Revista Brasileira de Farmacognosia Brazilian Journal of Pharmacognosy Received 10/26/05. Accepted 04/13/06 16(2): 258-285, Abr./Jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase

José M. Barbosa Filho1*, Karina C. Paula Medeiros1, Margareth de Fátima F.M. Diniz1, Leônia M. Batista1, Petrônio F. Athayde-Filho1, Marcelo S. Silva1, Emídio V.L. da-Cunha1, Jackson R.G. Silva Almeida2, Lucindo J. Quintans-Júnior2

Revisão 1Laboratório de Tecnologia Farmacêutica “Delby Fernandes de Medeiros”, Universidade Federal da Paraíba, Caixa Postal 5009, 58051-970, João Pessoa, PB, Brazil, 2Universidade Federal do Vale do São Francisco, Caixa Postal 252, 56306-410, Petrolina, PE, Brazil

RESUMO: “Produtos naturais inibidores da enzima acetilcolinesterase”. A Doença de Alzheimer (DA) é uma patologia neurodegenerativa, progressiva, que afeta principalmente a população idosa, responsável por 50-60% dos casos de demência em pessoas com mais de 65 anos de idade. Os principais sintomas associado a DA envolve defi ciência orgânica cognitiva, principalmente perda de memória. Outras características associadas com os estágios avançados de DA inclui défi cit na linguagem, depressão, problemas de comportamento, inclusive agitação, alterações de humor e psicose.Um dos mais promissores caminhos para tratar esta doença é aumentar o nível de acetilcolina no cérebro usando inibidores da acetilcolinesterase (AChE). Este trabalho teve como objetivo revisar a literatura das plantas e substâncias encontradas nas plantas, inibidores da enzima acetilcolinesterase. Foram levantadas 309 plantas e 260 substâncias isoladas de plantas que foram classifi cados em grupos químicos adequados, os modelo testados, e suas atividades. Foram consultados 175 referências.

Unitermos: Inibidores da Acetilcolinesterase, AchE, doença de Alzheimer, distúrbios neurodegenetivos, plantas medicinais, produtos naturais, revisão.

ABSTRACT: Alzheimer’s disease (AD) is a progressive, neurodegenerative pathology that primarily affects the elderly population, and is estimated to account for 50-60% of dementia cases in persons over 65 years of age. The main symptoms associated with AD involve cognitive dysfunction, primarily memory loss. Other features associated with the later stages of AD include language defi cits, depression, behavioural problems including agitation, mood disturbances and psychosis. One of the most promising approaches for treating this disease is to enhance the acetylcholine level in the brain using acetylcholinesterase (AChE) inhibitors. The present work reviews the literature on plants and plant-derived compounds inhibitors of enzyme acetylcholinesterase. The review refers to 309 plant extracts and 260 compounds isolated from plants, which are classifi ed in appropriate chemical groups and model tested, and cites their activity. For this purpose 175 references were consulted. Keywords: Acetylcholinesterase inhibitors, AChE, Alzheimer’s disease, neurodegenerative disorders, medicinal plants, natural products, review.

INTRODUCTION and cognitive defi cits of the patients by diminishing the breakdown of acetylcholine at the synaptic site in the The enzyme acetylcholinesterase (AChE) brain. However, the therapeutic window is small, and catalyses the hydrolysis of the ester bound of acetylcholine testing of the inhibitory effect on acetylcholinesterase (ACh) to terminate the impulse transmitted action of ACh (AChE) in erythrocytes has been proposed as a guide to through cholinergic synapses (Stryer, 1995). Although the effi cacy and safety of putative therapies. the basic reason of Alzheimer’s disease (AD) is not Alzheimer’s disease is a progressive clear so far, AD is fi rmly associated with impairment in degenerative neurologic disorder resulting in impaired cholinergic transmission. A number of AChE inhibitors memory and behavior. Epidemiological data indicate a have been considered as candidates for the symptomatic potentially considerable increase in the prevalence of the treatment of AD as the most useful relieving strategy disease over the next two decades (Johnson et al., 2000). (Howes et al., 2003). AD affects up to 5% of people over 65 years, rising to Reversible inhibitors of cholinesterase are 20% of those over 80 years (Camps et al., 2000a). Most currently used in clinical trials examining the treatment treatment strategies have been based on the cholinergic of Alzheimer’s disease. Anticholinesterase may interact hypothesis which postulated that memory impairments with the central cholinergic system to improve memory in patients suffering from this disease result from a

258 * E-mail: [email protected], Tel./Fax: + 55-83-32167364 ISSN 0102-695X José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al.

defi cit of cholinergic function in brain. Cholinergic Huperzia serrata (Thumb.) in 1986, is a potent, reversible neurotransmission is specially affected in patients and selective inhibitor of AChE. with Alzheimer’s disease. One of the most promising In a previous paper this research group has approaches for treating this disease is to enhance the reviewed crude plant extracts and chemically defi ned acetylcholine level in brain using acetylcholinesterase molecules with potential antitumor activity for mammary inhibitors (Enz et al., 1993). Several AChE inhibitors (Moura et al., 2001), cervical (Moura et al., 2002) and are being investigated for the treatment of Alzheimer’s ovarian neoplasias (Silva et al ., 2003), as inhibitors of disease. However, only tacrine (1), donezepil (2), HMG CoA reductase (Gonçalves et al., 2000), central rivastigmine (3) and galanthamine (4) have been approved analgesic activity (Almeida et al., 2001), employed in by the Food and Drug Administration in the United States prevention of osteoporosis (Pereira et al., 2002), for the (Zarotsky et al., 2003). Among the other strategies under treatment of Parkinson’s disease (Morais, 2003), with investigation, monoamine oxidase B (MAO-B) inhibitors antileishmanial (Rocha et al., 2005), hypoglycaemic have also been proposed for the treatment of AD. Recent (Barbosa-Filho et al., 2005) and antiinfl ammatory studies have shown that MAO-B activity can increase up activity (Falcão et al., 2005, Barbosa-Filho et al., to 3-fold in the temporal, parietal and frontal cortex of AD 2006). The present work reviews the literature on plants patients compared with controls. This increase in MAO-B and plant-derived compounds inhibitors of enzyme activity produces an elevation of brain levels of hydroxyl acetylcholinesterase. radicals, which has been correlated with the development of Aβ plaques. Aβ is the main component of the senile MATERIALS AND METHODS plaques found in AD brains and any compound able to inhibit its aggregation might be regarded as potentially The keywords used for this review were useful in the treatment of the disease (Bruhlmann et al., medicinal plants, natural products, and acetylcholinesterase 2001). inhibitors. The search perfound using Chemical Abstracts, Nature is a rich source of biological and Biological Abstracts and the data bank of the University chemical diversity. The unique and complex structures of of Illinois at Chicago, NAPRALERT (Acronym for natural products cannot be obtained easily by chemical NAtural PRoducts ALERT), updated to December 2004. synthesis. A number of plants in the world have been The references obtained were later consulted. used in traditional medicine remedies. Huperzine A (5) is a natural compound fi rst isolated from Chinese medicine

O MeO NH2 Me Me Me O N Me MeO N N Me O N

(1) (2) (3)

OH Me Me O H N H O H NO Me MeO Me N ON Me Me N NH2 H Me

(5) (4) (6)

Figure 1. Representative examples of synthetic (1-3) and natural (4-6) products inhibitors of the enzyme acetylcholinesterase

259 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase

RESULTS AND DISCUSSION However, its severe side effects such hepatotoxicity and gastrointestinal upset, represent an important drawback Consultation of various types of literature (Camps et al., 2000). The results of the studies on sources resulted in elaboration of a list of natural tacrine spurred the development of other centrally products (Table 1 and 2) evaluated specifi cally for acting reversible AChE inhibitors, such as the recently acetylcholinesterase inhibition. It should be noted that marketed galanthamine (Nivalin®), donezepil (Aricept®) most of references cited are not fi rst-hand observations, and rivastigmine (Exelon®) or the natural product (-)- but secondary sources. For details on the models or huperzine A, which is currently undergoing extensive mechanism-based bioassays utilized for selecting plant clinical trials, showing considerable promise for the extracts and pure compounds against acetylcholinesterase, palliative treatment of AD. the original references should be consulted. Galanthamine, a long acting, selective, reversible and competitive AChE inhibitor, is considered Plant extracts inhibitors of acetylcholinesterase to be more effective in the treatment of AD and to have enzyme fewer limitations (Rhee et al., 2001). Recently it has reported wich because of bioavailability problems and Acetylcholine is a neurotransmitter inhibited possible side-effects, there still is great interest in fi nding primarily by acetylcholinesterase (AChE) and secondly better AChE inhibitors. by butyrylcholinesterase (BChE), considered to play a Donezepil was developed in order to overcome role in the pathology of AD (Hebert et al., 1995). Despite the disadvantages of physostigmine and tacrine, and later the unknown etiology of AD, elevation of acetylcholine approved by the FDA for treatment of AD. It is highly amount through AChE enzyme inhibition has been selective for acetylcholinesterase with a signifi cantly accepted as the most effective treatment strategy against lower affi nity for butyrylcholinesterase (Racchi et al., AD. Therefore, AChE inhibitors have become the 2004). remarkable alternatives in treatment of AD. However, Rivastigmine is a carbamilating, pseudo- the present drugs (tacrine, rivastigmine and donezepil) irreversible acetylcholinesterase inhibitor which in with AChE inhibitory activity possess some side effects preclinical biochemical studies has shown a signifi cant (Schneider, 2001). Consequently, it is compulsory to nervous system selectivity (Racchi et al., 2004). develop new drugs in order to combat AD (Viegas-Junior (-)-Huperzine A is a natural compound fi rst et al., 2004). isolated from Chinese medicine Huperzia serrata The history of drug discovery showed that (Thumb.) in 1986. It is a potent, reversible and plants are highly rich sources in the search for new active selective inhibitor of AChE with a rapid absorption and compounds and they have become a challenge to modern penetration into the brain in animal tests. Compared pharmaceutical industry. Many synthetic drugs owe their to tacrine, physostigmine (6), galanthamine and origin to plant-based complementary medicine. Since donezepil, huperzine A possesses a longer duration of AD, one of the most common cause of death worldwide, action and higher therapeutic index, and the peripheral has become a threaten to public health, new treatment cholinergic side effects are minimal at therapeutic strategies based on medicinal plants have been focused doses (Camps et al., 2000; Li et al., 2004). Huperzine A (Howes et al., 2003; Orhan et al., 2004). possesses higher selectivity and has almost no effect on A recent study with Brazilian plants showed butyrylcholinesterase. In China, huperzine A has already excellent results for the species Amburana cearensis, been approved as a palliative drug for AD (Högenauer et Lippia sidoides, Paullinia cupana, Plathymiscium al., 2001). fl oribundum and Solanum asperum (Trevisan; Macedo, We founded 260 chemically defi ned natural 2003). Since the plants have been used in treatment molecules reported in the literature, which have been of memory disfunction in some folk medicines since evaluated for acetylcholinesterase inhibition. The centuries the present study presents a review of 309 compounds tested, which have been isolated and identifi ed plants belong to 92 botanical families tested against belong to the classes of alkaloids (139), monoterpenes acetylcholinesterase inhibition. The plants are listed in (27), coumarins (18), triterpenes (17), fl avonoids (14), Table 1, in alphabetical order of their family, scientifi c benzenoids (13), diterpenes (8), oxygen heterocycles name, country, plant part used, type of extract, dose/ (5), sesquiterpenes (5), stilbenes (3), lignans (2), sulfur concentration, result and references. compounds (2), proteids (2), polycyclic (1), quinoid (1), benzoxazinone (1), carotenoid (1) and alycyclic (1). Chemically-defi ned molecule as inhibitors of acetylcholinesterase enzyme CONCLUSION

The prototype for the centrally acting AChE The present work shows that most of the inhibitors was tacrine, the fi rst drug to be approved in plant extracts tested showed inhibitory activity against the United States (Cognex®) for the treatment of AD. acetylcholinesterase and they could be considered for Rev. Bras. Farmacogn. Braz J. Pharmacogn. 260 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al.

further studies in the treatment of AD. In particular, Farmacogn 15: 392-413. the species belonging to Amaryllidaceae, Apiaceae, Barbosa-Filho JM, Piuvezam MR, Moura MD, Silva MS, Lima Asteraceae, Fabaceae and Fumariaceae were the most KVB, Cunha EVL, Fechine IM, Takemura OS 2006. studied. Since most of acetylcholinesterase inhibitors Anti-infl ammatory activity of alkaloids: A twenty- century review. Rev Bras Farmacogn 16: 109-139. are known to contain nitrogen, the higher activity Benishin CG, Lee R, Wang LCH, Liu HJ 1991. Effects of of these extracts may be due to their rich alkaloidal ginsenoside RB-1 on central cholinergic metabolism. content. The alkaloids are the major compounds isolated Pharmacology 42: 223-229. from this species and shows inhibitory activity for the Breuer H, Rangel M, Medina E 1982. Pharmacological acetylcholinesterase. 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Rev. Bras. Farmacogn. Braz J. Pharmacogn. 266 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Howes et al., 1999 Howes et al., 1999 2001 al., et Rhee 2001 al., et Rhee Rhee et al., 2001 2001 al., et Rhee 2001 al., et Rhee Rhee et al., 2003 2003 al., et Rhee 2001 al., et Rhee 2001 al., et Rhee 2002 al., et Marston 2001 al., et Rhee 2001 al., et Rhee Rhee et al., 2001 2001 al., et Rhee 2001 al., et Rhee Rhee et al., 2003 2003 al., et Rhee 2001 al., et Rhee 2001 al., et Rhee 2001 al., et Rhee 2001 al., et Rhee Rhee et al., 2003 2003 al., et Rhee 2002 al., et Marston 2001 al., et Rhee 2001 al., et Rhee Rhee et al., 2001 2001 al., et Rhee 2001 al., et Rhee Inactive Inactive Active Active Active Active Active Active Active Active Weak activity Weak activity Inactive Inactive Active Active Active Active Weak activity Active Active Weak activity Inactive Inactive Inactive /disc Active Marston et al., 2002 2002 al., et Active /disc Marston g 0.02 mg/mL mg/mL 0.02 9.5 mcg/mL Variable Variable Variable Variable 10.0 mg/mL mg/mL 10.0 Not stated Variable mcg/disc 15.0 Variable Variable Variable Variable 10.0 mg/mL mg/mL 10.0 Variable Variable Variable Variable 10.0 mg/mL mg/mL 10.0 mcg/disc 15.0 Variable Variable Variable Variable O 50% O 2 O ext. 2 MeOH MeOH Toluene H Toluene EtOH 70% MeOH Toluene EtOH 95% Toluene Toluene EtOH 70% MeOH Toluene Toluene EtOH-H EtOH 70% EtOH 95% Toluene Toluene Dried bulb bulb Dried Dried bulb bulb Dried bulb Dried bulb Fresh Dried bulb bulb Dried Root Dried bulbs bulbs Dried bulbs Fresh USA South Korea Root MeOH Not stated Active Lee et al., 1997 USA Dried bulb MeOH MeOH bulb Dried USA Switzerland Switzerland bulb Fresh 95% EtOH mc 15.0 Netherlands Netherlands USA MeOH Switzerland bulb Dried USA India Leaf/Stem/Root EtOH 2 mm slices Inactive Gupta et al., 1997 1997 al., 1997 et al., Gupta et Inactive slices Gupta Inactive mm slices EtOH India 2 mm India Leaf/Stem/Root India Leaf India EtOH Leaf 2 Leaf EtOH EtOH slices 2 mm slices 2 mm Active Active 1997 al., et Gupta 1997 al., et Gupta Netherlands Bulb Bulb Netherlands MeOH bulb Dried USA

USA Dried bulb MeOH MeOH Netherlands Switzerland bulb Dried USA USA Dried bulb MeOH MeOH bulb Dried USA Switzerland Switzerland bulb Fresh Entire plant 95% EtOH EtOH 95% mcg/disc 15.0 15.0 mcg/disc Active Active 2002 al., et Marston Marston etal., 2002 USA Dried bulb MeOH MeOH bulb Dried USA

China Korea South Rhizome MeOH stated Not activity Weak 1997 al., et Lee sp sp

seudo-narcissus seudo-narcissus p Plant extracts showing acetylcholinesterase inhibition Amaryllis belladona belladona Amaryllis Achyranthes japonica japonica Achyranthes Amaryllidaceae plantago Alisma Amaranthaceae fragrans Chlidanthus Crinum powellii powellii Crinum Hippeastrelia Acanthaceae name botanical and Family Acanthaceae gendarussa Justicia Origin used Part Extract Dose/Concent. Result References Agavaceae portulacastrum Trianthema Adiantaceae capillus-veneris Adiantum Agavaceae deremensis Dracaena tuberosa Polianthes Eucharia amazonica amazonica Eucharia Hymenocallis festalis Alismataceae Alismataceae orientale Alisma Galanthus nivalis nivalis Galanthus Hymenocallis Habranthus robustus festalis Ismene vernum Leucojum Narcissus Table 1. Table 267 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Lee et al., 1997 1997 al., et Lee Park et al., 1996 Rhee et al., 2003 2003 al., et Rhee 2001 al., et Rhee 2001 al., et Rhee 2002 al., et Marston Rhee et al., 2001 2001 al., et Rhee 2001 al., et Rhee Rhee et al., 2001 2001 al., et Rhee 2001 al., et Rhee 2002 al., et Marston Lee et al., 1997 1997 al., et Lee 2001 al., et Khang Weak activity Inactive Active Active Active Active Inactive Inactive Inactive Inactive Inactive Inactive Active Not stated mcg/mL 200.0 10.0 mg/mL mg/mL 10.0 Variable Variable mcg/disc 15.0 Variable Variable Variable Variable mcg/disc 15.0 Not stated mcg/mL 100.0 1.4 mg/mL Inactive Trevisan; Macedo, 2003 2003 Macedo, Trevisan; Inactive mg/mL 1.4 3 O 50% O mg/mL 0.05 Active 50% O 1999 al., et Howes mg/mL 0.05 Active 1999 al., et Howes 2 2 MeOH 80% EtOH 70% MeOH Toluene bulb Fresh Toluene MeOH MeOH Toluene EtOH 95% MeOH MeOH Dried bulb bulb Dried bulb Dried bulb Dried bulb Fresh India Leaf EtOH 2 mm slices Inactive Gupta et al., 1997 al., et Gupta Inactive slices South Korea India Korea South Korea South Rhizome mm Korea South South Korea Fruit Korea South Root Korea South Root specified Not Leaf India EtOH MeOH Rhizome Root 2 Root 80% MeOH India MeOH Thailand MeOH 80% MeOH EtOH India Korea South Dichloromethane Not stated mcg/mL 200.0 MeOH Root Leaf Tuber 200.0 mcg/mL stated Not mcg/mL 200.0 Inactive Leaf stated Not Active sl 2 mm Inactive Active MeOH EtOH MeOH stated Not activity Weak 1996 al., et Park Inactive EtOH Lee et al., 1997 1997 al., et Lee Inactive 1996 al., Park et 1996 al., et Park Inactive 1997 al., et Lee 0.1 mg/mL slices 2 mm 1997 al., Gupta et 1997 al., et Lee slices 2 mm Weakactivity Active Inactive Ingkaninan et al.,2003 1997 al., et Gupta 1997 al., et Gupta stated Not Leaf EtOH-H Brazil Leaf Hexane:CHCl USA Dried bulb MeOH Variable Inactive Rhee et al., 2001 2001 al., et Rhee MeOH Inactive Variable bulb Dried USA Netherlands USA Switzerland USA Dried bulb MeOH MeOH bulb Dried USA USA Dried bulb bulb Dried USA India Leaf EtOH 2 mm slices Inactive Gupta et al., 1997 al., 2003 et Macedo, Gupta Inactive slices Trevisan; Inactive mg/mL USA mm Bark Brazil EtOH India 2.3 Leaf India EtOH bulb Dried 2 Korea South Leaf MeOH Root EtOH MeOH Variable sl 2 mm activity Weak al., 2001 et Rhee Inactive 1997 al., Gupta et South Korea Korea South Korea South China Korea South Root South Korea Root India Leaf EtOH-H Root Root Entire plant Dichloromethane MeOH Saponin fraction MeOH mcg/mL 200.0 80% MeOH Not stated Active stated Not 200.0 mcg/mL stated Not Active 1996 al., et Park Inactive activity Weak Inactive 1997 al., et Lee Wu and yu, 1984 1996 al., Park et 1997 al., et Lee

Cnidium officinale officinale Cnidium carota Daucus Foeniculum vulgare Glehnia littoralis seseloides Ledebouriella wallichii Ligusticum incisum Notopterygium koreanum Ostericum Thevetia peruviana Apocynaceae roseus Catharanthus coronaria Ervatamia Araceae Colocasia esculenta ternata Pinellia Apocynum lancifolium Philodendron imbe imbe Philodendron Narcissus tazzeta Nerine bowdenii bowdenii Nerine Rhodophiala bifida bifida Rhodophiala Sprekelia formosissima formosissima Sprekelia Apiaceae candida Zephyranthes Anacardiaceae occidentale Anacardium indica Mangifera Annonaceae longifolia Polyalthia Apiaceae Angelica gigas Angelica sinensis sinensis Angelica Anthriscus sylvestris Bupleurum chinense Bupleurum falcatum scorzonerifolium Bupleurum asiatica Centella

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 268 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. O 50% O mg/mL 0.3 Inactive 1999 al., et Howes 2 2.5 mg/mL Active Trevisan; Macedo, 2003 2003 2003 Macedo, Macedo, Trevisan; Trevisan; Active Inactive mg/mL mg/mL 2.5 2.7 3 3 India Leaf EtOH 2 mm slices Inactive Gupta et al., 1997 al., et Gupta 2003 Inactive slices Macedo, Korea South mm India Pericarp+Seeds India Trevisan; Lyophilized Inactive Leaf India EtOH mg/mL India 2 Leaf India Leaf Stem Brazil Hexano stated Not 1.5 Stem/Branch EtOH Leaf EtOH EtOH Inactive 2003 al., et Yu EtOH slices 2 mm slices 2 slices 2 mm mm Active Active Active slices 2 mm 1997 al., et Gupta Active 1997 al., 1997 et Gupta al., Gupta et 1997 al., et Gupta South Korea Korea South Korea South Root India Korea South Seed India India Root Flowers MeOH Stem/Branch India MeOH India Stem/Branch EtOH MeOH 80% MeOH Leaf EtOH Leaf stated Not Seed oil stated Not 200.0 mcg/mL EtOH slices 2 mm mg/mL 0.5 activity Weak EtOH Seed oil slices 2 mm Inactive 1997 al., et Lee activity Weak Active activity Weak 1997 al., et Lee Active 1996 al., Park et slices 2 mm 1997 al., et Lee 1997 al., Gupta et slices 2 mm 200 mg/kg Active 1997 al., Gupta et Active Inactive 1997 al., et Gupta 1997 al., et Gupta Gattuet al., 1997 China Root EtOH-H EtOAc 0.6 mg/mL Inactive Trevisan; Macedo, 2003 2003 Macedo, Trevisan; 2003 Inactive mg/mL Macedo, 0.6 EtOAc Trevisan; Active Brazil Root CHCl mg/mL Iraq Korea South India Hexane Resin Brazil Root 3.3 parts Aerial Leaf Acid-EtOH MeOH oil Essential EtOH mg/mL 0.4 - stated Not Active Inactive slices 2 mm 1987 al., et Mahmoud mg/mL 17 Active 1997 al., et Lee Active 1997 al., et Gupta 2003 Macedo, Trevisan; India Leaf EtOH 2 mm slices Inactive Gupta et al., 1997 al., et 2003 Gupta Macedo, Inactive slices Trevisan; Inactive mg/mL mm EtOH Flower Brazil Leaf India EtOH 1.6 2 India Brazil Stem CHCl Leaf EtOH slices 2 mm Active 1997 al., et Gupta

Combretaceae scarabaeicola Cordyceps Combretaceae indica Quisqualis Commelinaceae virginiana Tradescantia Convolvulaceae nummularius Evolvulus nil Ipomoea Crassulaceae pinnata Kalanchoe Cucurbitaceae Mormodica charantia Platycodon grandiflorum grandiflorum Platycodon Cannabaceae sativa Cannabis Caprifoliaceae japonica Lonicera nigra Sambucus Caricacaceae papaya Carica Caryophyllaceae media Stellaria Celastraceae Celastrus paniculatus Clavicipitaceae Codonopsis pilosula pilosula Codonopsis Burseraceae piauhiensis Cordia ramosissimum Heliotropium erythrorhizon Lithospermum Burseraceae wightii Commiphora heptaphyllum Protium Campanulaceae Verbesina diversifolia diversifolia Verbesina Bombacaceae conyzoides Vernonia Bombacaceae ceiba Bombax Boraginaceae glazioviana Auxemma

269 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Jang et al., 2003 al., et Jang 2003 al., et Jang 2003 al., et Jang Lee et al., 1997 1997 al., et Lee Park et al., 1996 Active Inactive Active Weak activity Inactive 27.3 mcg/mL mcg/mL 27.3 >80 mcg/mL mcg/mL 49.5 50 50 50 IC IC IC Not stated mcg/mL 200.0 O ext. 2 MeOH MeOH H MeOH MeOH MeOH 80% Root India Leaf EtOH 2 mm slices Inactive Gupta et al., 1997 al., et Gupta Inactive slices 2003 Korea South mm Korea South Macedo, Korea South Rhizome Rhizome Leaf India EtOH Korea South Root 2 India MeOH Trevisan; MeOH Active parts Aerial India mg/mL India Brazil MeOH Brazil MeOH Latex India Stem/Branch India stated Not India Stem/Branch 1.5 stated Not India Leaf EtOH India Fruit + Leaf India EtOH India Leaf stated Not mg/mL 0.1 activity Weak India Leaf activity Weak India Stem/Branch EtOH Korea South Leaf EtOH 1997 al., et Lee latex Fresh 1997 al., et Lee Leaf activity Weak EtOH slices 2 mm activity Weak Leaf EtOH Leaf Leaf EtOH slices 2 mm Latex 1997 al., et Lee Leaf 1997 al., et Lee EtOH Active mg/mL 0.6 EtOH slices 2 mm Active EtOH fract Alkaloid EtOH slices 2 mm EtOH slices 2 mm Inactive 1997 al., Gupta et slices 2 mm Variable Active 1997 al., Gupta et slices 2 mm Active Active 2003 slices 2 mm Macedo, Trevisan; Active slices 2 mm 1997 al., et Gupta slices 2 mm Active Active slices 2 mm 1997 al., Gupta et Active 1997 al., et Gupta Active 1997 al., et Gupta Active 1984 Agarwal, and Sing Active 1997 al., et Gupta 1997 al., et Gupta 1997 al., Gupta et 1997 al., et Gupta 1997 al., et Gupta India South Korea Brazil Korea South Bark Leaf Root bark Stem 80% MeOH EtOH EtOH 200.0 mcg/ml mg/mL 2.3 slices 2 Inactive mm Active Active 1996 al., Park et 2003 Macedo, Trevisan; 1997 al., et Gupta South Korea Korea South India Root India Leaf MeOH Leaf EtOH EtOH stated Not activity Weak slices 2 mm slices 2 mm 1997 al., et Lee Active Active 1997 al., et Gupta 1997 al., et Gupta Brazil Bark Hexane 0.6 mg/mL Inactive Trevisan; Macedo, 2003 2003 Macedo, Trevisan; Inactive mg/mL Brazil Bark Brazil Hexane Thailand 0.6 India Korea South Leaf Rootbark Wood Leaf MeOH EtOH MeOH EtOH mg/mL 0.1 mg/mL 1 mg/mL 0.1 slices 2 mm activity Weak Inactive activity Weak 2003 al., et Ingkaninan Active 1997 al., et Lee 2003 Macedo, Trevisan; 1997 al., et Gupta

Cyperus rotundus rotundus Cyperus fluviatilis Scirpus Dioscoreaceae batatas Dioscorea Ephedraceae foliata Ephedra sinica Ephedra Equisetaceae ramosissimum Equisetum Euphorbiaceae indica Acalypha variegatum Codiaeum urucunama Croton fernanendesii Dalechampia Euphorbia hirta milii Euphorbia neriifolia Euphorbia pulcherrima Euphorbia royleana Euphorbia integerrima Jatropha fraternus Phyllanthus Putranjiva roxburghii Ricinus communis suffruticosa Securinega Fabaceae indica Aeschynomene julibrissin Albizia cearensis Amburana membranaceus Astralagus Trichosanthes kirilowii kirilowii Trichosanthes Cycadaceae Cupressaceae orientalis Biota Cycadaceae revoluta Cycas Cyperaceae Bauhinia chyilantha chyilantha Bauhinia virgilioides Bowdichia superba Butea pulcherrima Caesalpinia sappan Caesalpinia

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 270 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Lee et al., 1997 1997 al., et Lee 1996 al., et Salvati Mahanta; Mukherjee, 2001 2001 Mukherjee, Mahanta; 2001 Mukherjee, Mahanta; 2001 Mukherjee, Mahanta; 2001 Mukherjee, Mahanta; Active Inactive Inactive Active Active Inactive 1.31 mg/mL mg/mL 1.31 Active 2001 al., et Permtermsin 50 Not stated diet of 15% 100.0 mcg/mL mcg/mL 100.0 mcg/mL 100.0 mcg/mL 100.0 mcg/mL 100.0 O ext. 2 O soluble fraction IC O ext. 2 2 Hot H MeOH MeOH oil Seed MeOH MeOH H Seed oil Seed India India Korea South Korea South Italy Seed Leaf MeOH EtOH stated Not slices 2 mm activity Weak Active 1997 al., et Lee 1997 al., et Gupta India Root EtOH 100% Korea South India Brazil Brazil Root India RootEtOH Leaf bark Stem bark Stem MeOH EtOH EtOH EtOH stated Not mg/mL 2.5 mg/mL 1.8 slices 2 mm activity Weak Inactive 1997 al., et Lee Active Active 2003 Macedo, Trevisan; 2003 1997 Macedo, al., et Trevisan; Gupta Korea South Root MeOH stated Not activity Weak 1997 al., et Lee Brazil Heartwood EtOH 2.8 mg/mL Active Trevisan; Macedo, 2003 2003 2003 Macedo, Macedo, Trevisan; Active mg/mL Trevisan; Inactive mg/mL EtOH Heartwood Brazil 2.8 Seed Brazil EtOAc Korea South India 2.3 Brazil Root Turkey Turkey Turkey Turkey Leaf stated Not Turkey Turkey parts Aerial MeOH Turkey parts Aerial Turkey parts Aerial EtOH Turkey parts Aerial Turkey fract. Alkaloid parts EtOH Aerial Turkey fract. Alkaloid parts Aerial Turkey fract. Alkaloid parts Aerial Turkey fract. Alkaloid parts Aerial Turkey fract. Alkaloid stated Not parts Aerial stated Turkey Not fract. Alkaloid parts Aerial stated Turkey Not fract. Alkaloid parts Aerial mg/mL 1.2 stated Turkey Not fract. Alkaloid parts Aerial stated Turkey Not fract. Alkaloid parts slices Aerial 2 mm Turkey stated Not fract. Alkaloid parts Aerial Inactive stated Not fract. Alkaloid Active parts Aerial stated Not fract. Alkaloid Active parts Aerial Active stated Not fract. Alkaloid Active parts Aerial stated Active Not fract. Alkaloid Active parts Aerial stated Not fract. Alkaloid Active 1997 al., et Lee parts Aerial stated Not fract. Alkaloid Active 2002 Sener, stated Not fract. Alkaloid Active 2002 Sener, 2003 Macedo, Trevisan; stated Not fract. Alkaloid Active 2002 Sener, stated Not fract. Alkaloid Active 1997 al., et Gupta 2002 Sener, stated Not Active 2002 Sener, stated Not Active 2002 Sener, stated Not Active 2002 Sener, stated Not Active 2002 Sener, stated Not Active 2002 Sener, Active 2002 Sener, Active 2002 Sener, Active 2002 Sener, Active 2002 Sener, Active 2002 Sener, 2002 Sener, 2002 Sener, 2002 Sener, 2002 Sener, 2002 Sener, South Korea Korea South Thailand India Thailand Leaf Root H Root Leaf MeOH MeOH EtOH stated Not 0.1 mg/mL slices 2 mm Active Weakactivity Active 2002 al., et Sung Ingkaninan et al.,2003 1997 al., et Gupta

Crotalaria juncea lablab Dolichos Glycine max Glycyrrhiza uralensis uralensis Glycyrrhiza leucocephala Leucaena sericeus Lonchocarpus acustipula Mimosa pudica Mimosa Gentiana scabra scabra Gentiana Plathymiscium floribundum floribundum Plathymiscium polygalaeflorus Pterodon thunbergiana Pueraria sesban Sesbania arborea Vanilosmopsis Fumariaceae asepala Fumaria bastardii Fumaria boissieri Fumaria bracteosa Fumaria capreolata Fumaria cilicica Fumaria densiflora Fumaria flabellata Fumaria gaillardotii Fumaria Fumaria judaica Fumaria kralikii macrocarpa Fumaria microcarpa Fumaria officinalis Fumaria parviflora Fumaria petteri Fumaria rostellata Fumaria schleicheri Fumaria Fumaria vailantii Gentianaceae Caragana chamlagu chamlagu Caragana fistula Cassia occidentalis Cassia siamea Cassia

271 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Perry et al., 2000 2000 al., et Perry 2002 al., et Perry Lee et al., 1997 1997 al., et Lee 1999 al., et Howes 1999 al., et Howes 1974 Pal, Thomas; 2003 al., et Sharifi Park et al., 1996 1997 al., et Lee Active Active Weak activity Active Active Active Active Inactive Inactive mg/mL mg/mL mg/mL 0.03 μL/mL 0.03 μL/mL

50 20.0 μL/animal μL/animal 20.0 0.2 0.1 9.5 mcg/mL Not stated mg/kg 50.0 200.0 mcg/mL mcg/mL 200.0 Not stated 1.0 mg/mL 1.0 mg/mL 1.0 mg/mL 1.0 mg/mL Inactive Weak activity Inactive Inactive Orhan Orhan etet al., al., 2003 2003 Orhan et al., 2003 Orhan et al., 2003 3 3 3 3 O 50% O 50% O mg/mL 0.089 activity Weak 1999 al., et Howes 2 2 O ext. O 2 2 MeOH MeOH EtOH-H H MeOH 80% MeOH Essential oil oil Essential H Root Root Branchlets Dried bulb bulb Dried bulb Dried South Korea Korea South China India Korea South Korea South Flowers leaf Dried Bark MeOH MeOH MeOH stated Not stated Not stated Not activity Inactive Weak activity Weak 1997 al., et Lee 1977 Singh, Lahon; 1997 al., et Lee Turkey Aerial parts MeOH-CHCl MeOH-CHCl parts MeOH-CHCl parts parts Turkey Aerial Turkey Aerial Turkey Aerial Turkey parts Aerial specified Not mg/mL 1.0 Inactive 2003 al., et Orhnan England Essential oil Essential oil IC Korea South Bark South Korea Korea South Korea South Korea South parts Aerial Korea South Root Root MeOH Stem MeOH-CHCl parts MeOH 80% MeOH South Korea Korea South MeOH Korea South stated Not Rhizome Aerial Turkey Root mcg/mL 200.0 Tuber stated Not activity Weak MeOH Inactive stated Not 1997 al., et MeOH Lee MeOH activity Weak 1996 al., et Park 1997 al., et Lee activity Weak Not stated 1997 al., et Lee stated Not mg/mL 1.0 Active activity Weak activity Weak 1997 al., et Lee 1997 al., et Lee Lee et al., 1997 South Korea India Iran Wood MeOH Not stated Active Lee et al., 1997 India India India Korea South India Korea South Leaf India parts Aerial Korea South Stem/Branch Korea South Root Leaf England Leaf EtOH-H MeOH EtOH parts Aerial EtOH parts Aerial Leaf MeOH MeOH MeOH EtOH stated Not slices mm 2 EtOH slices 2 mm stated Not stated Not Active mg/mL 0.2 activity Weak Active slices 2 mm 1997 al., et Lee slices 2 mm activity Weak activity Weak activity Weak 1997 al., et Gupta Active 1997 al., et Gupta 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee Inactive 1997 al., et Gupta 1997 al., et Gupta

Salvia miltiorrhiza miltiorrhiza Salvia Lawsonia inermis inermis Lawsonia Magnoliaceae kobus Magnolia obovata Magnolia Lycopodium annotinum annotinum Lycopodium clavatum Lycopodium complantum Lycopodium selago Lycopodium Lythraceae Salvia lavandulaefolia lavandulaefolia Salvia Cinnamomum cassia cassia Cinnamomum Schizonepeta tenuifolia tenuifolia Schizonepeta baicalensis Scutellaria baicalensis Scutellaria Lardizabalaceae quinata Akebia Lauraceae aspodheloides Anemarrhena cochinchinensis Asparagus platyphylla Liriope Lycopodiaceae alpinum Lycopodium Cinnamomum japonicum japonicum Cinnamomum Liliaceae Allium sativum Ginkgoaceae Ginkgoaceae biloba Ginkgo Hydrocharitaceae verticillata Hyderilla Lamiaceae rugosa Agastache blumei Coleus arvensis Mentha sanctum Ocimum frutescens Perilla vulgaris Prunella officinalis Rosmarinus

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 272 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al.

Park et al., 1996 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Lee 1997 al., et Gupta 2003 al., et Ingkaninan 1997 al., et Lee 2003 Macedo, Trevisan; 2003 Macedo, Trevisan; 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Gupta Gupta et al.,1997 Park et al., 1996 1997 al., et Gupta Gupta et al.,1997 2003 al., et Siqueira 1997 al., et Lee 2000 al., et Cruz La De 1997 al., et Gupta 1997 al., et Lee 1997 al., et Gupta 1997 al., et Lee 1997 al., et Lee Park et al., 1996 1997 al., et Gupta 2002 al., et Marston 1996 al., et Hwang Hwang et al., 1996 Hwang et al., 1996

Active Inactive Active

5.0 mcg/mL 10.0 mcg/mL 5.0 mcg/mL

-MeOH (2:1) 3 CHCl H2O fraction MeOH India Leaf/Stem EtOH 2 mm slices Inactive Inactive Active slices slices Inactive sl mm Active mm slices Korea South EtOH mm Active Leaf India activity EtOH 2 Leaf/Stem India slices Bark Inactive 2 Korea South slices mm Inactive Active Leaf India EtOH mg/mL Active Weak mg/mL slices Leaf Active Inactive 2 Root Thailand slices mg/mL Korea South MeOH slices 80% MeOH mm Active EtOH Stem Brazil Hexane slices mm 2 0.1 Leaf Brazil EtOH Root 1.8 Stem/Branch India mm MeOH Leaf India EtOH 1.1 Active mm Active mcg/mL 200.0 mm mg/kg 2 Leaf India EtOH slices mm 2 Leaf India EtOH MeOH Leaf India EtOH Inactive EtOH 2 2 100 stated Not 2 Inactive Leaf India EtOH Stem/Branch India mm slices 2 Root Brazil EtOH stated Not Inactive Korea South EtOH Spain Inactive sl 2 mm Stem/Root India Fruit activity Weak Korea South Leaf India EtOH Fruit fixed oil mm Rhizome 2 Korea South MeOH South Korea Fixed oil Korea South Root EtOH Stem India MeOH Bark Switzerland Root 2 Korea South stated Not 10.0% of diet Aerial parts Tuber MeOH MeOH 80% MeOH stated Not Active EtOH 95% activity Weak activity Weak stated Not mcg/mL 200.0 Not stated 15.0 mcg/disc Inactive activity Weak Active Active South Korea Root MeOH 200.0 mcg/mL Inactive Inactive mcg/mL Root MeOH Korea 200.0 South

Meliaceae officinalis Magnolia Malvaceae herbaceum Gossypium Hibiscus rosa-sinensis verticillata Malva Meliaceae Melia azedarach Menispermaceae suberosa Stephania tetrandra Stephania Moraceae anguria Cecropia pachystachya Cecropia Ficus elastica krishnae Ficus Musaceae Musa parasidiaca Myrtaceae lanceolatus Callistemon guajava Psidium aromaticum Syzygium Nyctaginaceae diffusa Boerhavia Bougainvillea glabra Olacaceae olacoides Ptychopetalum Oleaceae Forsythia suspensa europaea Olea Oleandraceae biserrata Nephrolepis Orchidaceae Gastrodia elata Oxalidaceae Oxalis corniculata Paeoniaceae albiflora Paeonia moutan Paeonia obovata Paeonia Papaveraceae mexicana Argemone majus Chelidonium ternata Corydalis

273 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Gupta et al., 1997 al., et Gupta Turkal., et 1995 1997 al., et Gupta 2003 al., et Ingkaninan 2003 al., et Ingkaninan 1997 al., et Lee 1997 al., et Lee 1997 al., et Gupta 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee 1999 al., et Howes 1999 al., et Howes Park et al., 1996 1997 al., et Gupta 1997 al., et Lee 1999 al., et Howes Park et al., 1996 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee Park et al., 1996 1997 al., et Gupta 1997 al., et Gupta Gupta et al.,1997 1997 al., et Gupta Active Active Active Weak activity Weak activity Weak activity Inactive Active Active Weak activity Weak activity Inactive Weak activity Inactive Inactive Weak activity Inactive Weak activity Inactive Inactive Weak activity Weak activity Weak activity Inactive Active Inactive Active Active mg/mL mg/mL mg/mL 110.0 mg/mL 110.0 mg/mL

50 2 mm slices slices 2 mm IC slices 2 mm mg/mL 0.1 0.1 μmols/mL Not stated Not stated slices 2 mm Not stated mg/mL 1.0 Not stated Not stated Not stated mg/mL 0.3 9.5 mcg/mL mcg/mL 200.0 slices 2 mm 0.1 0.2 mcg/mL 200.0 mg/mL 0.1 Not stated Not stated mcg/mL 200.0 slices 2 mm slices 2 mm slices 2 mm slices 2 mm O 50% O 50% 2 2 O ext. 2 MeOH 80% EtOH EtOH 75% EtOH MeOH MeOH MeOH MeOH EtOH MeOH MeOH MeOH MeOH MeOH EtOH-H EtOH MeOH EtOH-H MeOH MeOH MeOH MeOH 80% EtOH EtOH EtOH EtOH H MeOH 80% Leaf Not specified Leaf Stem Seed Seed Seed Stem/Branch Fruit Caules Entire plant Seed Root Root Root Leaf/Stem Root Root Root Rhizome Entire plant Entire plant Fruitbody Stem/Branch Leaf Leaf Leaf India Organism Adriatic Sea India Thailand Thailand Korea South Korea South India Korea South Korea South Korea South Korea South China Korea South India Korea South China Korea South Korea South Korea South Korea South India India India India

Papaver somniferum somniferum Papaver Parazoanthidae axinellae Parazoanthus Piperaceae betle Piper interruptum Piper nigrum Piper Plantaginaceae asiatica Plantago Poaceae lacryma-jobi Coix dactylon Cynodon Hordeum vulgare nigra Phyllostachys aestivum Triticum Polygalaceae tenuifolia Polygala Polygonaceae leptopus Antigonon multiflorum Polygonum ondulatum Rheum Polyporaceae umbellatus Polyporus Poria cocos Pontederiaceae crassipes Eichhornia Portulacaceae Portulaca quadrifida Pteridaceae multifida Pteris Punicaceae granatum Punica Ranunculaceae

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 274 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Park et al., 1996 1997 al., et Lee 1997 al., et Lee 2003 al., et Rhee Park et al., 1996 Park et al., 1996 1997 al., et Lee Park et al., 1996 1997 al., et Lee Howes et al., 1999 Howes et al., 1999 1997 al., et Lee Park et al., 1996 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee Gupta et al.,1997 1997 al., et Lee 1997 al., et Lee Gupta et al.,1997 1997 al., et Lee 2001 al., et Miyazawa 1997 al., et Lee 1997 al., et Lee Park et al., 1996 1997 al., et Lee 1997 al., et Lee Park et al., 1996 2003 Macedo, Trevisan; 2003 Macedo, Trevisan; Trevisan; Macedo, 2003 2003 Macedo, Trevisan; Gupta et al.,1997 1997 al., et Lee Inactive Active Weak activity Inactive Active Active Weak activity Inactive Weak activity Inactive Inactive Weak activity Inactive Weak activity Weak activity Weak activity Weak activity Weak activity Weak activity Inactive Inactive Weak activity Active Weak activity Active Weak activity Weak activity Active Inactive Weak activity Active Inactive Active Inactive Active Active Weak activity 0.13 mcg/mL 0.13 mcg/mL 50 200.0 mcg/mL mcg/mL 200.0 Not stated Not stated mg/mL 10.0 mcg/mL 200.0 mcg/mL 200.0 mg/mL 0.1 mcg/mL 200.0 Not stated mg/mL 0.05 mg/mL 0.03 Not stated mcg/mL 200.0 Not stated mg/mL 1.0 Not stated Not stated Not stated mg/mL 0.2 sl 2 mm Not stated mg/mL 0.2 slices 2 mm Not stated IC Not stated Not stated mcg/mL 200.0 Not stated stated Not mcg/mL 200.0 mg/mL 1.1 mg/mL 1.4 mg/mL 1.8 mg/mL 2.1 slices 2 mm Not stated O 50% O 2

3 O ext. 2 MeOH MeOH MeOH 80% MeOH 80% MeOH MeOH EtOH 70% Dichloromethane MeOH 80% MeOH 80% MeOH MeOH EtOH-H MeOH MeOH MeOH MeOH MeOH MeOH EtOH MeOH MeOH EtOH MeOH oil Essential MeOH MeOH Dichloromethane MeOH MeOH Dichloromethane Hexane CHCl EtOAc MeOH EtOH MeOH H Root Tuber Rhizome Rhizome Rhizome Rhizome Fruit Seed Seed Fruit Fruit Leaf Seed Seed Fruit Fruit Leaf Root Branchlets Leaf Fruit Essential oil Pericarp Fruit Aerial parts Bark Fruit Leaf Leaf Wood South Korea Korea South Korea South USA Korea South Korea South Korea South China Korea South Korea South Korea South Korea South Korea South Korea South Korea South India Korea South Korea South India Korea South USA Korea South Korea South Korea South Korea South Korea South Brazil India Korea South

Aconitum carmichaelii carmichaelii Aconitum heracleifolia Cimicifuga racemosa Cimicifuga chinensis Coptis japonica Coptis Rhamnaceae Ziziphus jujuba Rosaceae pinnatifida Crataegus japonica Eriobotrya armeniaca Prunus persica Prunus coreanus Rubus Rubiaceae jasminoides Gardenia coccinea Ixora Rubia cordifolia rhynchophylla Uncaria Rutaceae Citrus aurantiifolia aurantium Citrus paradisi Citrus unshiu Citrus Euodia officinalis Euodia rutaecarpa amurense Phellodendron trifoliata Poncirus trifolia Triphasia vinifera Vitis Santalaceae album Santalum

275 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Lee et al., 1997 1997 al., et Lee Park et al., 1996 1997 al., et Lee Park et al., 1996 Inactive Inactive Inactive Inactive Not stated mcg/mL 200.0 Not stated mcg/mL 200.0 O 50% O mg/mL 0.15 Active 1999 al., et Howes 2 MeOH MeOH 80% MeOH MeOH 80% MeOH Fruit Root Korea South Korea South Korea South Seed Rhizome Rhizome MeOH MeOH MeOH stated Not stated Not stated Not activity Weak Inactive Inactive 1997 al., et Lee 1997 al., et Lee 1997 al., et Lee EtOH 2.2 mg/mL Active Trevisan; Macedo, 2003 2003 Macedo, 2003 2003 Trevisan; Macedo, Active Macedo, mg/mL India Trevisan; Active India mg/mL Trevisan; India Inactive Brazil mg/mL Leaf Leaf Brazil Leaf MeOH EtOH 2.2 India 2.8 Leaf Leaf Brazil MeOH Korea South Leaf Leaf 1.7 India EtOH EtOH India Fruit India Leaf EtOH EtOH EtOH Leaf Leaf MeOH Leaf slices 2 mm EtOH slices 2 mm slices 2 mm EtOH slices 2 mm Active mg/mL Active 2.1 EtOH EtOH Active stated Not sl 2 mm Inactive Inactive 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Gupta slices 2 mm Inactive slices 2 mm 1997 al., et Gupta 2003 Macedo, Inactive slices 2 mm Trevisan; Active 1997 al., et Lee Active Active 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Gupta South Korea Korea South Brazil Korea South Arillus India Fruit stated Not Korea South MeOH Root EtOH Leaf stated Not EtOH mg/mL 1.5 activity Weak Active 1997 al., et Lee slices 2 mm 2003 Macedo, Trevisan; Active 1997 al., et Gupta Brazil Fruit EtOH 1.5 mg/mL Inactive Trevisan; Macedo, 2003 2003 Macedo, Trevisan; Inactive mg/mL Korea South India Fruit Brazil EtOH Root 1.5 Leaf MeOH EtOH stated Not slices 2 mm activity Weak 1997 al., et Lee Inactive 1997 al., et Gupta Brazil Leaf EtOH 1.4 mg/mL Active Trevisan; Macedo, 2003 2003 Macedo, Trevisan; Active India mg/mL Korea South India India Leaf Brazil EtOH Bark India India Leaf RootEtOH-H 1.4 Leaf Leaf MeOH Leaf EtOH EtOH EtOH EtOH stated Not slices 2 mm slices 2 mm slices activity 2 mm Weak Active slices 2 mm 1997 al., et Lee Active Active Active 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Gupta 1997 al., et Gupta

Amomum xanthioides xanthioides Amomum zedoaria Curcuma officinale Zingiber Tiliaceae Tiliaceae aestuans Corchorus Tropeolaceae majus Tropaeolum Verbenaceae Lantana camara alba Lippia sidoides Lippia arbor-tristis Nictanthes castus agnus Vitex rotundifolia Vitex Zamiaceae edule Dioon spinulosum Dioon Zamia furfuraceae Zingiberaceae Euphoria longana longana Euphoria Paullinia cupana cupana Paullinia Schisandraceae chinensis Schisandra Mazus pumilus glutinosa Rehmannia Scrophulariaceae buergeriana Scrophularia chinense Verbascum Simaroubaceae versicolor Simarouba Solanaceae Datura innoxia innoxia Datura Lyceum chinense Nicotiana rustica Physalis minima asperum Solanum nigrum Solanum somnifera Withania

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 276 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Kuno et al., 1996 1996 al., et Kuno Otoguro etal., 2000 Permtersinet al., 2001 Permtersinet al., 2001 1993 Niemeyer, Cuevas; 1993 Niemeyer, Cuevas; 1993 Niemeyer, Cuevas; 1993 Niemeyer, Cuevas; 1993 Niemeyer, Cuevas; Kuno et al., 1996 1996 al., et Kuno Otoguro etal., 2000 Singh; Singh, 1996 Singh, Singh; 1996 Singh, Singh; Astrachan etal., 1980 Astrachan etal., 1980 Strong activity activity Strong activity Strong Active Active Weak activity activity Weak Active activity Weak Equivocal Active Active activity Strog Active Active Inactive Inactive Inactive 2.88 mg/L mg/L 2.88 221 μmols Active Mroue etal., 1996 0.026 μmols 2.5 μmols 4.0 μmols Active Otoguro Active etal., 2000 Ogino et al., 1997 188 μmols 48.6 μmols Active Active 1.0 nmols 1.0 nmols Mroue etal., 1996 Rahman etal., 0.001 μmols 2003 25.8 nmols 3.5 μmols Active 1995 al., et Omrua 10.0 μmols Active 2.5 μmols 5.21 μmols Active 227.9 μmols Otoguro etal., 2000 182.0 μmols Active 0.4 mmols 0.21 mmols Active activity Weak Ogino etal., 1997 activity Weak Ogino et 2002 al., al., et 1997 Rahman 2002 al., et Rahman Rahman etal., 2002 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 IC IC IC 5.0 mmols 1.0 mmols 10.0 mmols 10.0 mmols 5.0 mmols 12 mcg 12 mcg LC IC IC IC 0.016 mg mg 0.016 mg 0.016 In vitro vitro In vitro In vitro In vitro In In vitro vitro In vitro In vitro In In vitro vitro In In vivo/ Blood Alkaloid In vitro IC vitro In Alkaloid Benzoxazinone In vitro Benzoxazinone In Alkaloid In vitro IC vitro In Alkaloid ned natural compounds showing acetylcholinesterase inhibition fi Chemically de -acetyl -nor

Alkaloid C C Alkaloid Allicin Alkaloid compound Sulfur A Arisugacin vitro Brain vivo/ In vitro In Triterpene E Arisugacin F Arisugacin G IC Arisugacin In H Arisugacin vitro Alkaloid Atherospermoline IC Triterpene vitro In heterocycle Triterpene 2’- Atherospermoline, Triterpene In N Triterpene Auraptene A Axillaridine C Axillarine F Axillarine vitro In acid Baccabolivic vitro In vitro Oxygen In Barakol vitro Alkaloid In Coumarin Alkaloid Diterpene stated Not Alkaloid stated Not stated Not stated Not vitro In vitro In vitro In vitro In vitro In Inactive Inactive Inactive IC mcg/mL 0.16 Inactive ppm 10.0 IC 2000 al., et Otoguro IC 2000 al., et Otoguro 2000 al., et Otoguro 2000 al., et Otoguro Active Active 2001 al., et Miyazawa 2001 al., et Calderon Arisugacin B B Arisugacin Triterpene vitro In 1,4: Benzoxazin-3-one, 2,4-dihydroxy-7-methoxy Akuammidine Alkaloid In vitro vitro IC Alkaloid Akuammidine In D Arisugacin Triterpene 12- Atherospermoline, O vitro In IC Arisugacin C C Arisugacin Triterpene vitro In IC Almazole D, (+) (+) D, Almazole Alopecuridine Anabasamine Anabasine A Anatoxin Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid vitro In vitro In vitro In vitro In stated Not Brain vivo/ In stated Not stated Not stated Not Inactive Active Active 1996 Active al., et N’Diaye 2003 al., et Hirasawa 1998 Abduvakhabov, Tilyabaev; 1998 Abduvakhabov, Tilyabaev; Akuammicine Alkaloid In vitro vitro IC Chemical name Acetophenone Alkaloid Akuammicine In Class Benzenoid vitro In Model stated Not Dose/Concent. Result Inactive References 1998 al., et Miyazawa Arisugacin Triterpene In vitro IC vitro Anisodamine Triterpene Arisugacin In Alkaloid vitro In stated Not Active 1992 al., et Guo Table 2. Table 277 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Miyazawa et al., 1997 1997 al., et Miyazawa Gracza, 1985 Schmeller et al., 1997 1997 al., et Schmeller 1993 al., Shin et Hwang et al., 1996 Jang et al., 2003 Ulrichova etal., 1985 1979 al., et Chun Ulrichova etal., 1983 Ulrichova etal., 1985 Ulrichova etal., 1983 Alozie et al., 1979 1979 al., et Alozie 1979 al., et Alozie 1979 al., et Alozie 1979 al., et Alozie 1979 al., et Alozie Active Active Weak activity activity Weak Active Active Active Active Active activity Strong Active activity Strong Active Active activity Weak Active Active mmols 167.4 μmols μmols 167.4 0.98 μmols μmols 0.98 8.0 μmols 5.1 μmols Strong activity Strong activity Ulrichova etal., 1983 Ulrichova etal., 1983 9.4 μmols 0.02 mmols 0.09 mmols Active Active Ulrichova etal., 1983 Ulrichova etal., 1983 0.91 μmols 162.0 μmols Active 443.6 μmols Active 143.0 μmols Ulrichova etal., 25.4 1985 μmols Active 33.0 μmols 2001 al., et Rahman Active Active2003 al., et Choudhary Active 1.85 mmols 1.38 mmols 2001 al., et Rahman Rahman etal., 2001 Kvaltinova et al.,1991 Active 9.40 μmols 197 mmols 1997 al., et Miyazawa 241.0 μmols Active Active Mroue etal., 1996 1996al., et Mroue

50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 1.0 mmols ID 0.1 μmols 0.125 mcg/mL 0.52 μmols 0.98 mcg/mL 0.30 ID IC mg/Kg 10.0 Kg mg/ 30.0 Kg mg/ 60.0 μmols 8.3 mol 0.016 IC IC In vitro vitro In In vivo In vivo vitro In vitro In In vitro/ Brain Brain vitro/ In In vitro vitro In vitro In vitro In vitro In vitro In vitro In Alkaloid In vitro IC vitro Alkaloid In Alkaloid Alkaloid vitro In vitro In stated Not stated Not Inactive Inactive 2003 al., et Choudhary 2003 al., et Choudhary - -iso- - N N N

Berberine, 13-methyl 13-methyl Berberine, Alkaloid Buxahyrcanine, Buxahyrcawine, (+) benzoyl: Brain vitro/ In (-) Buxakashmiramine, E Buxaminol ID B2 Alkaloid Calystegine N1 Calystegine Camphor β Carotene, Carvacrol Alkaloid Alkaloid (+) Carvone, Alkaloid vitro In Castoramine, (-) Monoterpene α Chaconine, Carotenoid Monoterpene IC Monoterpene vitro In vitro In vitro Alkaloid vitro In IC vitro In Alkaloid tissue Stomach vitro In In vitro mmols IC 1.0 mmols 1.0 diet of 0.02% Alkaloid Cimicine In stated Not In vitro vivo In 1.0 mmols Inactive Inactive Inactive 0.5 mmols Inactive 1996 al., et Asano 1996 al., et Active Man 1996 al., et Asano 2000 al., et Perry Active Gracza, 1985 Miyazawa et al., 1998b butyroyl butyroyl Buxahyrcanine, tygloyl: (+) (-) Buxakarachiamine, Alkaloid vitro In IC Carvone, (-) Monoterpene In vitro IC Berberine, 13-ethyl 13-ethyl Berberine, pseudo epi: Berberine, (+) Bicuculline, Alkaloid (-) Alkaloid Buxahejramine, Alkaloid Alkaloid vitro In Brain vitro/ In ID Spinal vivo/ In vitro In IC ID mg/Kg 5.0 Brain IC Inactive IC vitro/ vitro Chelilutine 1974 al., et Nistri Alkaloid Chelirubine Alkaloid Cimicidine In In Alkaloid Brain vitro/ In ID Chelerythrine Alkaloid In vitro vitro Alkaloid Chelerythrine In Berberine Alkaloid In vitro vitro Alkaloid Berberine In

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 278 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Kuno et al., 1996 1996 al., et Kuno 1993 al., et Kurokawa Ulrichova etal., 1983 Ulrichova etal., 1985 Ulrichova etal., 1983 Perry et al., 2000 2000 et al., Perry Gracza, 1985 1983 al., et Antonious Active Active Active Active activity Strong Active Active Inactive 5.8 μmols mmols 0.011 1.3 μmols Strong activity Ulrichova etal., 1983 76.0 nmols nmols 76.0 1.30 μmols/L 1.30 μmols/L 0.13 mmols 0.24 mmols Active 235.0 μmols 2.04 μmols Active 76.0 nmols 38.8 μmols 2001 al., et Kang 105.7 μmols Active activity Weak 2001 al., et Kang 0.39 mmols μmols 28.0 1996 Active al., et Kuno Active 2001 al., 105.5 et μmols Rahman Active Active 37.8 μmols Rahman et al., 2001 al., et 2001 1.5 Rahman μmols/L Active 3.2 μmols 10.0 nmols 2001 al., et Kang 5.8 μmols 2001 al., et Kang Active Active 2002b al., 6.2 et Rahman μmols Active Active Active 1996 al., et Park Ulrichova etal., 1986 Active Ogino etal., 1992 1997 al., et Ogino Ogino etal., 1997 Ogino etal., 1997 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 IC ID IC IC ID 0.67 mmols 1.0 mmols stated Not In vitro vitro In In vitro vitro In vitro In In vitro vitro In vitro In Coumarin In vitro IC vitro In Coumarin IC vitro In Alkaloid Coumarin In vitro IC vitro Coumarin In Coumarin In vitro 17.6 μmols Active Bruhlmann etal., 2001 -nor Alkaloid Alkaloid -nor vitro In IC N -dinor

Cyclophostin Oxygen heterocycle In vitro vitro In IC vitro 7-methoxy- Coumarin, heterocycle 5-prenyl-oxy Crooksiine Curcumin IC A Cyclomicrophylline vitro Alkaloid Cyclopenin Oxygen In Cyclophostin Alkaloid IC IC vitro vitro Alkaloid A Cyclovirobuxeine Benzenoidpara Cymene, S-allyl Cysteine, In Coumarin Alkaloid Decursin Coumarin Decursinol vitro In In Deguelin IC vitro Alkaloid Delavine Proteid In Monoterpene acid Derrisic In vitro In vitro acid Elagic Embelin vitro IC dehydro Evodiamine, IC vitro In Alkaloid Fagaronine vitro In Faleoconitine In Flavonoid Benzenoid Alkaloid 3.06 Alkaloid mcg/mL Fangchinoline 20.0 μmols 2’-nor vitro In Fangchinoline, Coumarin 2,2’- In Fangchinoline, IC N,N Alkaloid Quinoid 2- Fangchinoline, mmols 1.2 Alkaloid Ileum vitro/ In In vitro mcg/mL 400.0 Active vitro In vitro Active In stated Not vitro In In vivo activity Weak 0.40 mcg/mL In vitro activity Weak IC Mroue; Alam, 1991 stated Not Korutla; Kumar, 1994 1997 al., et Miyazawa 1992 al., et Welch IC Inactive 20.0 mg/kg 20.0 microliters Weakactivity Active 1980 al., et Ashack Ashack et al., 1980 Active Active 1999 al., et Ho Rahman etal., 2000 Dhar etal., 1986 Cycloprotobuxin C C Cycloprotobuxin Alkaloid vitro In IC Cordifoline Cordifoline Cordifoline, desoxy pseudo Cotisine, Alkaloid 7-hydroxy- Coumarin, 3,4-dimethyl Alkaloid Alkaloid In vitro vitro In Brain vitro/ In Dose variable variable Dose Active Inactive 2004 al., et Cardoso Cardoso et al., 2004 Coumarin, 7-hydroxy- 7-hydroxy- Coumarin, 6-(2(R)-hydroxy-3- methyl-but-3-enyl Cineol, 1,8 Cineol, Monoterpene vitro In Coptisine Coptisine Alkaloid Brain vitro/ In ID

279 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Greenwood, 1998 Greenwood, 1976 prozorovskii, Tonkopii; 1976 prozorovskii, Tonkopii; 1996 al., et Prozorovskii 1995 Harvey, 2001 al., et Pak 2001 al., et Pak 2002 al., et Marston 2001 al., et Rhee 2001 al., et Rhee 2001 al., et Rhee Active Active Active Active Active Active Active Active Active Active Active mmols 5.96 mg/mL mg/mL 5.96 Active 1999 al., et Singh

3.9 μmols 28.0 μmols Active Active Ogino etal., 1997 Ahmad et al., 2003 45.75 μmols 97.61 μmols Active 40.0 μmols Active 2002 al., et Kalauni 2002 al., et Kalauni 225.0 μmols Active 1996 al., et Mroue 50 50 50 50 50 50 50 3.0 mg/kg mg/kg 3.0 kg mg/ 3.0 mcg/plate 0.01 mcg/mL 0.01 mcg/plate 0.6 mcg/plate 0,2 4.0 mg/kg mg/kg 4.0 stated Not IC Not stated stated Not 0.01 In vitro/ Brain Brain vitro/ In In vivo In vivo Brain vitro/ In In vivo/ Plasma In vivo/ Brain vitro In vitro In vitro In vitro In Flavonoid In vitro IC vitro Flavonoid In Flavonoid Flavonoid Flavonoid In vitro Flavonoid In vitro 50.0 ppm In vitro 50.0 ppm In vitro 50.0 ppm Weakactivity 50.0 ppm Weakactivity Calderonet al., 2001 Equivocal Calderonet al., 2001 Weakactivity Calderonet al., 2001 Calderonet al., 2001 -methyl Alkaloid Alkaloid -methyl vitro In IC N

Haplophytine Alkaloid In vitro vitro IC RB-1 Ginsenoside Alkaloid Haplophytine In Triterpene vitro In μmols 1.0 Inactive 1991 al., et Benishin Flavanone, 2(S): 2’,5- 2’,5- 2(S): Flavanone, dihydroxy-5’,7-dimethoxy Flavone, 2’,4’,5,7- tetrahydroxy-3,5’,6,8- tetramethoxy vitro Funtumine, Galanthamine Alkaloid In acid Harman-3-carboxylic Alkaloid Heliotrine Heliotropamide 3,4-dimethyl Herniarin, Coumarin Alkaloid Alkaloid vitro In vitro In variable Dose vitro In vitro In stated Not stated Not Inactive mg/mL 0.5 Active 2004 al., et Cardoso Active Active 2001 al., et Bruhlmann 2003 al., et Guntern 1987 al., et Mahmoud Flavone, 2’,5,7- 2’,5,7- Flavone, trihydroxy-3,4’,5’,6,8- pentamethoxy Flavone, 2’,5-dihydro- xy-3,4’,5’,6,7,8-hexa- hexamethoxy 4’,5,7- Flavone, trihydroxy-3,6,8- trimethoxy Forticine C Funtumafrine Alkaloid Alkaloid vitro In vitro In IC stated Not Inactive 2002b al., et Rahman Galanthamine, (-) Geraniol Gingerol, 6 Alkaloid Monoterpene Benzenoid In vitro vitro In In vitro Not stated stated Not LC Active Inactive Greenblattet al., 1999 2000 al., et Perry Fasciculin 2 2 Fasciculin Fawcettimine Fenchone E Fenfangjine Proteid Alkaloid Alkaloid Monoterpene vitro In vitro In In vitro vitro In stated Not stated Not 1.0 mmols IC Active activity Weak Active 2000 al., et Tan 2002 al., et Tai Gracza, 1985

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 280 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Ahmad et al., 2003 Tanet al., 2000 Tanet al., 2002 1998 Tang, Cheng; 1998 Tang, Cheng; Anon, 1992a Grunwaldal., et 1994 1995 al., et Kozikowski Anon, 1992b Wang et al.,2000 2000 al., et Rajendran 2001 al., et Hogenaurer 2002 Tang, Zhao; Li et al., 2004 1991 al., et Kozikowski Anon, 1991 Zhangal., et 2002b 1991 al., et Yamada 1991 al., et Mc-Kinney 1994 al., et Tang 1994 al., et Tang 2000a et al., Camps Zhangal., et 2002b He et al., 2003 1991 al., et Yamada 1991 al., et Mc-Kinney 1994 al., et Tang 1994 al., et Tang et 2000b al., Camps 1991 al., et Yamada 1991 al., et Kozikowski 1991 al., et Mc-kinney Kozikowski et al., 1991b Wang et al.,1999 1996 al., et Kozikowski 1990 al., et Kozikowski 1999 al., et Liu Liu and Huang,1994 Liu and Huang,1994 Tanet al., 2000 Weak activity activity Weak Inactive Inactive Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active mg/kg μmols 11.6 μmols Active 3.153 μmols 1448 nmols 0.1 μmols nmols 260.0 mols 65.0 n nmols 475.0 44.5 nmols 0.3 μmols 0.074 μmols 71.5 nmols 0.3 μmols 71.5 nmols 6.0 μmols 0.54 μmols Active activity Strong

50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 IC stated Not IC IC IC IC stated Not IC IC IC stated Not IC 1.0 μmols/L μmols/L 1.0 μmols 0.082 mg/kg 0.5 mg/kg 0.5 stated Not mg/kg 0.5 μmols 0.02 stated Not 0.1 5.9 nmols μmols 0.024 7.0 nmols stated Not 0.1 mg/kg 0.25 IC mg/Kg 0.5 IC mg/kg 0.5 IC In vitro vitro In In vivo In vivo In vivo In vivo vitro In In vivo In vivo vitro In vitro In vitro In vitro In vitro In In vivo vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In Alkaloid Alkaloid vitro In stated Not Active : (DL) (DL) : Alkaloid vitro In IC cis

Hispidone Flavonoid In vitro IC vitro Hispidone Flavonoid In A Huperzine Alkaloid vitro In (+) A, Huperzine (-) A, Huperzine Alkaloid Alkaloid (DL) A, Huperzine vitro In Alkaloid Brain vivo/ In 1-methyl A, Huperzine 10,10- A, Huperzine Alkaloid dimethyl A, Huperzine Brain vivo/ In B Huperzine C Huperzine D Huperzine P Huperzine vitro In Alkaloid Alkaloid Alkaloid Alkaloid μmols/L 6.48 vitro In vitro In vitro In vitro In Active IC stated Not stated Not stated Not Active Inactive activity Weak

281 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Tanet al., 2002 Tanet al., 2002 1994 Huang, Liu; 1998 al., et Rahman Okamoto et al.,2001 Okamoto et al.,2001 2001 al., et Kang 2002b al., et Rahman 2002b al., et Rahman 1998 al., et Miyazawa 1998 al., et Miyazawa 1993 al., et Kumar 1998 al., et Miyazawa 2002 al., et Sung Mroue etal., 1996 19831 al., et Kozik 1997 al., et Miyazawa 1997 al., et Miyazawa 2000 et al., Perry 1998 Abduvakhabov, Tilyabaev; 1998 Abduvakhabov, Tilyabaev; 2001 al., et Takayama 2001 al., et Kang Breuer etal., 1982 1997 al., et Miyazawa 1997 al., et Miyazawa 1997 al., et Miyazawa 1997 al., et Miyazawa 1997 al., et Miyazawa 1997 al., et Miyazawa 1998 al., et Rahman 1998 al., et Rahman 2002 al., et Choudhary 2002 al., et Choudhary Ashack et al., 1980 1998 al., et Miyazawa 2001 al., et Kalauni 2001 al., et Kang 2001 al., et Miyazawa Strong activity activity Strong activity Weak 0.082 μmols 0.082 μmols μmols 10.0 3.0 μmols 3.0 μmols 69.0 μmols 67.97 μmols Inactive 36.7 mcg/mL 53.3 mcg/mL Active Active Active 78.3 mcg/mL 115.8 μmols Active 383.0 μmols Active Active activity Weak Active activity Weak 67.0 μmols 1.64 mmols 2.0 mmols Active 1.42 mmols 1.57 mmols Active 10.0 μmols/mL 10.0 Active μmols/mL 79.14 μmols Active Strog activity Active Active 55.0 mcg/mL Active 50.1 μmols 68.0 μmols Active Active Active 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 95.0 μmols μmols 95.0 IC In vitro vitro In Polycyclic In vitro IC vitro Coumarin In Polycyclic vitro In stated Not Inactive : (+) (+) : Monoterpene vitro In IC - O para Alicyclic In vitro IC vitro Alicyclic In cis

Huperzine R R Huperzine IC Huperzinine vitro (-) Hyrcanine, stated Iantheran A Active Iantheran B Alkaloid iso Imperatorin, Imperialine Alkaloid Alkaloid Impericine Alkaloid In α Ionone, β Ionone, Oxygen Coumarin heterocycle Not vitro Isatin IC Oxygen heterocycle Jasmine, vitro vitro In A Kobophenol Alkaloid Alkaloid Lanceomigine InIC vitro vitro In Leurocristine vitro In In vitro vitro Sesquiterpene (+) Limonene, In Sesquiterpene (-) Limonene, vitro In (DL) Benzenoid Linalool, Alkaloid Lupinine In Alkaloid epi Lupinine, IC vitro In stated Not Alkaloid A IC vitro Lycoposerramine Monoterpene In IC Coumarin Marmesin vitro In In Monoterpene (R) (-): IC Monoterpene Melochinine, activity Alkaloid Menth-1-ene, vitro In (+) Menthol, Alkaloid Alkaloid stated Not Menthol,(-) IC vitro In In vitro/mcg/mLMenthol, Brain iso: (+) mcg/mL IC vitro vitro Active In (-) activity Menthone, Weak IC In vivo Weak vitro In vitro (+) iso: Menthone, Alkaloid IC Moenjodaramine IC 1.5 mmols Monoterpene homo Moenjodaramine, vitro In Monoterpene vitro Coumarin Murranganon Monoterpene 0.24 mmols 1.2 IC Alkaloid Monoterpene vitro vitro In In In Murrangatin, vitro 2’- Monoterpene Inactive In 0.16 mmols 1.2 vitro stated Not ethyl 1.5 mcg/animal Mutarotenone Flavonoid β- ketone, Naphtyl vitro In μmols 200.0 In methyl In vitro A Nepapakistanamine Active In vitro vitro In mg/L stated 100.0 Not Coumarin Nodakenin vitro In In vitro In Equivocal In Nootkatone Active Alkaloid Sesquiterpene Equivocal Inactive IC 1.2 mmols Inactive 1.2 IC mmols IC IC Active Active vitro In Equivocal Weakactivity IC

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 282 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Miyazawa et al., 1998b 1998b al., et Miyazawa Shimosaka, 1955 1998b al., et Miyazawa 1998b al., et Miyazawa 2003 al., et Orhan 1982 al., et Zhu 2002 al., et Rahman 1997 al., et Schmeller 2002 al., et Choudhary Mroue etal., 1996 2002b al., et Rahman 2001 al., et Kang Tanet al., 2000 2002 al., et Choudhary 2002 al., et Marston al.,Yu et 1988 Brossi etal., 1986 Brossi etal., 1986 al.,Yu et 1988 2003 et al., Rasomiaranjanahary 2003 et al., Rasomiaranjanahary 2003 et al., Rasomiaranjanahary 2000 et al., Perry 2000 et al., Perry 1993 al., et Suga Ulrichova etal., 1983 Wratten et al., 1977 1978 Liston, Wekell; Wratten et al., 1977 1978 Liston, Wekell; 1997 al., et Miyazawa 1997 al., et Miyazawa Kozubck et al., 1992 Strong activity activity Strong Active activity Weak Active Active Inactive Active activity Weak Active Active Active Active activity Weak Active Active Active Active Active Active Active activity Weak Active Active Active Inactive Active Active Active Active Active Active Active Active mcg/plate /mL /mL Inactive 1980 al., et Ashack g

5.2 μmols 5.2 μmols 78.2 mmols 124.5 μmols 31.65 μmols 0.135 mmols 352.2 μmols 0.18 mmols 31.65 μmols 61.0 nmols 56.0 nmols 0.63 mmols 2.0 mmols 0.89 mmols 62.0 μmols 25.0 μmols 65.0 μmols 90.0 μmols 24.0 μmols 18.0 μmols Active Active Active Active Active Kozubck et al., 1992 Kozubck et al., 1992 Kozubck et al., 1992 Kozubck et al., 1992 Kozubck et al., 1992 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 0.01 IC 0.5 mmols/L stated Not 0.5 mmols 0.5 mmols/L IC Dose variable IC IC IC IC IC IC stated Not IC stated Not stated Not IC 0.2 mcg/mL mcg/plate 25.0 mcg/plate 0.5 IC 4.7 mmols nmols 10.0 mmols 0.034 stated Not 0.36 mmols stated Not 1.5 mmols IC IC IC In vitro vitro In vitro In vitro In vitro In vitro In In vivo vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In In vitro vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In Brain vitro/ In vitro In vitro In vitro In vitro In vitro In vitro In vitro In Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Triterpene Alkaloid Alkaloid Alkaloid Flavonoid Alkaloid Alkaloid Coumarin Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Diterpene Diterpene Diterepene Monoterpene Monoterpene Stilbene Alkaloid Diterpene Diterpene Monoterpene Monoterpene Benzenoid -1-methyl N Resorcinol, heptadecyl heptadecyl Resorcinol, pentadecyl Resorcinol, Resorcinol, Benzenoid tricosenyl Resorcinol, Benzenoid tricosyl Resveratrol BenzenoidRhapontin Rotenone Benzenoid vitro In vitro In Stilbene Stilbene In vitro Flavonoid In vittro IC IC vitro In IC vitro In IC In vitro/ Ileum stated Not 0.4 mc stated Not Inactive Inactive 2002 al., et Sung 2002 al., et Sung Nupharidine, 7-epi: 7-epi: Nupharidine, (-) deoxy deoxy Nupharidine, (-) Nupharmine, Nupharolutine Onocerin, α Pachycarpine Pachysamine, epi: 2-β- hydroxy Palmatine Paniculatin 10- Pericyclivine, methoxy- A Persicanidine Peucedanone Phlegmariunine B Physostigmine (+) Physostigmine, (-) Physostigmine, nor Physostigmine, Pimara-7,15-dien-1-one, 14α-hydroxy iso: Pimara-7,15-diene, iso: 1β-14α-dihydroxy Pimara-8,15-dien-14-one, 7β-hydroxy iso: α Pinene, β Pinene, monomethyl Pinosylvin ether Protoberberine Ptilosarcenone Ptilosarcone Pulegole, iso: (-) Pulegone, (+) dimethoxy- Resorcinol, pentadecyl heptadecenyl Resorcinol, Benzenoid vitro In IC

283 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006 Natural products inhibitors of the enzyme acetylcholinesterase Peng et al., 1996 1996 al., et Peng 1996 al., et Peng al.,Xu et 1992 Ashack et al., 1980 1980 al., et Ashack Ashack et al., 1980 Ashack et al., 1980 2002 al., et Rahman 2002 al., et Rahman 2002 al., et Rahman 2002 al., et Rahman 2002 al., et Rahman 2002 al., et Rahman 2003 al., et Rahman 2003 al., et Rahman Ulrichova etal., 1983 1997 al., et Schmeller Ulrichova etal., 1984 Ulrichova etal., 1983 Ulrichova etal., 1983 2002 al., et Rahman 1974 al., et Ne’Eman 2002 al., et Rahman 2002 al., et Rahman 2002 al., et Rahman Itoh et al., 1989 1991 al., et Akiyama Mroue etal., 1993 Mroue etal., 1996 Jang et al., 2003 2001 al., et Rahman Hirasawa al.,2003 et 1981 al., et Tyutyulkova 1993 al., et Reddy 1982 al., et Zhu Active Active Active Active Inactive Inactive activity Weak activity Weak Active Active Active Active Active Active Active Inactive Active activity Weak Active Active Active activity Weak Active Active Active Active Active Active Active Active Active Inactive Active Inactive Active Inactive 2.4 mmols 2.4 mmols 200.0 mcg/mL Active Active 2003 al., et El-Hassan 2001 al., et Kang 0.011 mmols mmols 0.011 mmols 0.035 0.06 mmols 19.99 μmols 19.99 μmols 50.64 μmols 61.3 μmols 185.2 μmols 6.21 μmols 6.357 μmols 33.4 μmols 10.9 μmols 204.2 μmols 69.99 μmols 5.83 μmols 7.02 μmols 0.203 mmols 18.9 mcg/mL 2.0 μmols 63.0 μmols 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 4.03 mol mol 4.03 mol 4.92 0.1 mmols Not stated stated Not ID Not stated stated Not 0.155 mcg/mL mcg/mL 0.62 IC IC IC IC IC IC IC stated Not ID IC ID IC mg/L 0.2 IC IC IC mg/Kg 3.0 mcg/mL 2.88 μmols 0.21 IC IC stated Not IC mg/kg 100.0 IC Dose variable In vitro vitro In In vitro/ Ileum In vitro/ Ileum In vitro/ Ileum In vitro/ Ileum vitro In vitro In vitro In vitro In vitro In vitro In vitro In vitro In Brain vitro/ In vitro In Brain vitro/ In Brain vitro/ In Brain vitro/ In vitro In In vitro/ Ileum vitro In vitro In vitro In In vivo vitro In vitro In vitro In vitro In vitro In vitro In In vivo vitro In In vivo Alkaloid Alkaloid Alkaloid In vitro In vitro In vitro Dose variable Dose variable Dose variable Inactive Inactive Inactive Cardoso etal., 2004 Cardoso etal., 2004 Cardoso etal., 2004 Flavonoid Flavonoid Flavonoid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Diterpene Alkaloid Alkaloid Alkaloid Lignan Benzenoid Alkaloid Alkaloid Alkaloid Alkaloid Flavonoid Diterpene Alkaloid - α (3)- (3)- N Syringaresinol Lignan In vitro IC Syringaresinol Lignan (+) Terpinen-4-ol, (-) Terpinen-4-ol, In Monoterpene Monoterpene vitro In vitro In mmols 1.2 mmols 1.2 Equivocal Equivocal 1997 al., et Miyazawa 1997 al., et Miyazawa Suberogorgin Sesquiterpene In vitro vitro 3,4- Strictosidine, dehydro acid Strictosidinic 3,4- acid, Strictosidinic dehydro Strychnine In Sesquiterpene Alkaloid Suberogorgin Alkaloid vitro In variable Dose In vivo Inactive 5.0 mg/kg 2004 al., et Cardoso Inactive Nistriet al., 1974 carboxy Rotenone, dehydro dehydro Rotenone, dihydro Rotenone, iso Rotenone, Saligcinnamide A Salignenamide C Salignenamide D Salignenamide E Salignenamide F Salignenamide A Salonine B Salonine Sanguilutine Sanguinarine Sanguirubine Saracodine, demethyl Sarcophine Sarcorine Sarsalignenone Sarsalignone Schisandrin Scirpus fluviatilis trimer tetrahydro: Secodine, decarbomethoxy Securinine, dihydro Semperviraminol Sieboldine A Silymarin 1 cembranoid Sinularia Sparteine Strictosidine 5 Strictosidine, Alkaloid In vitro Dose variable Inactive Cardoso etal., 2004 Suberosin, 7-demethyl 7-demethyl Suberosin, Coumarin vitro In IC

Rev. Bras. Farmacogn. Braz J. Pharmacogn. 284 16(2):abr/jun. 2006 José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al. Singh et al., 1999 1999 al., et Singh Gracza, 1985 Miyazawa et al., 1997 1997 al., et Miyazawa 2000 et al., Perry Omrua et al., 1995 Kuno et al., 1996 2000 al., et Otoguro 1995 Peng, Omrua et al., 1995 Kuno et al., 1996 2000 al., et Otoguro Active Active Active Equivocal Inactive Active Active activity Strong activity Strong Active Active activity Strong activity Strong 2.89 mg/L mg/L 2.89 57.0 μmols 2.0 μmols μmols 54.0 mmols 0.15 Active Active Active Active Mroue etal., 1996 2002 al., et Sung 2001 al., et Kang 2001 al., et Kang 1.0 mmols 1.0 mmols 0.2 μmols Active 7.6 nmols 7.6 nmols 0.008 μmols 0.26 μmols Active 6.8 nmols 1997 al., et Miyazawa 6.8 nmols 0.007 μmols 2002 al., et Kim 108.0 μmols μmols 28.0 0.01 μmols 29.0 mmols 7.5 nmols Active 8.59 μmols 46.9 μmols Active Active activity Weak 1996 al., et Mroue Active Active 2001 al., et Active Kang 2000 al., et Kigoshi 1993 al., et Van-Wagenen 2001 al., et Chung al., Rahman et 2002 2001 al., et Kalauni 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 1.0 mmols 1.2 mmols 4.7 mmols IC IC IC IC IC IC IC LC In vitro vitro In vitro In vitro In vitro In In vitro vitro In vitro In vitro In Alkaloid In vitro IC vitro In Alkaloid Sulfur compound compound Sulfur vitro In μmols 300.0 Inactive 1991 al., et Kumar Xanthotoxin Coumarin In vitro IC IC vitro vitro α Viniferin, Coumarin Xanthotoxin In Coumarin Xanthyletin In A Xyloketal Zoanthoxanthin, pseudo Benzenoid Alkaloid heterocycle Oxygen vitro In vitro In In vitro μmols 1.5 IC 4.0 μmols Active Active 2001 al., et Lin Turk etal., 1995 Vinervine, 16- 16- Vinervine, decarbomethoxy Terpinene, γ γ Terpinene, A’ Territrem Territrem B Monoterpene Triterpene Triterpene vitro In IC vitro vitro In vitro IC vitro In Turbinatine A Turbotoxin Alkaloid Ulosantoin In Coumarin ng/mL 0.5 Umbelliferone acid Ursolic In A Vaganine (-) D, Vaganine Alkaloid Alkaloid Triterpene Active Alkaloid Alkaloid vitro In vitro In 1986 al., et Ling vitro In vitro In vitro In variable Dose IC IC IC IC Active 2004 al., et Cardoso Tubotaiwine Alkaloid In vitro IC vitro Toosendanin Alkaloid Tubotaiwine In Triterpene In vitro Not stated Inactive Zhang and Chiu, 1992 Terpinene, α α Terpinene, Monoterpene vitro In IC Terpineol Terpineol Terreulactone A Sesquiterpene Monoterpene In vitro vitro In IC mmols 4.7 Inactive 2000 al., et Perry Thymol Monoterpene In vitro B’ Territrem Territrem C iso: Thiocyanate, In benzyl Triterpene Thymol Monoterpene Triterpene vitro In vitro In ng/mL 5.0 Active 1986 al., et Ling

285 Rev. Bras. Farmacogn. Braz J. Pharmacogn. 16(2):abr/jun. 2006