrative Review of Therapeutic Potentials of Donepezil in Different DiseasesIran J Pharm Res202221e12840810.5812/ijpr-12840836942075PMC10024338DuHLiuXXieJMaFNovel Deoxyvasicinone-Donepezil Hybrids as Potential Multitarget Drug Candidates for Alzheimer’s DiseaseACS Chem Neurosci201910239740710.1021/acschemneuro.8b0069930720268ZhangHZhaoYYuMZhaoZLiuPChengHet al.Reassembly of native components with donepezil to execute dual-missions in Alzheimer’s disease therapyJ Control Release2019296142810.1016/j.jconrel.2019.01.00830639387KrishnaKVSahaRNDubeySKBiophysical, Biochemical, and Behavioral Implications of ApoE3 Conjugated Donepezil Nanomedicine in a Aβ1-42 Induced Alzheimer’s Disease Rat ModelACS Chem Neurosci20201141395110.1021/acschemneuro.0c0043033251785KhoJIoannouAMandalAKJMissourisCGDonepezil induces ventricular arrhythmias by delayed repolarisationNaunyn Schmiedebergs Arch Pharmacol20213945596010.1007/s00210-020-02028-433230575HsiehCTsengPChenTLinPChenYHoBet al.The association of changes of sleep architecture related to donepezil: A systematic review and meta-analysisJ Formos Med Assoc202212114667710.1016/j.jfma.2021.10.01334753629WangHLiouLHsuCLinHLetter to the editor: Donepezil-induced parkinsonism in end-stage renal diseaseNeurol Sci20214248091210.1007/s10072-021-05522-634346013SutthapitaksakulLDassCRSriamornsakPDonepezil—an updated review of challenges in dosage form designJ Drug Deliv Sci Technol20216310254910.1016/j.jddst.2021.102549AdlimoghaddamANeuendorffMRoyBAlbensiBCA review of clinical treatment considerations of donepezil in severe Alzheimer’s diseaseCNS Neurosci Ther2018248768810.1111/cns.1303530058285PMC6489741MarucciGBuccioniMBenDDLambertucciCVolpiniRAmentaFEfficacy of acetylcholinesterase inhibitors in Alzheimer’s diseaseNeuropharmacology202119010835210.1016/j.neuropharm.2020.10835233035532SaitoTHisaharaSIwaharaNEmotoMCYokokawaKSuzukiHet al.Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer’s diseaseFree Radic Biol Med2019145203210.1016/j.freeradbiomed.2019.09.01431536772SimoniEDanieleSBottegoniGPizziraniDTrincavelliMLGoldoniLet al.Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer’s diseaseJ Med Chem20125597082110.1021/jm300945823033965SinghalMMerinoVRosiniMCavalliAKaliaYNControlled Iontophoretic Delivery in Vitro and in Vivo of ARN14140-A Multitarget Compound for Alzheimer’s DiseaseMol Pharm2019163460810.1021/acs.molpharmaceut.9b0025231241959VaradharajanADavisADGhoshAJagtapTXavierAMenonAJet al.Guidelines for pharmacotherapy in Alzheimer’s disease - A primer on FDA-approved drugsJ Neurosci Rural Pract2023145667310.25259/JNRP_356_202338059250PMC10696336LimaEMedeirosJTerpenes as Potential Anti-Alzheimer’s Disease AgentsAppl Sci202414389810.3390/app14093898ShahHPatelAParikhVNaganiABhimaniBShahUet al.The β-Secretase Enzyme BACE1: A Biochemical Enigma for Alzheimer’s DiseaseCNS Neurol Disord Drug Targets2020191849410.2174/187152731966620052614414132452328LiuWLiuXTianLGaoYLiuWChenHet al.Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer’s diseaseEur J Med Chem202122211355410.1016/j.ejmech.2021.11355434098466PatelSSRaghuwanshiRMasoodMAcharyaAJainSKMedicinal plants with acetylcholinesterase inhibitory activityRev Neurosci20182949152910.1515/revneuro-2017-005429303784SaadSAAbd-AllaHIAlyHFShalabyNMMAfifyAEMMRAliHFMet al.Citharexylum spinosum promotes antioxidant, anti-inflammatory, and anti-acetylcholinesterase activitiesEgypt J Chem202467637510.21608/ejchem.2023.235755.8594da Silva BarbosaDCHolandaVNde AssisCRDde Oliveira Farias de AguiarJCRdoNascimentoPHda SilvaWVet al.Chemical composition and acetylcholinesterase inhibitory potential, in silico, of Myrciaria floribunda (H. West ex Willd.) O. Berg fruit peel essential oilInd Crops Prod202015111237210.1016/j.indcrop.2020.112372NwiduLLElmorsyEThorntonJWijamunigeBWijesekaraATarboxRet al.Anti-acetylcholinesterase activity and antioxidant properties of extracts and fractions of Carpolobia luteaPharm Biol20175518758310.1080/13880209.2017.133928328629287PMC6130458AdewusiEASteenkampVIn vitro screening for acetylcholinesterase inhibition and antioxidant activity of medicinal plants from southern AfricaAsian Pac J Trop Med201148293510.1016/S1995-7645(11)60203-422014742ArmijosCGilardoniGAmayLLozanoABraccoFRamirezJet al.Phytochemical and ethnomedicinal study of Huperzia species used in the traditional medicine of Saraguros in Southern Ecuador; AChE and MAO inhibitory activityJ Ethnopharmacol20161935465410.1016/j.jep.2016.09.04927686269Cardoso-LopesEMMaierJASilvaMRdRegasiniLOSimoteSYLopesNPet al.Alkaloids from stems of Esenbeckia leiocarpa Engl. (Rutaceae) as potential treatment for Alzheimer diseaseMolecules20101592051310.3390/molecules1512920521160449PMC6259197AazzaSEl-GuendouzSMiguelMScreening for acetylcholinesterase inhibition, lipid peroxidation inhibition and antioxidant activity of medicinal plants from MoroccoBol Latinoam Caribe Plant Med Aromat20232211810.37360/blacpma.23.22.1.1KukEBJoAROhSISohnHSSeongSHRoyAet al.Anti-Alzheimer’s disease activity of compounds from the root bark of Morus alba LArch Pharm Res2017403384910.1007/s12272-017-0891-428093699AliMYJungHAChoiJSAnti-diabetic and anti-Alzheimer’s disease activities of Angelica decursivaArch Pharm Res20153822162710.1007/s12272-015-0629-026152875FawoleOAAmooSONdhlalaARLightMEFinnieJFStadenJVAnti-inflammatory, anticholinesterase, antioxidant and phytochemical properties of medicinal plants used for pain-related ailments in South AfricaJ Ethnopharmacol20101272354110.1016/j.jep.2009.11.01519932161LimaJACostaRSEpifânioRACastroNGRochaMSPintoACGeissospermum vellosii stembark: anticholinesterase activity and improvement of scopolamine-induced memory deficitsPharmacol Biochem Behav2009925081310.1016/j.pbb.2009.01.02419463267PenumalaMZinkaRBShaikJBMallepalliSKRVaddeRAmooruDGPhytochemical profiling and in vitro screening for anticholinesterase, antioxidant, antiglucosidase and neuroprotective effect of three traditional medicinal plants for Alzheimer’s Disease and Diabetes Mellitus dual therapyBMC Complement Altern Med2018187710.1186/s12906-018-2140-x29499679PMC5834903LinHQHoMTLauLSWongKKShawPCWanDCCAnti-acetylcholinesterase activities of traditional Chinese medicine for treating Alzheimer’s diseaseChem Biol Interact2008175352410.1016/j.cbi.2008.05.03018573242OhbaTYoshinoYIshisakaMAbeNTsurumaKShimazawaMet al.Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in miceBiosci Biotechnol Biochem20157918384410.1080/09168451.2015.105277326059088Suciati, Poerwantoro D, Widyawaruyanti A, Ingkaninan K. Acetylcholinesterase inhibitory activity of extract and fractions from the root of Rauvolfia serpentina(L.) Bth.ex KurzJ Basic Clin Physiol Pharmacol202132313710.1515/jbcpp-2020-040134214376IdrisMParumasivamTAwangKZahariALitaudonMApelCet al.Bioassay-guided isolation of acetylcholinesterase and butyrylcholinesterase inhibitors from Horsfieldia tomentosa fruits (Myristicaceae)Phytochem Lett2025651334010.1016/j.phytol.2025.01.007da Silva LopesFFLuísEloi Silva Jde Morais Pereira EloiNMoreiraRodrigues ALda SilvaMVFMontesRAet al.Chemical Characterization, Phenolic Compounds Quantification, and Assessment of Antioxidant and Anti-Acetylcholinesterase Activities of Byrsonima sericea DC fruitsChem Biodivers202421e20230176010.1002/cbdv.20230176038217459BonesiMLoizzoMRConfortiFPassalacquaNGSaabAMenichiniFet al.Berberis aetnensis and B. libanotica: a comparative study on the chemical composition, inhibitory effect on key enzymes linked to Alzheimer’s disease and antioxidant activityJ Pharm Pharmacol20136517263510.1111/jphp.1217224236982JungHAAliMYJungHJJeongHOChungHYChoiJSInhibitory activities of major anthraquinones and other constituents from Cassia obtusifolia against β-secretase and cholinesterasesJ Ethnopharmacol20161911526010.1016/j.jep.2016.06.03727321278YangZZhangDRenJYangMLiSAcetylcholinesterase inhibitory activity of the total alkaloid from traditional Chinese herbal medicine for treating Alzheimer’s diseaseMed Chem Res201221734810.1007/s00044-011-9582-8YamanCErenlerRAtalarMNAdemŞÇalişkanUKPhytochemical Properties, Antioxidant and in Vitro/in Silico Anti-Acetylcholinesterase Activities of Hypericum heterophyllum Leaf from TürkiyeBrazilian Arch Biol Technol202467e2423004310.1590/1678-4324-2024230043YangZZhangXDuJMaZGuoFLiSet al.An aporphine alkaloid from Nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure-activity correlationsNat Prod Res2012263879210.1080/14786419.2010.48718821732870HlilaMBOmriAJannetHBLamariAAouniMSelmiBPhenolic composition, antioxidant and anti-acetylcholinesterase activities of the Tunisian Scabiosa arenariaPharm Biol2013515253210.3109/13880209.2012.74671323368937PenumalaMZinkaRBShaikJBGangaiahDAIn Vitro Screening of Three Indian Medicinal Plants for Their Phytochemicals, Anticholinesterase, Antiglucosidase, Antioxidant, and Neuroprotective EffectsBiomed Res Int20172017514050610.1155/2017/514050629204442PMC5674485CortesNPosada-DuqueRAAlvarezRAlzateFBerkovSCardona-GómezGPet al.Neuroprotective activity and acetylcholinesterase inhibition of five Amaryllidaceae species: a comparative studyLife Sci2015122425010.1016/j.lfs.2014.12.01125529145SherNAhmedMMushtaqNPhytochemical analysis, antioxidant, acetylcholinesterase, and α-amylase inhibitors from Hippeastrum hybridum extractJ Tradit Chin Med20244449650410.19852/j.cnki.jtcm.2024.03.00138767633PMC11077154LeiteDODCamiloCJNonatoCFACarvalhoNKGSalazarGJTde MoraisSMet al.Chemical Profile and Evaluation of the Antioxidant and Anti-Acetylcholinesterase Activities of Annona squamosa L. (Annonaceae) ExtractsFoods202110234310.3390/foods1010234334681391PMC8535769MoyoMNdhlalaARFinnieJFVanStaden JPhenolic composition, antioxidant and acetylcholinesterase inhibitory activities of Sclerocarya birrea and Harpephyllum caffrum (Anacardiaceae) extractsFood Chem20101236976AhmadSUllahFAyazMSadiqAImranMAntioxidant and anticholinesterase investigations of Rumex hastatus D. Don: potential effectiveness in oxidative stress and neurological disordersBiol Res2015482010.1186/s40659-015-0010-225857346PMC4381421TungBTHaiNTThuDKAntioxidant and acetylcholinesterase inhibitory activities in vitro of different fraction of Huperzia squarrosa (Forst.) Trevis extract and attenuation of scopolamine-induced cognitive impairment in miceJ Ethnopharmacol2017198243210.1016/j.jep.2016.12.03728025162da Silva MendesJWCamiloCJde CarvalhoNKGAlvesNonato CdFPereirade Lima RDAlvesDRet al.In vitro antioxidant and acetylcholinesterase inhibitory properties of the alkaloid fraction of Cissampelos sympodialis EichlerS Afr J Bot20211419910410.1016/j.sajb.2021.04.027ZhaoYDouJWuTAisaHAInvestigating the antioxidant and acetylcholinesterase inhibition activities of Gossypium herbaceamMolecules2013189516210.3390/molecules1801095123344203PMC6269909AtolaniOAdewaraJOnojahJIn-vitro Cholinesterase Inhibition Potential and Fatty Acid Profiling of Lipids Obtained via Direct Trans-esterification from Sarcocephalus latifolius (sm.) Fruits and LeavesAl-Bahir202561510.55810/2313-0083.1080TundisRMenichiniFConfortiFLoizzoMRBonesiMStattiGet al.A potential role of alkaloid extracts from Salsola species (Chenopodiaceae) in the treatment of Alzheimer’s diseaseJ Enzyme Inhib Med Chem2009248182410.1080/1475636080239966218720188AhmadSUllahFSadiqAAyazMImranMAliIet al.Chemical composition, antioxidant and anticholinesterase potentials of essential oil of Rumex hastatus D. Don collected from the North West of PakistanBMC Complement Altern Med2016162910.1186/s12906-016-0998-z26810212PMC4727414JungHAKarkiSKimJHChoiJSBACE1 and cholinesterase inhibitory activities of Nelumbo nucifera embryosArch Pharm Res20153811788710.1007/s12272-014-0492-425300425OvaisMAyazMKhalilATShahSAJanMSRazaAet al.HPLC-DAD finger printing, antioxidant, cholinesterase, and α-glucosidase inhibitory potentials of a novel plant Olax nanaBMC Complement Altern Med201818110.1186/s12906-017-2057-929295712PMC5751879AyazMJunaidMAhmedJUllahFSadiqAAhmadSet al.Phenolic contents, antioxidant and anticholinesterase potentials of crude extract, subsequent fractions and crude saponins from Polygonum hydropiper LBMC Complement Altern Med20141414510.1186/1472-6882-14-14524884823PMC4018186Zavala-OcampoLMLópez-CamachoPYAguirre-HernándezECárdenas-VázquezRBonilla-JaimeHBasurto-IslasGNeuroprotective effects of Petiveria alliacea on scopolamine-induced learning and memory impairment mouse modelJ Ethnopharmacol202431811688110.1016/j.jep.2023.11688137460029CahlíkováLValterováIMacákováKOpletalLAnalysis of Amaryllidaceae alkaloids from Zephyranthes grandiflora by GC/MS and their cholinesterase activityRev bras farmacogn2011215758010.1590/S0102-695X2011005000089BhadraSMukherjeePKKumarNSBandyopadhyayAAnticholinesterase activity of standardized extract of Illicium verum Hook. f. fruitsFitoterapia201182342610.1016/j.fitote.2010.11.00321075180IslamMAZamanSBiswasKAl-AminMYHasanMKAlamAHMKet al.Evaluation of cholinesterase inhibitory and antioxidant activity of Wedelia chinensis and isolation of apigenin as an active compoundBMC Complement Med Ther20212120410.1186/s12906-021-03373-434315449PMC8317308ImranMUllahFAyazMSadiqAShahMRJanMSet al.Anticholinesterase and antioxidant potentials of Nonea micrantha Bioss. & Reut along with GC-MS analysisBMC Complement Altern Med20171749910.1186/s12906-017-2004-929169349PMC5701353NazirNZahoorMUddinFNisarMChemical composition, in vitro antioxidant, anticholinesterase, and antidiabetic potential of essential oil of Elaeagnus umbellata ThunbBMC Complement Med Ther2021217310.1186/s12906-021-03228-y33618705PMC7898454FeitosaCMFreitasRMLuzNNNBezerraMZBTrevisanMTSAcetylcholinesterase inhibition by somes promising Brazilian medicinal plantsBraz J Biol201171783910.1590/s1519-6984201100040002521881804BonesiMMenichiniFTundisRLoizzoMRConfortiFPassalacquaNGet al.Acetylcholinesterase and butyrylcholinesterase inhibitory activity of Pinus species essential oils and their constituentsJ Enzyme Inhib Med Chem201025622810.3109/1475636090338985620429778TuzimskiTPetruczynikAApplication of HPLC-DAD for In Vitro Investigation of Acetylcholinesterase Inhibition Activity of Selected Isoquinoline Alkaloids from Sanguinaria canadensis ExtractsMolecules20212623010.3390/molecules2601023033466254PMC7796366KamalZUllahFAyazMSadiqAAhmadSZebAet al.Anticholinesterase and antioxidant investigations of crude extracts, subsequent fractions, saponins and flavonoids of atriplex laciniata L.: potential effectiveness in Alzheimer’s and other neurological disordersBiol Res2015482110.1186/s40659-015-0011-125889712PMC4393635FatimaISafdarNAkhtarWMunirASaqibSAyazAet al.Evaluation of potential inhibitory effects on acetylcholinesterase, pancreatic lipase, and cancer cell lines using raw leaves extracts of three fabaceae speciesHeliyon20239e1590910.1016/j.heliyon.2023.e1590937206037PMC10189167CarpinellaMCAndrioneDGRuizGPalaciosSMScreening for acetylcholinesterase inhibitory activity in plant extracts from ArgentinaPhytother Res2010242596310.1002/ptr.292319585484EltahawyNAAliAIIbrahimSANafieMSSindiAMAlkharobiHet al.Analysis of Marrubiin in Marrubium alysson L. Extract Using Advanced HPTLC: Chemical Profiling, Acetylcholinesterase Inhibitory Activity, and Molecular DockingMetabolites2023142710.3390/metabo1401002738248830PMC10821196JanHUsmanHShahMZamanGMushtaqSDrouetSet al.Phytochemical analysis and versatile in vitro evaluation of antimicrobial, cytotoxic and enzyme inhibition potential of different extracts of traditionally used Aquilegia pubiflora Wall. Ex RoyleBMC Complement Med Ther20212116510.1186/s12906-021-03333-y34098912PMC8186222SaleemHAhmadIShahidMNGillMSANadeemMFMahmoodWet al.In Vitro Acetylcholinesterase and Butyrylcholinesterase Inhibitory Potentials of Jatropha Gossypifolia Plant ExtractsActa Pol Pharm20167341923Erratum in: Acta Pol Pharm. 2016;73:808. 27180434LaiDYangZXueWShengJShiYYaoXIsolation, characterization and acetylcholinesterase inhibitory activity of alkaloids from roots of Stemona sessilifoliaFitoterapia2013892576410.1016/j.fitote.2013.06.01023831460MukherjeePKKumarVHoughtonPJScreening of Indian medicinal plants for acetylcholinesterase inhibitory activityPhytother Res2007211142510.1002/ptr.222417639556ChenXHeXSunJWangZPhytochemical Composition, Antioxidant Activity, α-Glucosidase and Acetylcholinesterase Inhibitory Activity of Quinoa Extract and Its FractionsMolecules202227242010.3390/molecules2708242035458616PMC9032577AyazMJunaidMUllahFSadiqAKhanMAAhmadWet al.Comparative chemical profiling, cholinesterase inhibitions and anti-radicals properties of essential oils from Polygonum hydropiper L: a preliminary anti- Alzheimer’s studyLipids Health Dis20151414110.1186/s12944-015-0145-826530857PMC4632677ChaiyanaWOkonogiSInhibition of cholinesterase by essential oil from food plantPhytomedicine201219836910.1016/j.phymed.2012.03.01022510493UddinMJRussoDRahmanMMUddinSBHalimMAZidornCet al.Anticholinesterase Activity of Eight Medicinal Plant Species: In Vitro and In Silico Studies in the Search for Therapeutic Agents against Alzheimer’s DiseaseEvid Based Complement Alternat Med20212021999561410.1155/2021/999561434257698PMC8260289SahooAKDandapatJDashUCKanharSFeatures and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer’s diseaseJ Ethnopharmacol2018215427310.1016/j.jep.2017.12.01529248451JinZYaoGAmaryllidaceae and Sceletium alkaloidsNat Prod Rep20193614628810.1039/c8np00055g30707215BerkovSAtanasovaMGeorgievBBastidaJDoytchinovaIThe Amaryllidaceae alkaloids: an untapped source of acetylcholinesterase inhibitorsPhytochem Rev20222114154310.1007/s11101-021-09790-0SahinerMYilmazASGungorBSahinerNA Review on Phyto-Therapeutic Approaches in Alzheimer’s DiseaseJ Funct Biomater2023145010.3390/jfb1401005036662097PMC9861153GajendraKPratapGKPoornimaDVShantaramMRanjitaGNatural acetylcholinesterase inhibitors: A multi-targeted therapeutic potential in Alzheimer’s diseaseEur J Med Chem Rep20241110015410.1016/j.ejmcr.2024.100154PratapGKAshwiniSShantaramMAlzheimer’s Disease: A Challenge In Managing with Certain Medicinal Plants – A ReviewInt J Pharm Sci Res2017849607210.13040/IJPSR.0975-8232.8(12).4960-72PratapGKJayakarVLokapurVShantaramMRole of Functional Foods in the Amelioration of Alzheimer’s and Related DiseasesFunctional Foods for Health MaintenanceUnderstanding their Role in Cancer Prevention. Bentham Science Publishers2023pp. 433–49.10.2174/9789815179217123010021OrhanIEOrhanGGurkasEAn overview on natural cholinesterase inhibitors--a multi-targeted drug class--and their mass productionMini Rev Med Chem2011118364210.2174/13895571179657543421762104AhmedFGhalibRMSasikalaPAhmedKKMCholinesterase inhibitors from botanicalsPharmacogn Rev201371213010.4103/0973-7847.12051124347920PMC3841990HeinrichMMahJAmirkiaVAlkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity—An Update and Forward LookMolecules202126183610.3390/molecules2607183633805869PMC8036335MukherjeePKKumarVMalMHoughtonPJAcetylcholinesterase inhibitors from plantsPhytomedicine20071428930010.1016/j.phymed.2007.02.00217346955Dall’AcquaSPlant-derived acetylcholinesterase inhibitory alkaloids for the treatment of Alzheimer’s diseaseBot: Targets Ther20133192810.2147/BTAT.S17297WilliamsPSorribasAHowesMRNatural products as a source of Alzheimer’s drug leadsNat Prod Rep201128487710.1039/c0np00027b21072430PMC4917364LoizzoMRTundisRMenichiniFMenichiniFNatural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders: an updateCurr Med Chem20081512092810.2174/09298670878431042218473814YarnellEAbascalKTreating Hypertension BotanicallyAltern Complementary Ther200172849010.1089/107628001753312121DeyPKunduAKumarAGuptaMLeeBMBhaktaTChapter 15 - Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids)SanchesSilva ANabaviSFSaeediMNabaviSMRecent Advances in Natural Products AnalysisElsevier; 2020. pp. 505–67.10.1016/B978-0-12-816455-6.00015-9KashyapPKalaiselvanVKumarRKumarSAjmalicine and Reserpine: Indole Alkaloids as Multi-Target Directed Ligands Towards Factors Implicated in Alzheimer’s DiseaseMolecules202025160910.3390/molecules2507160932244635PMC7180484WiatrakBKubis-KubiakAPiwowarABargEPC12 Cell Line: Cell Types, Coating of Culture Vessels, Differentiation and Other Culture ConditionsCells2020995810.3390/cells904095832295099PMC7227003JiangBMengLZouNWangHLiSHuangLet al.Mechanism-based pharmacokinetics-pharmacodynamics studies of harmine and harmaline on neurotransmitters regulatory effects in healthy rats: Challenge on monoamine oxidase and acetylcholinesterase inhibitionPhytomedicine20196215296710.1016/j.phymed.2019.15296731154274ZhangLLiDYuSPharmacological effects of harmine and its derivatives: a reviewArch Pharm Res20204312597510.1007/s12272-020-01283-633206346LiSWangYQiSZhangYDengGDingWet al.Analogous β-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in MiceFront Pharmacol2018934610.3389/fphar.2018.0034629755345PMC5932362PuriBHallAPhytochemical Dictionary: A Handbook of Bioactive Compounds from PlantsIn: Baxter H, Harborne JB, Moss GP. 2 nd ed. London: CRC Press; 1998.10.4324/9780203483756MakSLukWWKCuiWHuSTsimKWKHanYSynergistic inhibition on acetylcholinesterase by the combination of berberine and palmatine originally isolated from Chinese medicinal herbsJ Mol Neurosci201453511610.1007/s12031-014-0288-524793543ImenshahidiMHosseinzadehHBerberis Vulgaris and Berberine: An Update ReviewPhytother Res20163017456410.1002/ptr.569327528198ImenshahidiMHosseinzadehHBerberine and barberry (Berberis vulgaris): A clinical reviewPhytother Res2019335042310.1002/ptr.625230637820HostalkovaAMarikovaJOpletalLKorabecnyJHulcovaDKunesJet al.Isoquinoline Alkaloids from Berberis vulgaris as Potential Lead Compounds for the Treatment of Alzheimer’s DiseaseJ Nat Prod2019822394810.1021/acs.jnatprod.8b0059230701972CarradoriSD’AscenzioMChimentiPSecciDBolascoASelective MAO-B inhibitors: a lesson from natural productsMol Divers2014182194310.1007/s11030-013-9490-624218136CaiZWangCYangWRole of berberine in Alzheimer’s diseaseNeuropsychiatr Dis Treat20161225092010.2147/NDT.S11484627757035PMC5055107HungTMNaMDatNTNgocTMYounUKimHJet al.Cholinesterase inhibitory and anti-amnesic activity of alkaloids from Corydalis turtschaninoviiJ Ethnopharmacol2008119748010.1016/j.jep.2008.05.04118601993SeidlCCorreiaBLStinghenAEMSantosCAMAcetylcholinesterase inhibitory activity of uleine from Himatanthus lancifoliusZ Naturforsch C J Biosci201065440410.1515/znc-2010-7-80420737911BrunhoferGFallareroAKarlssonDBatista-GonzalezAShindePMohanCGet al.Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrineBioorg Med Chem20122066697910.1016/j.bmc.2012.09.04023062825ZhangYWangQLiuRZhouHCrommenJMoaddelRet al.Rapid screening and identification of monoamine oxidase-A inhibitors from Corydalis Rhizome using enzyme-immobilized magnetic beads based methodJ Chromatogr A201915921810.1016/j.chroma.2019.01.06230712820WangYPeiHChenWDuRLiJHeZPalmatine Protects PC12 Cells and Mice from Aβ25-35-Induced Oxidative Stress and Neuroinflammation via the Nrf2/HO-1 PathwayMolecules202328795510.3390/molecules2824795538138445PMC10745955LongJSongJZhongLLiaoYLiuLLiXPalmatine: A review of its pharmacology, toxicity and pharmacokineticsBiochimie20191621768410.1016/j.biochi.2019.04.00831051209WianowskaDGarbaczewskaSCieniecka–RoslonkiewiczATypekRDawidowiczALChemical composition and antifungal activity of Chelidonium majus extracts – antagonistic action of chelerythrine and sanguinarine against Botrytis cinereaChemistry and Ecology2018345829410.1080/02757540.2018.1462345BaekSCRyuHWKangMLeeHParkDChoMet al.Selective inhibition of monoamine oxidase A by chelerythrine, an isoquinoline alkaloidBioorg Med Chem Lett2018282403710.1016/j.bmcl.2018.06.02329925480PlazasEHagenowSMurilloMAStarkHCucaLEIsoquinoline alkaloids from the roots of Zanthoxylum rigidum as multi-target inhibitors of cholinesterase, monoamine oxidase A and Aβ1-42 aggregationBioorg Chem20209810372210.1016/j.bioorg.2020.10372232155491JungHAMinBYokozawaTLeeJKimYSChoiJSAnti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloidsBiol Pharm Bull2009321433810.1248/bpb.32.143319652386MasiMMubaiwaBMabankTKarakoyunÇCimminoAVanOtterlo WALet al.Alkaloids isolated from indigenous South African Amaryllidaceae: Crinum buphanoides (Welw. ex Baker), Crinum graminicola (I. Verd.), Cyrtanthus mackenii (Hook. f) and Brunsvigia grandiflora (Lindl)S Afr J Bot20181181889110.1016/j.sajb.2018.07.021DasariRBanulsLMYMasiMPellySCMathieuVGreenIRet al.C1,C2-ether derivatives of the Amaryllidaceae alkaloid lycorine: retention of activity of highly lipophilic analogues against cancer cellsBioorg Med Chem Lett201424923710.1016/j.bmcl.2013.12.07324393582NairJJStadenJvPharmacological and toxicological insights to the South African AmaryllidaceaeFood Chem Toxicol2013622627510.1016/j.fct.2013.08.04223994658KohelováEPeřinováRMaafiNKorábečnýJHulcováDMaříkováJet al.Derivatives of the β-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer’s DiseaseMolecules201924130710.3390/molecules2407130730987121PMC6480460ChooCYHirasawaYKarimataCKoyamaKSekiguchiMKobayashiJet al.Carinatumins A–C, new alkaloids from Lycopodium carinatum inhibiting acetylcholinesteraseBioorg Med Chem2007151703710.1016/j.bmc.2006.12.00517188496TangXCHeXCBaiDLHuperzine A: A novel acetylcholinesterase inhibitorDrugs of the Future1999246476310.1358/dof.1999.024.06.545143TangXCHuperzine A (shuangyiping): a promising drug for Alzheimer’s diseaseZhongguo Yao Li Xue Bao19961748149863136TangCXHanYFPharmacological Profile of Huperzine A, a Novel Acetylcholinesterase Inhibitor from Chinese HerbCNS Drug Rev1999528130010.1111/j.1527-3458.1999.tb00105.xZhangHNew insights into huperzine A for the treatment of Alzheimer’s diseaseActa Pharmacol Sin2012331170510.1038/aps.2012.12822941287PMC4003111ZhangHYYanHTangXCNon-cholinergic effects of huperzine A: beyond inhibition of acetylcholinesteraseCell Mol Neurobiol2008281738310.1007/s10571-007-9163-z17657601PMC11516533IslamMTTabrezSJabirNRAliMKamalMAAraujoLdSet al.An Insight into the Therapeutic Potential of Major Coffee ComponentsCurr Drug Metab2018195445610.2174/138920021966618030215455129512445PohankaMDobesPCaffeine inhibits acetylcholinesterase, but not butyrylcholinesteraseInt J Mol Sci20131498738210.3390/ijms1405987323698772PMC3676818WengPHChenYCChenTFSunYWenLLYipPKet al.P1-387: Caffeine Intake and Cognitive Response to Acetylcholinesterase Inhibitors in Alzheimer’s DiseaseAlzheimer’s Dementia201410P45610.1016/j.jalz.2014.05.629AkomolafeSFThe effects of caffeine, caffeic acid, and their combination on acetylcholinesterase, adenosine deaminase and arginase activities linked with brain functionJ Food Biochem201741e1240110.1111/jfbc.12401LorenzoCDColomboFBiellaSStockleyCRestaniPPolyphenols and Human Health: The Role of BioavailabilityNutrients20211327310.3390/nu1301027333477894PMC7833401Tressera-RimbauAArranzSEderMVallverdú-QueraltADietary Polyphenols in the Prevention of StrokeOxid Med Cell Longev20172017746796210.1155/2017/746796229204249PMC5674514ChengYSheenJHuWLHungYPolyphenols and Oxidative Stress in Atherosclerosis-Related Ischemic Heart Disease and StrokeOxid Med Cell Longev20172017852643810.1155/2017/852643829317985PMC5727797KatalinićMRusakGBarovićJDSinkoGJelićDAntolovićRet al.Structural aspects of flavonoids as inhibitors of human butyrylcholinesteraseEur J Med Chem2010451869210.1016/j.ejmech.2009.09.04119879672FaléPLVAscensãoLSerralheiroMLHarisPIInteraction between Plectranthus barbatus herbal tea components and acetylcholinesterase: binding and activity studiesFood Funct2012311768410.1039/c2fo30032j22801419MelroseJThe Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive DeclineAntioxidants (Basel)20231266310.3390/antiox1203066336978911PMC10045397PancheANDiwanADChandraSRFlavonoids: an overviewJ Nutr Sci20165e47Erratum in: J Nutr Sci. 2025;14:e11. 10.1017/jns.2016.4128620474PMC5465813RajputMSSarkarPDModulation of neuro-inflammatory condition, acetylcholinesterase and antioxidant levels by genistein attenuates diabetes associated cognitive decline in miceChem Biol Interact20172689310210.1016/j.cbi.2017.02.02128259689HammondRGibbsRBGPR30 is positioned to mediate estrogen effects on basal forebrain cholinergic neurons and cognitive performanceBrain Res20111379536010.1016/j.brainres.2010.11.09821138734PMC3046317DarbandiNRamezaniMNooriMMespilus germanica Flavonoids Attenuate Cognitive Dysfunction in the Streptozotocin-induced Rat Model of Alzheimer’s DiseaseIndian J Pharm Sci2018806687510.4172/pharmaceutical-sciences.1000406ZhangXBaiLZhangSZhouXLiYBaiJTrx-1 ameliorates learning and memory deficits in MPTP-induced Parkinson’s disease model in miceFree Radic Biol Med2018124380710.1016/j.freeradbiomed.2018.06.02929960099CostaLGGarrickJMRoquèPJPellacaniCMechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and MoreOxid Med Cell Longev20162016298679610.1155/2016/298679626904161PMC4745323JungMParkMAcetylcholinesterase Inhibition by Flavonoids from Agrimonia pilosaMolecules2007122130910.3390/1209213017962731PMC6149129Vila-NovaNSMoraisSMFalcãoMJCBevilaquaCMLRondonFCMWilsonMELeishmanicidal and cholinesterase inhibiting activities of phenolic compounds of Dimorphandra gardneriana and Platymiscium floribundum, native plants from Caatinga biomePesq Vet Bras2012321164810.1590/S0100-736X2012001100015DzoyemJPEloffJNAnti-inflammatory, anticholinesterase and antioxidant activity of leaf extracts of twelve plants used traditionally to alleviate pain and inflammation in South AfricaJ Ethnopharmacol201516019420110.1016/j.jep.2014.11.03425476488BalkisATranKLeeYNgKScreening flavonoids for inhibition of acetylcholinesterase identified baicalein as the most potent inhibitorJ Agric Sci20157263510.5539/jas.v7n9p26SevindikHGGüvenalpZYerdelenKOYucaHDemirezerLOThe discovery of potential anticholinesterase compounds from Achillea millefolium LInd Crops Prod201576873910.1016/j.indcrop.2015.05.088ZhangSZhuQChenJOuYangDLuJThe pharmacological activity of epigallocatechin-3-gallate (EGCG) on Alzheimer’s disease animal model: A systematic reviewPhytomedicine20207915331610.1016/j.phymed.2020.15331632942205OladapoOMBen-AzuBAjayiAMEmokpaeOEneniAOOmogbiyaIAet al.Naringin Confers Protection against Psychosocial Defeat Stress-Induced Neurobehavioral Deficits in Mice: Involvement of Glutamic Acid Decarboxylase Isoform-67, Oxido-Nitrergic Stress, and Neuroinflammatory MechanismsJ Mol Neurosci2021714314510.1007/s12031-020-01664-y32767187SinhaRAndersonDEMcDonaldSSGreenwaldPCancer risk and diet in IndiaJ Postgrad Med200349222814597785AbbasiMAIlyasMAziz-ur-RehmanSoniaAShahwarDRazaMAet al.Curcumin and its derivatives: Moderate inhibitors of acetylcholinesterase, butyrylcholinesterase and trypsinSci Iran2012191580310.1016/j.scient.2012.10.014HatcherHPlanalpRChoJTortiFMTortiSVCurcumin: from ancient medicine to current clinical trialsCell Mol Life Sci20086516315210.1007/s00018-008-7452-418324353PMC4686230StrimpakosASSharmaRACurcumin: preventive and therapeutic properties in laboratory studies and clinical trialsAntioxid Redox Signal2008105114510.1089/ars.2007.176918370854KalaycıoğluZGazioğluIErimFBComparison of antioxidant, anticholinesterase, and antidiabetic activities of three curcuminoids isolated from Curcuma longa LNat Prod Res2017312914710.1080/14786419.2017.129972728287280WolkmerPSilvaCBPaimFCDuarteMMMFCastroVPalmaHEet al.Pre-treatment with curcumin modulates acetylcholinesterase activity and proinflammatory cytokines in rats infected with Trypanosoma evansiParasitol Int201362144910.1016/j.parint.2012.11.00423200738AkinyemiAJOkonkwoPKFaboyaOAOnikanniSAFadakaAOlayideIet al.Curcumin improves episodic memory in cadmium induced memory impairment through inhibition of acetylcholinesterase and adenosine deaminase activities in a rat modelMetab Brain Dis201732879510.1007/s11011-016-9887-x27491636JangMHPiaoXLKimJMKwonSWParkJHInhibition of cholinesterase and amyloid-β aggregation by resveratrol oligomers from Vitis amurensisPhytother Res200822544910.1002/ptr.240618338769SchmatzRMazzantiCMSpanevelloRStefanelloNGutierresJCorrêaMet al.Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic ratsEur J Pharmacol200961042810.1016/j.ejphar.2009.03.03219303406SchmatzRMazzantiCMSpanevelloRStefanelloNGutierresJMaldonadoPAet al.Ectonucleotidase and acetylcholinesterase activities in synaptosomes from the cerebral cortex of streptozotocin-induced diabetic rats and treated with resveratrolBrain Res Bull200980371610.1016/j.brainresbull.2009.08.01919723569YangXQiangXLiYLuoLXuRZhengYet al.Pyridoxine-resveratrol hybrids Mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer’s diseaseBioorg Chem2017713051410.1016/j.bioorg.2017.02.01628267984AdisakwattanaSCinnamic Acid and Its Derivatives: Mechanisms for Prevention and Management of Diabetes and Its ComplicationsNutrients2017916310.3390/nu902016328230764PMC5331594GuzmanJDNatural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activityMolecules2014191929234910.3390/molecules19121929225429559PMC6271800de Cássia da Silveira E SáRAndradeLNDosReis Barreto de Oliveira Rde SousaDPA review on anti-inflammatory activity of phenylpropanoids found in essential oilsMolecules20141914598010.3390/molecules1902145924473208PMC6270723AnantharajuPGGowdaPCVimalambikeMGMadhunapantulaSVAn overview on the role of dietary phenolics for the treatment of cancersNutr J2016159910.1186/s12937-016-0217-227903278PMC5131407ZhaoZMoghadasianMHChemistry, natural sources, dietary intake and pharmacokinetic properties of ferulic acid: A reviewFood Chem200810969170210.1016/j.foodchem.2008.02.03926049981ElufioyeTOObuotorEMAgbedahunsiJMAdesanyaSACholinesterase inhibitory activity and structure elucidation of a new phytol derivative and a new cinnamic acid ester from Pycnanthus angolensisRev Bras Farmacogn201626433710.1016/j.bjp.2016.01.010LanJHouJLiuYDingYZhangYLiLet al.Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer’s diseaseJ Enzyme Inhib Med Chem2017327768810.1080/14756366.2016.125688328585866PMC6009898BhadraSDalaiMKChandaJMukherjeePKChapter 13 - Evaluation of Bioactive Compounds as Acetylcholinesterase Inhibitors from Medicinal Plants. Evidence-Based Validation Herb MedMukherjeePKEvidence-Based Validation of Herbal MedicineBostonElsevier2015pp. 273–306.10.1016/B978-0-12-800874-4.00013-1BöttgerAVothknechtUBolleCWolfATerpenes and TerpenoidsLessons on Caffeine, Cannabis & Co. Learning Materials in Biosciences. Cham; Springer International Publishing; 2018. pp.153–70.10.1007/978-3-319-99546-5_10PerveenSIntroductory Chapter: Terpenes and TerpenoidsPerveenSAl-TaweelATerpenes and TerpenoidsRijekaIntechOpen201810.5772/intechopen.79683MinSLSLiewSYChearNJYGohBHTanWKhawKYPlant Terpenoids as the Promising Source of Cholinesterase Inhibitors for Anti-AD TherapyBiology (Basel)20221130710.3390/biology1102030735205173PMC8869317BrahmkshatriyaPPBrahmkshatriyaPSTerpenes: Chemistry, biological role, and therapeutic applicationsRamawatKMérillonJMNatural ProductsBerlinSpringer2013pp. 2665–91.10.1007/978-3-642-22144-6_120KrishnaSBustamanteLHaynesRKStainesHMArtemisinins: their growing importance in medicineTrends Pharmacol Sci200829520710.1016/j.tips.2008.07.00418752857PMC2758403WangGTangWBidigareRRTerpenoids As Therapeutic Drugs and Pharmaceutical AgentsZhangLDemainALNatural ProductsHumana Press; 2005. pp. 197–227.10.1007/978-1-59259-976-9_9DohiSTerasakiMMakinoMAcetylcholinesterase inhibitory activity and chemical composition of commercial essential oilsJ Agric Food Chem2009574313810.1021/jf804013j19358605Wojtunik-KuleszaKATargowska-DudaKKlimekKGinalskaGJóźwiakKWaksmundzka-HajnosMet al.Volatile terpenoids as potential drug leads in Alzheimer’s diseaseOpen Chem2017153324310.1515/chem-2017-0040HegazyMFIbrahimAYMohamedTAShahatAAHalawanyAMEAbdel-AzimNSet al.Sesquiterpene Lactones from Cynara cornigera: Acetyl Cholinesterase Inhibition and In Silico Ligand DockingPlanta Med20168213846Erratum in: Planta Med. 2016;82:E3. 10.1055/s-0035-155808826441064AlarcónJCespedesCLMuñozEBalbontinCValdesFGutierrezMet al.Dihydroagarofuranoid Sesquiterpenes as Acetylcholinesterase Inhibitors from Celastraceae Plants: Maytenus disticha and Euonymus japonicusJ Agric Food Chem20156310250610.1021/acs.jafc.5b0416826545100ChougouoRDKNguekeuYMMDzoyemJPAwouafackMDKouamouoJTanePet al.Anti-inflammatory and acetylcholinesterase activity of extract, fractions and five compounds isolated from the leaves and twigs of Artemisia annua growing in CameroonSpringerplus20165152510.1186/s40064-016-3199-927652098PMC5017989YangDLiWDongWWangJMeiWDaiHFive new 5,11-epoxyguaiane sesquiterpenes in agarwood “Qi-Nan” from Aquilaria sinensisFitoterapia2016112191610.1016/j.fitote.2016.05.01427242216Zardi-BergaouiAZnatiMHarzallah-SkhiriFJannetHBCaryophyllene Sesquiterpenes from Pulicaria vulgaris GAERTN.: Isolation, Structure Determination, Bioactivity and Structure-Activity RelationshipChem Biodivers201916e180048310.1002/cbdv.20180048330673162LiuYLiJLiDLiXLiDZhouGet al.Anti-cholinesterase activities of constituents isolated from Lycopodiastrum casuarinoidesFitoterapia201913910436610.1016/j.fitote.2019.10436631629868MurataTSelengeEOikawaSAgeishiKBatkhuuJSasakiKet al.Cholinesterase-inhibitory diterpenoids and chemical constituents from aerial parts of Caryopteris mongolicaJ Nat Med201569471810.1007/s11418-015-0908-625900047SenolFSŚlusarczykSMatkowskiAPérez-GarridoAGirón-RodríguezFCerón-CarrascoJPet al.Selective in vitro and in silico butyrylcholinesterase inhibitory activity of diterpenes and rosmarinic acid isolated from Perovskia atriplicifolia Benth. and Salvia glutinosa LPhytochemistry2017133334410.1016/j.phytochem.2016.10.01227817931NguyenVTToDCTranMHOhSHKimJAAliMYet al.Isolation of cholinesterase and β-secretase 1 inhibiting compounds from Lycopodiella cernuaBioorg Med Chem20152331263410.1016/j.bmc.2015.04.08026003344AdoMAMaulidianiMIsmailISGhazaliHMShaariKAbasFAcetylcholinesterase and α-glucosidase inhibitory compounds from Callicarpa maingayiNat Prod Res2021352992610.1080/14786419.2019.167913831631709JamilaNKhairuddeanMYeongKKOsmanHMurugaiyahVCholinesterase inhibitory triterpenoids from the bark of Garcinia hombronianaJ Enzyme Inhib Med Chem201530133910.3109/14756366.2014.89572024666300LiuYChenGChenXChenSGanLYuanTColocynthenins A–D, Ring-A seco-Cucurbitane Triterpenoids from the Fruits of Citrullus colocynthisJ Nat Prod2018812115910.1021/acs.jnatprod.8b0046130183289LiuJPengXLiXLiTZhangWShiLet al.Norfriedelins A–C with acetylcholinesterase inhibitory activity from acerola tree (Malpighia emarginata)Org Lett2013151580310.1021/ol400370223484960