Annona muricata: A comprehensive review on its traditional medicinal uses, phytochemicals, pharmacological activities, mechanisms of action and toxicity

rabian Journal of Chemistry Arabian Journal of Chemistry Available online 22 January 2016 open access In Press, Corrected ProofWhat are Corrected Proof articles? Arabian Journal of Chemistry Review Author links open overlay panelAna V.Coria-TéllezadEfigeniaMontalvo-GónzalezbElhadi M.YahiacEva N.Obledo-Vázquezd a Laboratorio de Análisis y Diagnóstico del Patrimonio, El Colegio de Michoacán A.C., Cerro de Nahuatzen No. 85, Fracc. Jardines del Cerro Grande, La Piedad, C.P. 59370 Michoacán, Mexico b Laboratorio Integral de Investigación en Alimentos, Instituto Tecnológico de Tepic, Av. Tecnológico 2595, C.P. 63175 Tepic, Nayarit, Mexico c Facultad de Ciencias Naturales, Universidad Autonoma de Queretaro, Avenida de las Ciencias S/N, Juriquilla, 76230 Queretaro, Qro., Mexico d Unidad de Biotecnología Vegetal, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, A.C., Av. Normalistas No. 800, Col. Colinas de la Normal, Guadalajara, C.P. 44270 Jalisco, Mexico Received 1 October 2015, Accepted 9 January 2016, Available online 22 January 2016. https://doi.org/10.1016/j.arabjc.2016.01.004 Get rights and content Open Access funded by King Saud University Under a Creative Commons license Abstract Annona muricata L. (Magnoliales: Annonaceae) is a tropical plant species known for its edible fruit which has some medicinal merits, but also some toxicological effects. This review focuses on the phytochemicals contents, bioactivity, biological actions and toxicological aspects of extracts and isolated compounds, as well as medicinal uses of A. muricata, with the objective of stimulating further studies on extracts and fruit pulp used for human consumption. Traditional medicinal uses of A. muricata have been identified in tropical regions to treat diverse ailments such as fever, pain, respiratory and skin illness, internal and external parasites, bacterial infections, hypertension, inflammation, diabetes and cancer. More than 200 chemical compounds have been identified and isolated from this plant; the most important being alkaloids, phenols and acetogenins. Using in vitro studies, extracts and phytochemicals of A. muricata have been characterized as an antimicrobial, anti-inflammatory, anti-protozoan, antioxidant, insecticide, larvicide, and cytotoxic to tumor cells. In vivo studies of the crude extracts and isolated compounds of A. muricata were shown to possess anxiolytic, anti-stress, anti-inflammatory, contraceptive, anti-tumoral, antiulceric, wound healing, hepato-protective, anti-icteric and hypoglycemic activities. In addition, clinical studies support the hypoglycemic activity of the ethanolic extracts of A. muricata leaves. Mechanisms of action of some pharmacological activities have been elucidated, such as cytotoxic, antioxidant, antimicrobial, antinociception and hypotensive activities. However, some phytochemical compounds isolated from A. muricata have shown a neurotoxic effect in vitro and in vivo, and therefore, these crude extracts and isolated compounds need to be further investigated to define the magnitude of the effects, optimal dosage, mechanisms of action, long-term safety, and potential side effects. Additionally, clinical studies are necessary to support the therapeutic potential of this plant. Keywords Annona muricata Traditional medicine Phytochemicals Bioactivity Cytotoxicity Health 1. Introduction Medicinal plants are considered as the basis for health preservation and care worldwide. Chronic degenerative diseases (diabetes, cardiovascular and cancer) have reached epidemic proportions and are considered as a serious health problem; therefore, the treatments of these diseases are of clinical importance (WHO, 2005). Annona muricata L. is a species of the Annonaceae family that has been widely studied in the last decades due to its therapeutic potential. The medicinal uses of the Annonaceae family were reported long time ago (Billón, 1869), and since then, this species has attracted the attention due to its bioactivity and toxicity. Ethnobotanical studies have indicated that A. muricata has been used as insecticide (Leatemia and Isman, 2004) and parasiticide (Langenberger et al., 2009). Fruit juice and infusions of leaves or branches have been used to treat fever (Betancur-Galvis et al., 1999, Dagar and Dagar, 1991, Magaña et al., 2010), sedative (Defilippis et al., 2004, Joyeux et al., 1995), respiratory illness (Beyra et al., 2004, Kossouoh et al., 2007, Vandebroek et al., 2010, Waizel and Waizel, 2009), malaria (Boyom et al., 2011, Nguyen-Pouplin et al., 2007), gastrointestinal problems (Atawodi, 2011, Magaña et al., 2010, Samuel et al., 2010), liver, heart and kidney affections (Badrie and Schauss, 2009, Coe, 2008). In recent years it has become widely used for hypoglycemic (De Souza et al., 2011, Rodríguez, 2011), hypotensive (De Souza et al., 2011, Hajdu and Hohmann, 2012, Samuel et al., 2010) and cancer treatments (Monigatti et al., 2013, Tisott et al., 2013). Some publications and reviews about A. muricata have been conducted to integrate the available scientific studies on this plant with special interest on acetogenins as principal bioactive compounds (Badrie and Schauss, 2009, Moghadamtousi et al., 2015a, Pinto et al., 2005) Other bioactive compounds have been identified, more bioactivities have been evaluated, and medicinal uses have been extended. The aim of this review was to integrate the scientific studies reported until 2015 that describe the traditional medicinal uses and phytochemical contents of A. muricata, and relate them with the pharmacological and its mechanisms of action and toxicological evaluation. The bioactivity tested can be the base for therapeutic utilization, but the toxicological research results are important to consider the therapeutical uses of this plant versus its toxicity, and the potential harmful effects of products prepared from this plant. 2. Botany and traditional uses 2.1. Botany A. muricata is known as soursop (English), graviola (Portuguese), guanábana (Latin American Spanish) and other local indigenous names listed in Table 1. This plant is species of the genus Annona, of the Annonaceae family, order Magnoliales and Division Magnoliophyta (Pinto et al., 2005). The genus Annona comprises over 70 species among which A. muricata is the most widely grown. Its synonyms are A. bonplandiana Kunth; A. cearensis Barb. Rodr., A. macrocarpa Wercklé; A. muricata var. borinquensis Morales and Guanabanus muricatus M. Gómez (Pinto et al., 2005). Table 1. A. muricata: local names, medicinal uses, plant part used, and type of preparations. Country or region Local name Medicinal uses Plant part Preparation/application References Benin Araticum, araticum-do-grande condessa; graviola; jaca-do-para; jaca-de-pobre; fruta-do conde, cameroon, soursop Insomnia, catarrh, febrifuge Leaf Bark Root Seed Decoction/oral Kossouoh et al. (2007) Bolivia Sinini Kidney disorders, hypertension Fruit Leaf Juice/oral Decoction/oral Hajdu and Hohmann (2012) Brazil Araticum, araticum-do-grande, coração-da-rainha, condessa; graviola; jaca-do-pará; jaca-de-pobre; fruta-do conde, cameroon, Soursop Snake bite Analgesic Leaf Macerate/topical Decoction/oral Ritter et al., 2012, Ross, 2010 Lactagogue, astringent, diarrhea, dysentery Fruit Juice/oral Badrie and Schauss (2009) and Cercato et al. (2015) Arthritis pain, rheumatism, neuralgia, weight loss Leaf Decoction/oral Cameroon Soursop, Sabasaba Ebom beti Malaria, anthelmintic, parasites, antimicrobial, anticonvulsant, digestive Typhoid fever Leaf Decoction/oral Boyom et al., 2011, Tsabang et al., 2012 Roger et al. (2015) Caribbean Graviola, Jamaica soursop, prickly custard apple, soursop Chills, febrifuge, flu, indigestion, nervousness, palpitations, rash, spasms, skin disease, sedative Leaf Bark NR Joyeux et al., 1995, TDRG, 2002, Boulogne et al., 2011 Colombia Guanábana Febrifuge, inflammation Fruit, Leaf Juice/oral Decoction/oral Betancur-Galvis et al. (1999) Diarrhea, abortifacient, lactagogue NR NR Gómez-Estrada et al. (2011) Cuba Guanábana Catarrh Leaf Decoction in milk or water/oral Beyra et al. (2004) Dominican Republic Guanábana Respiratory conditions, women in labor Galactogogue Leaf Fruit NR Infusion/oral Vandebroek et al., 2010, Ross, 2010 Plague Seed NR Brechelt (2004) Ecuador Guanábana Rheumatism Leaf Heated/topical Tene et al. (2007) Ghana Apre Malaria Root Decoction/bath Asase et al. (2012) Guyana Cachiman, corossol, Money Apple, soursop, sorasaka, kaiedi, zuurzak, soensaka, sroesaka, soeng sakka, sun-saka, corossolier Sedative, cardiotonic Convulsion Stem Leaf Seed Infusion/oral Infusion/oral NR Defilippis et al., 2004, TDRG, 2002 Haiti Guanábana, korosol Flu, heart affectation parasite, pellagra, anxiety, febrifuge, diarrhea, lactagogue Leaf Fruit NR Badrie and Schauss (2009) India Mamphal, Fófí, Suppurative, febrifuge Pain and pus from ulcers Leaf Decoction/oral Smeared in coconut oil/topical Dagar and Dagar (1991) Tonic Bark NR Badrie and Schauss (2009) Spasms, parasites Root Bechic Flower Insecticidal, astringent, fish-poison Seed Indonesia Sirsak; nangka belanda; nangka seberang; Zuurzak Wulanda Insecticidal Dermatitis Malaria Leaf and other tree parts Leaf NR Pounding Leatemia and Isman, 2004, Badrie and Schauss, 2009 Roosita et al. (2008) Abdillah et al. (2015) Jamaica Jamaica soursop Spasms, anxiety, asthenia, asthma, heart affections, febrifuge, parasites, diarrhea, lactagogue, dewormer, dysentery, pain, diuretic Branch Leaf Fruit Decoction/oral Asprey and Thornton, 1955, Badrie and Schauss, 2009 Madagascar Corossol Heart palpitation, malaria, liver maladies Leaf Decoction Novy (1997) Malaysia Durian belanda, durian blanda, durian, benggala, durian maki, durian makkah, seri kaya belanda Lice Leaf Crushed/topical Badrie and Schauss (2009) Stomach pain, hypertension Fruit Juice/oral Samuel et al. (2010) Martinique Kowosol Skin rashes, sedative Thoracic pain, inflammation, flatulence, liver disease Leaf Crushed/Bath Decoction/oral Longuefosse and Nossin (1996) Mauritius Corossol Corossol Hypertension Headache Leaf Infusion/oral Crushed/topical Mootoosamy and Fawzi, 2014, Sreekeesoon and Mahomoodally, 2014 Mexico Takole, pobox, ajpox Cabeza de negro; catuch, chincua, guanábana; guanábano; polvox; taḱob; taḱop caduts-at; xuńapill; llama de tehuantepec; zopote de viejas, zapote agrio. Anona, tzon te chkia nion Dysentery, diabetes Gastric cancer, gastrointestinal disorders, stomach pain Fruit Leaf Juice/oral Decoction/oral Alonso-Castro et al. (2011) Febrifuge, diarrhea, dysentery, stomach pain Young leaf Infusion/oral Magaña et al., 2010, Yasunaka et al., 2005 Bronchitis, asthma, leprae Leaf, stem Infusion/oral Waizel and Waizel (2009) Nicaragua Guanábana, pumo, puntar waithia, saput, sarifa, seremaia, soursap Ringworm Abdominal and back pain, menstrual hemorrhage, abortions, fever, vaginal infection Renal and skin disorders, diarrhea Insecticidal Leaf Seed Plaster/topical Infusion/oral Decoction/oral Benavides, 2003, Ross, 2010, Coe, 2008 Nigeria Soursop, graviola, pawpaw brasileña, Abo, Chop-chop, Sapi sapi Gastric disorders, Prostate cancer, diabetes, neuralgia, rheumatism, arthritic pain Leaf Unripe fruit Decoction/oral Juice/oral Pinto et al., 2005, Atawodi, 2011, Ezuruike and Prieto, 2014 Panama Guanábana Dyspepsia, allergy, helminthiasis Diarrhea Stomach ulcer Leaf Bark Pulp NR Decoction/oral Gupta et al., 1979, Ross, 2010 Philippines Babana Babaná, guyabano, gwabana Lice, dandruff Cancer, ascariasis, high blood pressure, stomach acidity, urination difficulty, cough Headache Diabetes Leaf Leaf Fruit NR Decoction/oral Poultice/topical Pulp/oral Badrie and Schauss, 2009, Langenberger et al., 2009 Ong and Kim (2014) New Guinea Saua sap Sow sop Kahiloko Stomach pain Leaf Heated/compression Badrie and Schauss, 2009, WHO, 2009 Peru Guanábano, guanábana, cashacushma Obesity, gastritis, dyspepsia, diabetes, inflammation, cancer, spasms, sedative, flu, febrifuge, anxiety, kidneys, prostate, urinary tract, infection, inflammation, panacea Fruit, Leaf Pulp, juice/oral Infusion/oral Badrie and Schauss, 2009, Bussmann et al., 2010, Rodríguez, 2011, Poma et al., 2011, Monigatti et al., 2013 South pacific countries Durian belanda, soursop, seremaia, sarifa, apele, katara ara tara Stomach ailments, indigestión Skin diseases Dizziness, fainting spells Leaf Leaf Infusion/oral Bath Inhaled WHO (1998) Ross (2010) Thailand Thu-rian-khack, thurian-thet, thurian khaek Insecticidal Seed NR Badrie and Schauss (2009) Trinidad y Tobago Soursop Hypertension Leaf NR Badrie and Schauss, 2009, Lans, 2006 Togo Anyigli, apele Hypertension, diabetes Malaria Leaf Decoction/oral De Souza et al. (2011)Ross (2010) Uganda Ekitafeli Diabetes Leaf Fruit Infusion/oral Pulp/oral Ssenyange et al. (2015) Vanuatu Soursop Karasol, korosol, saosop Scabies Leaf Infusion/Bath Bradacs et al. (2011) Venezuela Catoche, catuche Liver affectation, stomach pain, insecticidal Leaf Seed Decoction/oral Crushed/topical TDRG, 2002, Badrie and Schauss, 2009 West Africa Dukumé porto, niom, pinha, sawa sap, alukuntum, Sedative, nasopharyngeal affectation Diarrhea, dysentery, vermifuge, antidote Leaf Seed, bark root Decoction/oral Burkill (1985) West Indies Apple leaf, kowoso, soursopl Asthmas, diarrhea, hypertension, parasites, lactagogue, sedative Skin ailments Galactogogue Leaf Fruit Decoction/oral Decoction/bath Poultice/oral Feng et al., 1962, TDRG, 2002, Ross, 2010, Boulogne et al., 2011 Vietnam South Mãng câu xiêm Malaria Leaf Infusion/oral Nguyen-Pouplin et al. (2007) NR, Not reported. The soursop tree is about 5–10 m tall and 15–83 cm in diameter with low branches (Benavides, 2003, Evangelista-Lozano et al., 2003, Orwa et al., 2009). It tends to bloom and fruit most of the year, but there are more defined seasons depending on the altitude (Pinto et al., 2005). It is distributed in the tropical regions of Central and South America, Western Africa and Southeast Asia (Pinto et al., 2005), at altitudes below 1200 m above sea level, with temperatures between 25 and 28 °C, relative humidity between 60 and 80%, and annual rainfall above 1500 mm. The soursop fruit is an edible collective ovoid berry, dark green in color. Its average weight is 4 kg in some countries (Pinto et al., 2005), but in México (Evangelista-Lozano et al., 2003), Venezuela (Ojeda et al., 2007) and Nicaragua (Benavides, 2003), it ranges between 0.4 and 1.0 kg. Each fruit may contain 55–170 black seeds (Awan et al., 1980) when fresh and they turn light brown when dry. The flesh is white and creamy with a characteristic aroma and flavor (Pinto et al., 2005). 2.2. Traditional medicinal uses The leaves, bark, fruit and seed of A. muricata have been subject of countless medicinal uses (Badrie and Schauss, 2009, Billón, 1869). Table 1 enlists the traditional medicinal uses that have been reported for this species, as well as the places in which they are used. The most widely used preparation in traditional medicine is the decoction of bark, root, seed or leaf and applications are varied. In Indonesia, the Caribbean islands (Boulogne et al., 2011) and South Pacific countries, the leaves are used in bath (Longuefosse and Nossin, 1996) to treat skin ailments, while in Mauritius (Sreekeesoon and Mahomoodally, 2014), New Guinea (WHO, 2009) and Ecuador (Tene et al., 2007), the application of leaves is local on the pain site. The ingestion of leaves decoction is used as analgesic in Brazil (Ross, 2010), Martinique (Longuefosse and Nossin, 1996), Mexico and Nicaragua (Ross, 2010), while in several countries such as Benin (Kossouoh et al., 2007), the Caribbean (Joyeux et al., 1995), Cuba (Beyra et al., 2004) and México (Waizel and Waizel, 2009), it is used to treat discomfort associated with colds, flu and asthma. Natives of Malaysia used A. muricata leaves to treat cutaneous (external) and internal parasites (Badrie and Schauss, 2009). The use of leaves to treat malaria is very important in tropical countries as Cameroon, Togo, and Vietnam (Boyom et al., 2011, Nguyen-Pouplin et al., 2007, Ross, 2010). In Ghana, A. muricata and some other plants are decocted into a mixture and used in bath where females sit in (Asase et al., 2012). The fruit is not only appreciated as food, but the juice is used as galactogogue to treat diarrhea, heart and liver diseases (Badrie and Schauss, 2009, Hajdu and Hohmann, 2012), and against intestinal parasites in South America (Badrie and Schauss, 2009). Lately, the medicinal uses of A. muricata leaves included treatments for hypertension (Badrie and Schauss, 2009, Ezuruike and Prieto, 2014, Hajdu and Hohmann, 2012, Mootoosamy and Fawzi, 2014, TDRG, 2002), diabetes (Badrie and Schauss, 2009, De Souza et al., 2011, Ezuruike and Prieto, 2014) and cancer (Alonso-Castro et al., 2011, Atawodi, 2011, Bussmann et al., 2010, Monigatti et al., 2013). Some patients used decoctions or capsules of A. muricata for cancer and pharmacological treatments (Tisott et al., 2013). Unripe fruit, seeds, leaves and roots are also used as biopesticides, bioinsecticides and topical insect repellents (Brechelt, 2004, Isman and Akhtar, 2007, Leatemia and Isman, 2004). The importance of this species in pest control was indicated in the edition of “Pesticide action and alternatives for Latin America”, which recommended the use of aqueous extract of A. muricata to control lepidopteran larvae, aphids and thrips, among others (Brechelt, 2004). 3. Phytochemicals Two hundred and twelve bioactive compounds have been reported to be found in A. muricata. The predominant compounds are acetogenins followed by alkaloids, phenols and other compounds. Leaves and seeds are the main plant organs studied, probably because they are the most traditionally used. Table 2 lists the bioactive compounds, and their structures are shown in Figure 1, Figure 2, Figure 3, Figure 4. The majority of phytochemicals have been identified from organic extract, but recently focus has also been directed toward aqueous extracts. Several other compounds such as carbohydrates and essential oils have also been reported, but these are not considered in this review. Table 2. Bioactive compounds isolated from A. muricata. No Chemical name Part of plant Type Bioactivity References Alkaloids 1 Anonaine Fruit Leaf Aporphine Antidepressive Anti-plasmodium, Dopamine inhibitor Cytotoxic Hasrat et al., 1997a, Hasrat et al., 1997b, Fofana et al., 2011, Ocampo and Ocampo, 2006, Matsushige et al., 2012 2 Annonamine Leaf Aporphine Cytotoxic Matsushige et al. (2012) 3 Anomuricine Root Bark Isoquinoline NR Leboeuf et al. (1981) 4 Anomurine Root Bark Isoquinoline NR Leboeuf et al. (1981) 5 Asimilobine Fruit Leaf Aporphine Antidepressive Cytotoxic Hasrat et al., 1997a, Hasrat et al., 1997b, Fofana et al., 2012 6 Atherospermine Stem Aporphine NR Leboeuf et al. (1981) 7 Atherosperminine Root Bark Aporphine NR Leboeuf et al. (1981) 9 Casuarine Leaf/stem Imino sugar NR Mohanty et al. (2008) 10 Coclaurine Root Bark Leaf Isoquinoline NR Leboeuf et al., 1981, Fofana et al., 2012 11 Coreximine Root Bark Leaf Protoberberine Neurotoxic Leboeuf et al., 1981, Lannuzel et al., 2002 12 DMDP (2,5-Dihydroxymethyl-3,4,dihydroxypyrrolidine) Leaf/stem Imino sugar NR Mohanty et al. (2008) 13 DMJ (Deoxymannojirimycin) Leaf/stem Imino sugar NR Mohanty et al. (2008) 14 DNJ (Deoxynojirmycin) Leaf/stem Imino sugar NR Mohanty et al. (2008) 15 (R)-O,O-dimethylcoclaurine Leaf Isoquinoline Cytotoxic Matsushige et al. (2012) 16 Isoboldine Leaf Aporphine Antimalarial Fofana et al. (2012) 17 Isolaureline Leaf Aporphine Cytotoxic Fofana et al. (2011) 18 Liriodenine Leaf Aporphine NR Fofana et al. (2012) 19 (R)-4́O-methylcocaurine Leaf Isoquinoline Cytotoxic Matsushige et al. (2012) 20 N-methylcoclaurine Leaf Isoquinoline NR Fofana et al. (2012) 21 N-methylcoculaurine Leaf Pulp Isoquinoline NR Kotake et al. (2004) 22 Muricine Bark Isoquinoline NR TDRG (2002) 23 Muricinine Bark Isoquinoline NR TDRG, 2002 24 (S)-Narcorydine Leaf Aporphine Cytotoxic Matsushige et al. (2012) 25 Nornuciferine Fruit Isoquinoline Antidepressive/in vitro NIH-3T3 Hasrat et al., 1997a, Hasrat et al., 1997b 26 Remerine Leaf Isoquinoline NR Fofana et al. (2012) 27 Reticuline Stem Leaf Pulp Isoquinoline Neurotoxic TDRG (2002)Leboeuf et al., 1981, Lannuzel et al., 2002, Kotake et al., 2004 28 Stepharine Leaf Isoquinoline NR Leboeuf et al. (1981) 29 Swainsonine Leaf/stem Imino sugar Stimulate immune response Mohanty et al. (2008) 30 Xylopine Leaf Isoquinoline NR Fofana et al. (2011) Acetogenins 31, 32 Cohibin A, B Root Seed Linear, unsaturated, 2OH NR Alali et al., 1999, Gleye et al., 2000b 33, 34 Cohibin C, D Seed Linear, unsaturated, 2OH NR Gleye et al. (2000b) 35 Donhexocin Seed Linear, 6OH NR Yu et al. (1997) 36 Montecristin Root Pulp Nectar Linear, unsaturated, 2OH NR Alali et al., 1999, Champy et al., 2009 37 Muricatenol Seed Linear, unsaturated, 4OH NR Li et al. (2000) 38 Murihexol Seed Linear, 6OH NR Yu et al. (1997) 39 Coronin Root NR TDRG (2002) 40, 41 Epomuricenins A, B or epoxymurin Seed Root Pulp Mono epoxy unsaturated NR Zafra-Polo et al., 1996, Melot et al., 2009 42, 43 Epomurinins A, B Pulp Mono epoxy NR Melot et al. (2009) 44, 45 Epomusenins A B Pulp Mono epoxy unsaturated NR Melot et al. (2009) 46 Epoxyrollin-A = Dieporeticanin-1 Mono epoxy NR Zafra-Polo et al. (1996) 47 Murin A Stem Mono epoxy NR TDRG (2002) 48 Rolin B Seed Mono epoxy NR TDRG (2002) 49 Sabadelin Root Pulp Mono epoxy, 1 carbonyl Cytotoxic Gleye et al. (1999) Ragasa et al. (2012) 50 Corepoxylone Seed Diepoxy, 1 carbonyl NR Gromek et al. (1993) 51, 52 Diepomuricanin A, B = Epoxyrollin B Seed Diepoxy NR Zafra-Polo et al. (1996) 53 Annocatalin Leaf Mono THF, 4OH Cytotoxic Liaw et al. (2002) 54 Annoglaxin Seed Mono THF 4OH, 1 carbonyl NR Yang et al. (2010) 55 Annohexocin Leaf Mono THF, 6OH Cytotoxic Zeng et al. (1996) 56 Annomontacin Seed Leaf Mono THF, 4OH Cytotoxic Insecticidal Liaw et al., 2002, Nakanishi et al., 2003, Castillo-Sánchez et al., 2010 57 Annomontacin, cis Seed Mono THF, 4OH Cytotoxic Liaw et al., 2002, Nakanishi et al., 2003 58 Annomuricin Leaf Mono THF, 5OH Cytotoxic Kim et al. (1998b) 59 Annomuricin A Leaf Peric Mono THF, 5OH Cytotoxic Wu et al., 1995a, Jaramillo et al., 2000 60 Annomuricin B Leaf Mono THF, 5OH Cytotoxic Wu et al. (1995a) 61, 62 Annomuricin C, E Leaf Mono THF, 5OH Cytotoxic Zeng et al., 1996, Moghadamtousi et al., 2015c 63, 64 Cis, trans, Annomuricin-D-one Leaf Mono THF, 4OH Cytotoxic Alali et al. (1999) 65 Annomutacin Leaf Mono THF, 4OH Cytotoxic Wu et al. (1995c) 66 Annonacin Leaf Peric Seed Root Leaf Pulp Nectar Mono THF, 4OH Cytotoxic Insecticidal Antimicrobial Antitumor Neurotoxic Neurodegenerative Wu et al., 1995c, Guadaño et al., 2000, Liaw et al., 2002, Jaramillo et al., 2000, Nakanishi et al., 2003, Champy et al., 2004, Champy et al., 2009, Castillo-Sánchez et al., 2010, Ko et al., 2011 67 Annonacin A Peric Leaf Seed Mono THF, 4OH NR Jaramillo et al., 2000, Wu et al., 1995c 68 Annonacin, cis- Seed Mono THF, 4OH Cytotoxic Rieser et al. (1996) 69 Annonacin-10-one, cis- Seed Mono THF, 3OH, 1 carbonyl Cytotoxic Rieser et al. (1996) 70 Annonacinone Annonacin 10-one Leaf Seed Pulp Nectar Mono THF, 3OH 1 carbonyl Cytotoxic Antileishmaniasis Liaw et al., 2002, Nakanishi et al., 2003, Champy et al., 2009, Vila-Nova et al., 2013 71 (2,4-trans)-1OR-annonacin A-one Leaf Mono THF, 3OH, ketolactone Cytotoxic Wu et al. (1995c) 72, 73, 74 Annopentocin A, B, C Leaf Mono THF, 5OH Cytotoxic Alali et al. (1999) 75 Annoreticuin-9-one Seed Mono THF, 3OH, 1 carbonyl Cytotoxic Ragasa et al. (2012) 76 Annoreticuin, cis Pulp Mono THF, 4OH Cytotoxic Ragasa et al. (2012) 77 Arianacin Seed Mono THF, 4OH Cytotoxic Alali et al. (1999) 78 Corossolin Seed Leaf Mono THF, 3OH Cytotoxic Chang and Wu, 2001, Nakanishi et al., 2003, Champy et al., 2009 79 Corossolone Leaf Seed Pulp Mono THF, 2OH, 1 carbonyl Cytotoxic Zafra-Polo et al., 1996, Liaw et al., 2002, Chang and Wu, 2001, Nakanishi et al., 2003, Champy et al., 2009 80 Cis-corossolone Leaf Mono THF, 2OH, 1 carbonyl Cytotoxic Liaw et al., 2002, Nakanishi et al., 2003 81 Gigantetrocin A Seed Mono THF, 4OH Cytotoxic Insecticidal Alali et al. (1999) 82, Gigantetrocin B Seed Mono THF, 4OH Cytotoxic Alali et al. (1999) 83, 84 2,4 Cis or trans Gigantetrocinone Seed Mono THF, 3OH, ketolactone NR Li et al. (2001) 85 Gigantetronenin Leaf seed Mono THF, 4OH, 1 double bond Cytotoxic Wu et al. (1995b) 86 Goniothalamicin Seed Leaf Mono THF 4OH Cytotoxic Rieser et al. (1996) 87 Cis-goniothalamicin Seed Mono-THF 4OH Cytotoxic Rieser et al. (1996) 88 Isoannonacin Leaf Mono THF, 3OH Rieser et al. (1993), 89, 90 2,4-trans; cis-isoannonacin Leaf seed Mono THF NR Wu et al., 1995d, Li et al., 2001 91 2,4-trans-isoannonacin-10-one Seed Mono THF, 3OH, ketolactone NR Li et al. (2001) 92 Javoricin Seed Mono THF, 4OH Cytotoxic Rieser et al. (1996) 93 Longifolicin Seed Mono THF, 3OH Cytotoxic Chang and Wu, 2001, Nakanishi et al., 2003 94 Montanacin Leaf Mono THF, 5OH Cytotoxic Champy et al. (2009) 95 Montanacin H Leaf Nectar MonoTHF, 4OH, 1 carbonyl Cytotoxic Champy et al. (2009) 96 Muricapentocin Leaf Mono THF, 5OH Cytotoxic Alali et al. (1999) 97 Muricatalicin Leaf Mono THF, 5OH NR Yu et al. (1997) 98 Muricatalin Leaf Mono THF, 5OH NR Yu et al. (1997) 99, 100 Muricatetrocin A,B Seed Mono THF, 4OH Cytotoxic Chang and Wu, 2001, Nakanishi et al., 2003 101, 102 Muricatin A, B Seed Mono THF, 5OH NR Zafra-Polo et al. (1996) 103 Muricatin C Bark Pulp Nectar Mono THF, 4OH, 1 carbonyl NR Zafra-Polo et al., 1996, Champy et al., 2009 104 Muricatin D Seed Mono THF, 5OH NR TDRG (2002); 105 Muricatocin A Leaf Pulp Nectar Mono THF, 5OH Cytotoxic Wu et al., 1995d, Champy et al., 2009 106, 107 Muricatocin B, C Leaf Mono THF, 5OH Cytotoxic Wu et al. (1995d) 108 Muricenin Pulp Mono THF, 4OH Cytotoxic Sun et al. (2014) 109, 110, 111112, Muricin A, B, C D, Seed Mono THF, 4OH Cytotoxic Chang and Wu, 2001, Nakanishi et al., 2003 114, 115 Muricin F, G Seed Mono THF, 4OH, unsaturated Cytotoxic Chang and Wu (2001) 116 Muricin H Leaf seed Mono THF, 3OH Cytotoxic Liaw et al., 2002, Quispe et al., 2006 117 Muricin I Leaf Seed Mono THF, 3OH, unsaturated Cytotoxic Liaw et al., 2002, Lannuzel et al., 2006 118, 119, 120 Muricin J, K, L Fruit Mono THF, 4OH Cytotoxic Sun et al. (2014) 121 Muricin M Pulp Mono THF, 4OH Cytotoxic Sun et al. (2014) 122 Muricin N Pulp Mono THF, 4OH Cytotoxic Sun et al. (2014) 123 Muricoreacin Leaf Mono THF, 6OH Cytotoxic Alali et al. (1999) 124, 125 Muricoreacin A, B Leaf Mono THF, 5OH Cytotoxic Alali et al. (1999) 126 Murihexocin Leaf Mono THF, 6OH Cytotoxic Alali et al. (1999) 127 Murihexocin A Leaf Pulp Mono THF, 6OH Cytotoxic Zeng et al., 1996, Champy et al., 2009 128 Murihexocin B Leaf Mono THF, 6OH Cytotoxic Zeng et al. (1996) 129 Murihexocin C Leaf Mono THF, 6OH Cytotoxic Kim et al. (1998a) 130 Murisolin Seed Mono THF, 3OH Cytotoxic Nakanishi et al., 2003, Yang et al., 2010 131 Cis-panatellin Root Mono THF, 2OH NR Alali et al. (1999) 132 Cis-reticulatacin Root Mono THF, 2OH NR Alali et al. (1999) 133 Cis-reticulatacin-10-one Root Mono THF, 2OH, carbonyl NR Alali et al. (1999) 134 Solamin Seed Stem Root Leaf Mono THF, 2OH Cytotoxic Zafra-Polo et al., 1996, Liaw et al., 2002, Nakanishi et al., 2003 135 Cis-solamin Root Leaf Mono THF, 2OH NR Alali et al. (1999) 136 Cis-solamin A Leaf Root Seed Mono THF, 2OH NR Konno et al. (2008) 137, 138 Cis-uvariamicin I, IV Root Mono THF, 2OH NR Alali et al. (1999) 139 Xylomatenin Pulp Mono THF, 4OH, unsaturated Champy et al. (2009) 140 Xylomaticin Seed Mono THF, 4OH Cytotoxic Liaw et al., 2002, Nakanishi et al., 2003 141 Bullatalicin Seed Bis THF nonadjacent, 4OH Cytotoxic Alali et al. (1999) 142 Gigantecin Seed Leaf Bis THF nonadjacent, 4OH Cytotoxic, Antitumor in vitro Champy et al. (2009) 143, 144 Cis-squamostatin A, D Seed Bis THF nonadjacent, 4OH, 3OH Cytotoxic Yang et al. (2010) 145 Annocatacin A Seed Bis THF adjacent, 2OH Cytotoxic Chang et al., 2003, Nakanishi et al., 2003 146 Annocatacin B Leaf Bis THF adjacent, 2OH Cytotoxic Chang et al. (2003) 147 Asimicinone-9-oxo Leaf Bis THF adjacent, 2OH, 1 carbonyl, keto lactone Cytotoxic Champy et al. (2009) 148 Asiminecin Seed Bis THF adjacent, 3OH Cytotoxic Yang et al. (2010) 149 Bullatacin Seed Bis TFH adjacent, 3OH Cytotoxic Antitumor Neurotoxic Landolt et al., 1995, Wang et al., 2002, Nakanishi et al., 2003, Yang et al., 2010 150 Desacetyluvaricin Seed Bis THF adjacent, 2OH NR Yang et al. (2010) 151 Isodesacetyluvaricin Seed Bis THF adjacent, 2OH NR Yang et al. (2010) 152 Robustocin Seed Bis THF adjacent, 1OH NR Gleye et al. (2000a) 153 Rolliniastatin 1, 2 Seed Bis THF adjacent, 3OH Cytotoxic Gromek et al. (1994) 154 Squamocin Seed Bis THF adjacent, 3OH Cytotoxic Insecticide Guadaño et al., 2000, Nakanishi et al., 2003 155, 156 Montanacin D, E Leaf Pulp Mono THF, Mono THP, 2OH, 1 carbonyl NR Champy et al. (2009) Phenols 157 Emodin Leaf Anthraquinone NR George et al. (2014) 158 Caffeoylquinic acid Leaf Chlorogenic acid NR Marques and Farah (2009) Pulp Jiménez et al. (2014) 159 Chlorogenic acid Leaf Chlorogenic acid NR Nawwar et al. (2012) 160 Dicaffeoylquinic acid Leaf Chlorogenic acid NR Marques and Farah (2009) Pulp Jiménez et al. (2014) 161 Feruloylquinic acid Leaf Chlorogenic acid NR Marques and Farah (2009) 162 Cinnamic acid Leaf Pulp Cinnamic acid NR George et al. (2014) Jiménez et al. (2014) 163 Apigenin-6-C-glucoside Leaf Flavonoid Antioxidant George et al. (2012) 164 Argentinine Leaf Flavonoid Antioxidant Nawwar et al. (2012) 165 Catechin Leaf Flavonoid Antioxidant Nawwar et al. (2012) 166 Coumarid acid Leaf Pulp Flavonoid Flavonoid NR George et al. (2014) Jiménez et al. (2014) 167 Daidzein Leaf Flavonoid NR George et al. (2014) 168 Dihydrokaempferol-hexoside Pulp Flavonoid NR Jiménez et al. (2014) 169 Epicatechin Leaf Flavonoid Antioxidant Nawwar et al. (2012) 170 Fisetin Pulp Flavonoid NR Correa-Gordillo et al. (2012) 171 Gallocatechin Leaf Flavonoid NR George et al. (2014) 172 Genistein Leaf Flavonoid NR George et al. (2014) 173 Glycitein Leaf Flavonoid NR George et al. (2014) 174 Homoorientin Leaf Flavonoid Antioxidant George et al. (2014) 175 Isoferulic acid Leaf Flavonoid NR George et al. (2014) 176 Kaempferol Leaf Pulp Flavonoid Antioxidant Nawwar et al. (2012) Sandoval et al. (2014) 177 Kaempferol 3-O-rutinoside Leaf Pulp Flavonoid Antioxidant Nawwar et al. (2012) Sandoval et al. (2014) 178 Luteolin 3́7-di-O-glucoside Leaf Pulp Flavonoid Antioxidant George et al. (2012) Sandoval et al. (2014) 179 Morin Pulp Flavonoid Antioxidant Correa-Gordillo et al. (2012) 180 Myricetin Pulp Flavonoid Antioxidant Correa-Gordillo et al. (2012) 181 Quercetin Leaf Flavonoid Antioxidant George et al., 2012, Nawwar et al., 2012 182 Quercetin 3-O-glucoside Leaf Flavonoid Antioxidant Nawwar et al. (2012) 183 Quercetin 3-O- neohesperidoside Leaf Flavonoid Antioxidant Nawwar et al. (2012) 184 Quercetin 3-O-robinoside Leaf Flavonoid Antioxidant Nawwar et al. (2012) 185 Quercetin –O-rutinoside Leaf Flavonoid Antioxidant Nawwar et al. (2012) 186 Quercetin 3-O-α-rhamnosyl Leaf Flavonoid Antioxidant Nawwar et al. (2012) 187 Robinetin Leaf Flavonoid Antioxidant George et al. (2012) 188 Tangeretin Leaf Flavonoid NR George et al. (2014) 189 Taxifolin (+) Leaf Flavonoid NR 190 Vitexin Leaf Flavonoid George et al. (2012) 191 Caffeic acid Leaf Hydroxycinnamic acid Antioxidant Jiménez et al. (2014) 192 Gentisic acid Leaf Hydroquinone Antimicrobial Inhibitor TDRG (2002) 193 Gallic acid Leaf Tannin George et al., 2012, Nawwar et al., 2012; Other compounds 194, 195, 196 Annoionol A, B, C Leaf Megastigmane NR Matsushige et al. (2011) 197 Annoionoside Leaf Megastigmane NR Matsushige et al. (2011) 198 199 Annomuricatin A, B Seed Cyclopeptides Insecticide Li et al., 1995, Li et al., 1998 200 Annomuricatin C Seed Cyclopeptides Cytotoxic Wélé et al. (2004) 201 Vitamin A Leaf Vitamin Antioxidant Non published 202 Vitamin C Pulp leaf Vitamin, organic acid Antioxidant Vijayameena et al. (2013); non published 203 Vitamin E (tocopherols) Leaf Seed Pulp Vitamin Antioxidant Vijayameena et al., 2013, Correa-Gordillo et al., 2012 204 205 Carotenes α, β Pulp Carotenoid Antioxidant Correa-Gordillo et al. (2012) 206 Cryptoxanthin β Pulp Carotenoid Antioxidant Correa-Gordillo et al. (2012) 207 Lycopene Pulp Carotenoid Antioxidant Correa-Gordillo et al. (2012); 208 Lutein Pulp Carotenoid Antioxidant Correa-Gordillo et al. (2012) 209 Tocopherol α Pulp Carotenoid Antioxidant Correa-Gordillo et al. (2012) 210 211 Tocotrienol α, γ Pulp Carotenoid Antioxidant Correa-Gordillo et al. (2012) 212 N-p-coumaroyl tyramine Leaf Amide Antitumoral Wu et al. (1995c) NR, Not reported. Download high-res image (140KB)Download full-size image Figure 1. Chemical structure of alkaloids present in A. muricata. (A) Aporphine type. (B) Protoberberine type. (C). Iminosugar type. (D) Isoquinoline type. Representative compounds of alkaloids are found in Table 2 at numbers 2, 11, 12 and 27 respectively. Download high-res image (345KB)Download full-size image Figure 2. Chemical structures of six types of acetogenins present in A. muricata. (A) Chemical structure of linear derivatives corresponding to the acetogenins numbers 31–39 of Table 2. (B) Chemical structure of epoxy acetogenins corresponding to the acetogenins numbers 40–52 of Table 2. (C) Chemical structure of mono THF acetogenins corresponding to the acetogenins numbers 53–140 of Table 2. (D) Chemical structure of mono THF, mono THP acetogenins corresponding to the acetogenins numbers 155–156 of Table 2. (E) Chemical structure of Bis-THF nonadjacent acetogenins corresponding to the acetogenins numbers 141–144 of Table 2. (F) Chemical structure of Bis-THF adjacent acetogenins corresponding to the acetogenins numbers 145–154 of Table 2. Download high-res image (148KB)Download full-size image Figure 3. Chemical structures of types of phenols present in A. muricata. (A) Chlorogenic acid type. (B) Flavonoid type. (C) Hydroquinone type, (D) Tannin type. Representative compounds of these flavonoids are found in Table 2 for numbers 158, 181, 192 and 193, respectively. Download high-res image (291KB)Download full-size image Figure 4. Chemical structure of some compounds present in A. muricata. (A) Megastigmane type. (B) Vitamin type. (C) Cyclopeptide type. (D) Carotenoid type. (E) Amide type. Representative compounds are found in Table 2 for numbers 194, 205, 198, 204 and 212 respectively. 3.1. Alkaloids Alkaloids are naturally occurring compounds containing basic nitrogen atoms. The most abundant in A. muricata (Table 2) are reticuline and coreximine (Leboeuf et al., 1981), and leaves contain the higher alkaloid concentration (Fofana et al., 2011, Fofana et al., 2012, Matsushige et al., 2011), although they have also been found in roots, stems (Leboeuf et al., 1981) and fruit (Hasrat et al., 1997a, Hasrat et al., 1997b). The alkaloids reported in A. muricata are mainly of the isoquinoline, aporphine and protoberberine type (Mohanty et al., 2008). Their chemical structures and representative compounds are shown in Fig. 1. Previous studies have shown that alkaloids isolated from Annona species possess an affinity for the 5-HT1A receptors in vitro and participate in dopamine biosynthesis (Hasrat et al., 1997a, Hasrat et al., 1997b). Thus, it has been proposed that alkaloids derived from the Annona could induce antidepressant-like effects (Hasrat et al., 1997a, Hasrat et al., 1997b), and cytotoxic activity (Matsushige et al., 2012). Neurotoxic effects have also been reported for some alkaloids, and suggested that neuronal death occurred by apoptosis (Lannuzel et al., 2002). 3.2. Acetogenins More than 120 acetogenins have been identified in ethanolic, methanolic or another organic extracts of different organs and tissues of A. muricata such as leaves, stems, bark, seeds (Alali et al., 1999, Chang et al., 2003, Li et al., 2001, Liaw et al., 2002), pulp (Ragasa et al., 2012), and fruit peel (Jaramillo et al., 2000) (Table 2). Acetogenins are characterized by a long aliphatic chain of 35 to 38 carbons bonded to a γ-lactone α ring, terminally substituted by β-unsaturated methyl (sometimes it is a ketolactone), with one or two tetrahydrofurans (THF) located along the hydrocarbon chain and a determined number of oxygen groups (hydroxyl, acetoxyls, ketones, epoxy). Most of the acetogenins found in A. muricata contain a THF ring, although acetogenins have also been reported with two adjacent or nonadjacent THF rings. Acetogenins are linear and may have one or two epoxy groups. Fig. 2 shows the six basic chemical structures of acetogenins reported for A. muricata. Some studies suggested that its bioactivity depends on its structure (Landolt et al., 1995). Annonacin was the most abundant acetogenin reported in both, leaves (Liaw et al., 2002) and fruit (Champy et al., 2005, Champy et al., 2009) of A. muricata, but has also been reported in seeds (Wu et al., 1995a), peel (Jaramillo et al., 2000) and roots (Champy et al., 2004). The contents of acetogenins in leave extracts range from 3.38 to 15.05 mg/g measured by A 1H NMR, while HPLC-MALDI quantified 0.299 mg/g (Machado et al., 2014). Acetogenins are considered the main bioactive compounds of the Annonaceae family (Alali et al., 1999). Some studies have shown that acetogenins are more cytotoxic than alkaloids and rotenone, a synthetic cytotoxic compound. Acetogenins and alkaloids are widely studied in a controversial form, due to their therapeutic potential versus neurotoxic activity. 3.3. Phenolic compounds Thirty-seven phenolic compounds have been reported to be present in A. muricata (Table 2). The important phenolic compounds found in A. muricata leaves include quercetin (Nawwar et al., 2012) and gallic acid (Correa-Gordillo et al., 2012). The presence of flavonoids and lipophilic antioxidant compounds such as tocopherols and tocotrienols has been reported to be present in the pulp (Correa-Gordillo et al., 2012). In different studies, when organic or aqueous extracts have been used, the quantity of extractable total phenols is considerably different. This is important to mention because the most common medicinal use is aqueous infusion and the majority of phenols are soluble in water. Phenolic compounds are considered as the major phytochemicals responsible for the antioxidant activity (George et al., 2014). 3.4. Other compounds Other compounds such as vitamins, carotenoids, amides, cyclopeptides and megastigmanes have also been identified in A. muricata (Table 2). Vitamins and carotenoids have been found in leaves, seeds and fruit pulp (Correa-Gordillo et al., 2012, Vijayameena et al., 2013). The presence of the amide N-p-coumaroyl tyramine (Wu et al., 1995c) and cyclopeptides (Li et al., 1998, Wélé et al., 2004) has been reported in the seeds and showed to have anti-inflammatory and anti-tumor effects. Megastigmanes are present in leaves of A. muricata but had no cytotoxic or antioxidant activity (Matsushige et al., 2011). Examples of chemical structures of these compounds are shown in Fig. 3. On the other hand, 37 volatile compounds have been identified in the fruit pulp of A. muricata, and most of these compounds are aromatic and aliphatic esters (Cheong et al., 2011). In addition, 80 essential oils, mainly sesquiterpenes derivates (Kossouoh et al., 2007, Thang et al., 2012), have been identified in the leaf and have shown cytotoxic activity against MCF-7 (human breast carcinoma) cell line (99.2% kill at 100 μg/ml) (Owolabi et al., 2013). The study of volatiles of A. muricata is promising because of their bioactivity. 4. Pharmacological activities From the 50 reports of pharmacological studies we have reviewed for this manuscript, about 66% corresponded to in vitro studies, 32% to in vivo studies in murine models, and 2% to clinical studies. Regarding the type of extracts used, 84% corresponded to maceration of any part of the plant in organic solvents and 16% corresponded to aqueous preparations. 4.1. In vitro studies Most of the in vitro studies correspond to cytotoxic activity (30%) followed by antiprotozoal activity (23%) and insecticidal activity (18%). The remaining 29% was conformed to antioxidant activity and antimicrobial and antiviral activities, among others (Table 3). Table 3. Pharmacological activities of A. muricata extract evaluated in vitro. Activity Plant part Solvent Test model Effect References Cytotoxic Leaf H2O:EtOH 40% K562 ECV-304 MIC = 7 mg/ml MIC = 2 mg/ml Oviedo et al. (2009) Peri MeOH Hex EtOAc U-937 MEC > 1 mg/ml MEC = 1 mg/ml MEC = 0.1 mg/ml Jaramillo et al. (2000) Dried fruit H2O:Cet 50% MCF-10A BC MDA-MB-468 MDA-MB-231 MCF-7 IC50 > 200 μg/ml IC50 = 4.8 μg/ml IC50 > 200 μg/m IC50 > 200 μg/m Dai et al. (2011) Leaf EtOAc U-937 LC50 = 7.8 μg/ml Osorio et al. (2007) Stem EtOAc MeOH Hex EtOAc MeOH Hex IC50 = 10.5 μg/ml IC50 = 60.9 μg/ml IC50 = 18.2 μg/ml IC50 = 28.1 μg/ml IC50 = 38.5 μg/ml IC50 = 15.7 μg/ml Valencia et al. (2011) Leaf EtOH VERO H460 C-678 IC50 < 0.00022 mg/ml IC50 < 0.00022 mg/ml IC50 < 0.00022 mg/ml Quispe et al. (2006) Leaf/ stem DMSO PC FG/COLO357 PC CD18/HPAF IC50 = 200 μg/ml IC50 = 73 μg/ml Torres et al. (2012) Leaf n-But MDA-MB-435S HaCaT WRL-68 IC50 = 29.2 μg/ml IC50 = 30.1 μg/ml IC50 = 52.4 μg George et al. (2012) H2O:EtOH HaCat 1.6 to 50 μg/ml increase cellular activity, 100 μg/ml not change cell behavior Nawwar et al. (2012) H2O EtOH Pen A375 IC50 > 500 μg/ml IC50 = 320 μg/ml IC50 = 140 μg/ml Ménan et al. (2006) EtOH MCF-7 H-460 SF-268 ED50 = 6.2 μg/ml ED50 = 4.0 μg/ml ED50 = 8.5 μg/ml Calderón et al. (2006) Leaf Seed EtOH MDBK CC50 = 20x10–4 μg/ml CC50 = 24x10–5 μg/ml Betancur-Galvis et al. (1999) Leaf EtOAc EtOH + H2O Chl n-Hex HeLa 15.62 μg/ml = 11.37% inh 15.62 μg/ml = 3.97% inh 15.62 μg/m l = 18.42% inh 15.62 μg/ml = 21.41% inh Astirin et al. (2013) n-Hex EtOAc MeOH n-Hex EtOAc MeOH n-Hex EtOAc MeOH HT-29 HCT-116 CCD841 IC50 = 14.93 μg/ml IC50 = 4.29 μg/ml IC50 > 100 μg/ml IC50 = 12.26 μg/ml IC50 = 3.91 μg/ml IC50 > 100 μg/ml IC50 = 42.19 μg/ml IC50 = 34.24 μg/ml IC50 > 100 μg/ml Moghadamtousi et al. (2014) EtOH Spleen cell EACC MDA SKBR3 T47D IC50 > 750 μg/ml IC50 = 335.85 μg/ml IC50 = 248.77 μg/ml IC50 = 202.33 μg/ml IC50 = 17.15 μg/ml Gavamukulya et al. (2014) Rachmani et al. (2012) Leaf Twigs Roots EtOH HL-60 IC50 = 14 μg/ml IC50 = 49 μg/ml IC50 = 9 μg/ml Pieme et al. (2014) Leaf Com leaf Hex DMSO Capan-1 IC25 = 7.8 μg/ml IC25 = 0.9 μg/ml Mohamad et al. (2015) Antiprotozoal Leaf H2O EtOH Pen Plasmodium falciparum (chloroquine-sensitive strain) IC50 = 240 μg/ml IC50 = 52 μg/ml IC50 = 18 μg/ml Ménan et al., 2006, Nguyen-Pouplin et al., 2007 H2O EtOH Pen Plasmodium falciparum FcM29 IC50 = 230 μg/ml IC50 = 49 μg/ml IC50 = 16 μg/ml EtOH MeOH Ip Hex H2O Plasmodium falciparum strain W2 IC50 = 7.43 μg/ml IC50 = 3.55 μg/ml IC50 > 10 μg/ml IC50 = 2.03 μg/ml IC50 > 10 μg/ml Boyom et al. (2011) Twig EtOH MeOH Hex H2O IC50 = 8.56 μg/ml IC50 = 4.11 μg/ml IC50 > 10 μg/ml IC50 > 10 μg/ml Flow EtOH MeOH H2O IC50 = 5.12 μg/ml IC50 = 2.92 μg/ml IC50 > 10 μg/ml Peric EtOH MeOH Ip H2O IC50 = 6.87 μg/ml IC50 = 4.3 μg/ml IC50 > 10 μg/ml IC50 > 10 μg/ml Pulp EtOH MeOH Pp H2O IC50 = 6.01 μg/ml IC50 = 5.17 μg/ml IC50 = 4.42 μg/ml IC50 > 10 μg/ml Seed EtOH MeOH Pp H2O IC50 = 3.02 μg/ml IC50 = 2.42 μg/ml IC50 > 10 μg/ml IC50 > 10 μg/ml Leaf Stem Hex EtOAc MeOH Hex EtOAc MeOH Plasmodium falciparum F32/W2 IC50 = 7 μg/ml /38 μg/ml IC50 = 8 μg/ml /10 μg/ml IC50 = 9 μg/ml/36 μg/ml IC50 = 11 μg/ml/38 μg/ml IC50 = 40 μg/ml/34 μg/ml IC50 = 32 μg/ml/26 μg/ml Osorio et al. (2005) Leaf MeOH Plasmodium falciparum 3D7 IC50 = 0.715 μg/ml Yamthe et al. (2015) Peri Root Steam EtOH Plasmodium falciparum strain W2 IC50 = 1.01 μg/ml IC50 = 0.79 μg/ml IC50 = 1.45 μg/ml Boyom et al. (2011) Peri MeOH Hex EtOAc Leishmania braziliensis MEC > 1 mg/ml MEC > 1 mg/ml MEC = 0.1 mg/ml Jaramillo et al. (2000) Leaf Stem Hex EtOAc MeOH Hex EtOAc MeOH Leishmania sp. IC50 > 100 μg/ml IC50 = 25 μg/ml IC50 > 100 μg/ml IC50 = 76.3 μg/ml IC50 = 63.2 μg/ml IC50 = 98.6 μg/ml Osorio et al. (2007) Leaf EtOH Biomphalaria glabrata 500 ppm, 100% mort Luna et al. (2005) Leaf Stem Bark EtOAc MeOH Hex Hex EtOAc MeOH EtOH Trypanosoma cruzi Entamoeba histolytica IC50 = 40.2 μg/ml IC50 > 200 μg/ml IC50 > 200 μg/ml IC50 = 91 μg/ml IC50 = 93.5 μg/ml IC50 > 200 μg/ml MIC = 63 mcg/ml Valencia et al. (2011) Ross (2010) Leaf H2O Haemonchus contortus 12.5% extract 90% of larvae mot Ferreira et al. (2013) Insecticidal Seed EtOH Spodoptera litura larvae 5% extract, 18–96% inh Leatemia and Isman (2004) PE A. aegypti An. albimanus A. aegypti An. albimanus 18.75 ppm, 15% mort 4.7 ppm, 85% mort 37.5 ppm, 3% mort 9.4 ppm/, 2.5% mort Morales et al. (2004) Leaf and Bark H2O A. aegypti 5% extract, 99% mort Sanabria et al. (2009) Flow Seed Leaf Stem Root EtOH/ H2O A. aegypti CL50 = 3.33 mg/ml CL50 = 0.02 mg/ml CL50 = 8.25 mg/ml CL50 = 19.21 mg/ml CL50 > 50 mg/ml Bobadilla et al. (2005) Leaf EtOH Plutella xylostella 5 mg/ml by 12 days: 100% larvae mort Prédes et al. (2011) EtOH Callosobruchus maculatus Fabricius 1 g/l, 40.8% mort Adeoye and Ewete (2010) Seed EtOH/n-Hex A. aegypti LC50 = 73.77 ppm Komansilan et al. (2012) EtOH DicMet H2O Cx. Quinquefascia-tus 1 ml extract, 22% mort 1 ml extract, 22% mort 20% extract, 11.5% mort Raveloson et al. (2014) DicMe Ae. albopictus 1 ml extract, 25% mort Repellent Seed EtOH C. gestroi Wasmann 20% extract, 15.75% mort Acda (2014) Antioxidant Juice NR ABTS DPPH 6.09 μM of Tr/g 1.36 μM of Tr/g Almeida et al. (2011) Pulp NR FRAP ORAC ABTS DPPH Lipid peroxidation 503 μmol/l/g 14.51 μmol of Tr/g 287.67 μmol of Tr/g 2.88 μmol of Tr/g 3.5% with 10 μM GAE Correa-Gordillo et al. (2012) Leaf MeOH EtOH DPPH DPPH ABTS Lipid peroxidation Follow nitric oxide radical Follow superoxide radical IC50 = 221 μg/ml IC50 = 70 μg/ml IC50 = 305 μg/ml IC50 = 455 μg/ml IC50 = 350 μg/ml IC50 = 155 μg/ml Leaf H2O:EtOH (3:1) ORAC assay 14269537.4 μM Tr/g Nawwar et al. (2012) Fresh leaf H2O DPPH SC50 = 10.1 mg/l Alitonou et al. (2013) Leaf n-But DPPH 400 μg of extract, 60% inh George et al. (2012) Fresh-leaf Dried-leaf Pulp Seed EtOH MeOH EtOH MeOH EtOH MeOH EtOH MeOH ABTS 219.2 μmol of Tr/100 g 182.3 μmol of Tr/100 g 280.2 μmol of Tr/100 g 160.8 μmol of Tr/100 g 306 μmol of Tr/100 g 193.4.2 μmol of Tr/100 g 131.2 μmol of Tr/100 g 86.6 μmol of Tr/100 g Vit and Santiago (2014) Pulp MeOH DPPH 5 mg of pulp, 75.39% inh Boakye et al. (2015) Antibacterial Peel H2O S. aureus V. cholera E. coli (river) 50 μL/dish, DIH = 14 mm 50μL/dish, DIH = 17 mm 50μL/dish, DIH = 18 mm Viera et al. (2010a) Leaf EtOH H2O:EtOH S. aureus E. coli EC27 MIC = 128 mg/ml MIC > 1024 μg/ml Bussmann et al. (2010) Bento et al. (2013) H2O/ MeOH B. subtilis S. aureus K. pneumonia S. typhimurium E. coli S. pyogenes 400 mg/ml, DIH = 18.5/19.5m 400 mg/ml, DIH = 17.7/20.5m 400 mg/ml, DIH = 16.0/18.0m 400 mg/ml, DIH = 16.5/16.5m 400 mg/ml, DIH = 17.5/16.5m 400 mg/ml, DIH = 0/17.2 m Solomon-Wisdom et al. (2014) Seed, Stem MeOH E. coli C600 S. aureus 209P MIC > 1024 μg/ml MIC > 1024 μg/ml Yasunaka et al. (2005) Leaf H2O M. tuberculosis H37Rv M. tuberculosis MDR 5 mg/ml of extract, 82% inh 5 mg/ml of extract, 50% inh Radji et al. (2015) EtOH S. thypimurium S. thypimurium A S. thypimurium B MIC = 4096 μg/ml MIC = 2048 μg/ml MIC = 4046 μg/ml Roger et al. (2015) Antiviral Stem EtOH Herpes simplex HSV-1 strain #753166 MIC = 1 mg/ml Padma et al. (1998) Leaf EtOH EtOH Spleen cell EACC MDA SKBR3 T47D IC50 > 750 μg/ml IC50 = 335.85 μg/ml IC50 = 248.77 μg/ml IC50 = 202.33 μg/ml IC50 = 17.15 μg/ml Gavamukulya et al. (2014) Rachmani et al. (2012) Leaf Twigs Roots EtOH HL-60 IC50 = 14 μg/ml IC50 = 49 μg/ml IC50 = 9 μg/ml Pieme et al. (2014) Leaf Hex DMSO Capan-1 IC25 = 7.8 μg/ml IC25 = 0.9 μg/ml Mohamad et al. (2015) Leaf H2O BPH-I IC50 = 1.36 mg/ml Asare et al. (2014) NR, no reported; Cell line: ECV304, Human leukemia carcinoma cells; FG/COLO357 and CD18/HPAF, Pancreatic cancer cells; U937, Histiocytic lymphoma cell line; HeLa, Uterine cervical cancer cell line; MDA-MB-435S, Breast carcinoma cells; HaCat, immortalized human keratinocytes; WRL-68, normal human liver cells; MBDK, Bovine cell line; MCF-7, human breast carcinoma; K562, Human bladder carcinoma cells; H-460, Human large lung cell carcinoma; S-F-268, glioma; CCD841, normal human colon epithelial cells; HT-29 and HCT-116, colon cancer cell. VERO, kidney epithelial cells; C-678, stomach cancer cells; EACC: Ehrlich Ascites Carcinoma Cells; SKBR3: breast adenocarcinoma cell line; T47D, breast cancer cells; HL-60, human promyelocytic leukemia; Capan-1, pancreatic cancer cells; BPH-I, human benign prostate cells. Concentration: MEC: minimum effective concentration; MIC, minimum inhibitory concentration; IC50, medium inhibitory concentration; DIH, Diameter of inhibitory halo (mm); SC50, medium scavenging activity; ED50, medium effective dose; CC50, 50% cytotoxic concentration; CL50, 50% lethal concentration; inh, inhibitory; Ip, Interface precipitate. Extract: n-but, butanol; Chl, chloroform; EtOAc, ethyl acetate; EtOH, ethanol; Hex, hexane; n-hex, n-hexane; H2O, water; MeOH, methanol; PE, petroleum ether; Pen, pentane. Chemical: Tr, trolox; GAE, gallic acid equivalent. Activity: FRAP, Power reduction of iron; ORAC, Oxygen radical absorbance capacity; ABTS, Radical cation capture 2,2-azino-bis(3-ethylbenzthiazoline)-6 ammonium sulfonate; DPPH, 1,1-diphenyl-2-picrylhydrazyl radical activity. Plant part: flow, flower; peric, pericarp. Inh, inhibition; mor, mortality; MDR, multi drug resistant. 4.1.1. Cytotoxic activity The increasingly popular use of A. muricata as an anticancer treatment reported ethnobotanically may be related to reports of its selective cytotoxic activity (George et al., 2012). This bioactivity is considered selective as some of the extracts studied in vitro were shown to be more toxic to cancer cell lines than to normal cells (Betancur-Galvis et al., 1999, Dai et al., 2011, George et al., 2012, Valencia et al., 2011, Gavamukulya et al., 2014). Nawwar et al. (2012) reported that 1.6 μg/ml and 50 μg/ml from hydroalcoholic extract of A. muricata leaves increased the viability of non-cancerous cells while 100 μg/ml did not alter their viability. This selective activity has also been reported to induce healing. In tumor cells, healing time is increased (Torres et al., 2012), whereas in rodents, healing time of induced wound decreases (Padmaa et al., 2009). Likewise, in the study of other bioactivities, the type of extract is decisive in the results obtained. Organic solvents, pentanoic and ethanolic, were the most active A. muricata extracts against cancer cells grown in vitro. In these extracts, activity has been reported to be 10 and 4.5 times higher, respectively, than the activity of the aqueous extract in the A375 cell culture (Ménan et al., 2006). According to Osorio et al. (2007), extracts with LC50 < 10 μg/ml can be classified as highly cytotoxic while the National Cancer Institute (Pieme et al., 2014) suggested that plant extracts with LC50 values ⩽20 μg/ml are suitable for cancer drugs from plants. Ethyl acetate A. muricata leaf extract showed inhibition of the U-937 cell line with 7.8 μg/ml (Osorio et al., 2007). Although A. muricata extracts exhibit good cytotoxicity, there are plants with more cytotoxic effect, like Thevetia ahouai with LC50 < 1 μg/ml. Both plant species are used in Latin American countries to treat cancer (Calderón et al., 2006). The hexane extract of leaves had the highest content of flavonoids and the most effective inhibition of cell proliferation than the methanol or chloroform extracts (Mohamad et al., 2015). Moghadamtousi et al., 2015c, Pieme et al., 2014 proposed that the mechanism of action of the extract implies the disruption of mitochondrial membrane to arrest cells in G0/G1 phase, and the induction of apoptosis suppressing the migration and invasion of cancer cells. Pieme et al. (2014) suggested that A. muricata extracts induce apoptosis by Reactive Oxygen Species (ROS), and downregulates Bcl-2 proteins. Bax protein Bcl-2 are anti-apoptotic proteins that suppress the function of apoptosis, while Bax are proteins that mediate the leakage of pro-apoptotic factors, including cytochrome c, Ca2+ and the mitochondrial protein Smac/DIABLO into the cytosol through dimerization and translocation to the outer mitochondrial membrane; a property that was also observed for acetogenins (Asare et al., 2014). The acetogenins with antitumor and anticancer activity have also been studied in vitro assays, and cytotoxic effects against more than 15 cancer cell lines have been used (Alonso-Castro et al., 2011, Chang and Wu, 2001, Kim et al., 1998a, Kim et al., 1998b, Ko et al., 2011, Liaw et al., 2002, Quispe et al., 2006, Torres et al., 2012, Zeng et al., 1996). Isolated acetogenins have demonstrated selective cytotoxic effects (Moghadamtousi et al., 2015c). Acetogenins bioactivity has been related to their molecular structure (Landolt et al., 1995, Nakanishi et al., 2003). The two adjacent THF rings acetogenins are the most active (Table 2) (Castillo-Sánchez et al., 2010, Nakanishi et al., 2003, Yang et al., 2010), especially bullatacin and squamocin (Table 2), which have been reported mainly in the seeds (Landolt et al., 1995, Nakanishi et al., 2003). The mechanism of the acetogenin cytotoxic action is the inhibition of the mitochondrial complex I (Lannuzel et al., 2003), and the inhibition of ubiquinone-linked NADH oxidase in the plasma membranes of cancerous cells causing apoptosis (Alali et al., 1999). Torres et al. (2012) demonstrated that A. muricata extracts suppressed phosphorylation of the key molecules involved in the extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3’kinase (PI3 K/Akt) pathway which play a crucial role in the proliferation and survival of pancreatic cancer cells. Also, plant extract inhibited the expression of glucose transporter and glycolytic enzymes, all of which lead to the reduction of glucose uptake and ATP production by PC cells (Torres et al., 2012). Biochemical apoptosis implied a transverse redistribution of phosphatidylserine (PS) on the outer plasma membrane arises during early apoptosis (Moghadamtousi et al., 2015c). Other events in apoptosis are the complex cascade of caspases. Annomuricin E caused depletion of mitochondrial membrane potential (MMP) leading to opening of mitochondrial permeability transition pores and further release of pro-apoptotic proteins, such as cytochrome c from the mitochondria to the cytosol, resulting in the formation of the apoptosome and the activation of caspase 9 and caspase 3/7, which have been linked to the mitochondrial death pathway. A. muricata extracts isolated Annomuricin E downregulates Bcl-2 proteins and upregulates Bax protein. This finding confirms that Annonacin E-induced apoptosis was through the mitochondrial-mediated pathway (Moghadamtousi et al., 2015c). McLaughling (2008) suggested that selective cytotoxicity of A. muricata is due to the enhanced ATP demand of cancer cells with respect to normal cells. 4.1.2. Anti-protozoal activity A. muricata extracts and some of their isolated compounds have shown effectiveness against protozoans responsible for human diseases (Table 3), as is the case of the genera Plasmodium (Boyom et al., 2011), Leishmania (Osorio et al., 2007), Biomphalaria (Luna et al., 2005), Trypanosoma, and Entamoeba (Ross, 2010), responsible for malaria, leishmaniasis, schistosomiasis, chagas, and amebiasis diseases, respectively. The anti-plasmodic effect has particular interest due to the necessity for antimalarial drugs in tropical areas. Methanol extract of this species has shown inhibition of this parasite in vitro but with less effectivity than the commercial drugs chloroquine and artemisinin (Boyom et al., 2011). The highest effectiveness was found in seed extracts (Boyom et al., 2011). It has also been reported that alkaloids (Fofana et al., 2011, Fofana et al., 2012), acetogenin, anonaine, and gallic acid (Yamthe et al., 2015) isolated from A. muricata had antiplasmodial activity. It has been demonstrated that phenolic compounds inhibit the activity of β-ketoacyl-ACP-reductase (FabG), β-hydroxyacyl-ACP-dehydratase (FabZ) and enoyl acyl-ACP reductase (FaBI), important enzymes for fatty acid biosynthesis in P. falciparum that compromises its growth (Tasdemir et al., 2006). In the case of FabG, phenols like luteolin act as noncompetitive inhibitor of FabG with respect to acetoacetyl-CoA as well as NADPH, while in FabZ, luteolin acts as competitive inhibitor of the substrate crotonyl-CoA (Tasdemir et al., 2006). Methanolic and ethyl acetate extracts of A. muricata peel showed higher antileishmanial activity than the commercial compound Glucantime® (Jaramillo et al., 2000) used to treat diseases caused by different strains of protozoa. The trypanocidal activity of A. muricata was found in extracts from different plant parts and in different solvents, although its effectiveness was 100 times lower than the commercial trypanocide benznidazole (Osorio et al., 2007, Valencia et al., 2011). Extracts of A. muricata also have antiparasitic activity against the metazoan or helminth Haemonchus contortus, a gastrointestinal parasite of sheep (Ferreira et al., 2013). The extracts of A. muricata were active against eggs, infective larvae and adult forms of the parasite, and the effect was comparable to that obtained with using the anthelmintic drug, levamisole (Ferreira et al., 2013). Isoquinoline alkaloids are strongly implicated in the inhibition of an essential antioxidant enzyme of Leishmania and Trypanosoma, trypanothione reductase. This enzyme protects the parasites from ROS generated by the host defense cells (Tempone et al., 2005). 4.1.3. Insecticidal, larvicidal and repellent activity A. muricata showed insecticidal activity from seed, leaves, barks, stems, roots and flowers (Bobadilla et al., 2005, Leatemia and Isman, 2004, Prédes et al., 2011). Ethanolic extracts inhibited insect larvae of Aedes aegypti (Bobadilla et al., 2005, Morales et al., 2004, Sanabria et al., 2009), Anopheles albimanus (Morales et al., 2004), and insects that affect plants such as Spodoptera litura (Leatemia and Isman, 2004), Callosobruchus maculatus and Plutella xylostella (Prédes et al., 2011). A. muricata seed extracts have shown the most active insecticidal activity (Bobadilla et al., 2005, Morales et al., 2004, Sanabria et al., 2009), probably due to its content of chemical compounds such as alkaloids, fatty acids and acetogenins. The insecticidal action of soursop alkaloids has not been fully studied. Fatty acids are toxic to insects in different manners: by inhalation of volatile compounds, by contact with film at the surface of water, and by penetration due to the amphibolic property of some compounds (Raveloson et al., 2014). New technologies, such as nano science, are exploring the development of environmentally friendly, effective, inexpensive and easy to apply mosquito control products. For this purpose, green silver nanoparticles synthesized using aqueous crude extract of A. muricata show larvae toxicity of Aedes aegypti (Santhosh et al., 2015). Acetogenins have in vitro activity on larvae of Myzus persicae, Leptinotarsa decemlineata, Blattella germanica, Aedes aegypti, Rhodnius prolixus, and Rhodnius pallescens (Castillo-Sánchez et al., 2010, Guadaño et al., 2000). In studies that have evaluated the insecticidal activity of 44 acetogenins isolated from different species of Annona, there was a relationship between the acetogenin structure and their toxicity to mosquito larvae. As such, compounds with adjacent bis-tetrahydrofuran rings and three hydroxyls were more active than compounds with a mono-tetrahydrofuran ring. The majority of the active acetogenins evaluated in a study by Isman and Akhtar (2007) were equitoxic to the commercial compound rotenone (LC50 = 1.2 ppm). Some studies have suggested that the insecticidal mechanisms of acetogenins are due to THF ring having strong interaction with the interface of lipid bilayers, and alkyl spacer between the γ-lactone and hydroxylated THF ring moieties elicited potent inhibitory activities on the NADH oxidase, resulting in the inhibition of mitochondrial complex I (Guadaño et al., 2000, Isman and Akhtar, 2007), and thus damaging the respiration chain and the integrity and function of the cell. Using the insecticidal activity of isolated acetogenins as a base, commercial products were developed but failed mainly because their mechanism of action involves inhibition of mitochondrial electron transport with a specific action at complex I, thus becoming detrimental to other organisms. In the case of other plants, using crude extracts can be more promising than the development of products using individually isolated compounds as active ingredient (Isman and Akhtar, 2007). 4.1.4. Antioxidant activity Natural antioxidants from plant species have gained interest due to their protective effect against oxygen-derived from free radicals involved in the development of many diseases such as cancer, cardiovascular affections, arthritis, as well as degenerative illness such as Parkinson and Alzheimer (Almeida et al., 2011). Several antioxidant screenings have been conducted on A. muricata (Table 3). Correa-Gordillo et al. (2012) compiled studies on the antioxidant activity of A. muricata considering different assays, the different plant parts, and the different solvents used. Some of the methods used for determining the total antioxidant capacity included the free radical scavenging capacities using DPPH and the ABTS+ assays, determination of oxygen radicals by the ORAC assay, reduction power by the FRAP assay and β-carotene bleaching. The antioxidant activity has been evaluated in fresh and frozen pulp, juice, and fresh or dried leaves. The pulp antioxidant activity measured by ABTS, FRAP and ORAC suggested that the antioxidant compounds from A. muricata are mainly lipophilic, and the mechanism of action is by hydrogen donation (Correa-Gordillo et al., 2012). The composition of the extract varies depending on the solvent used. For example, methanolic, ethanolic, n-butanolic and aqueous leaf extracts showed different antioxidant activity measured by DPPH. For instance, the aqueous extract of fresh leaves of A. muricata was 1000 times less active than the commercial antioxidant butylated hydroxytoluene (Alitonou et al., 2013). A positive correlation between antioxidant activity and the total polyphenol content was reported (George et al., 2012). Antioxidant activities of phenols, flavonoids, vitamins and carotenoids in A. muricata are summarized in Table 2. 4.1.5. Antibacterial and antiviral activities A. muricata showed antibacterial activity against gram-positive and gram-negative bacteria, comparable with the standard antibiotic streptomycin (Table 3). Its bioactivity efficacy depends on the kind of solvent used in the extraction. For example, ethanolic and methanolic extracts of A. muricata showed antibacterial activity against Staphylococus aureus, while the peel aqueous extract did not show such activity. In addition to the direct antimicrobial activity, a modulatory activity has also been reported. The combination of ethanolic extract and antibiotic treatment increased the potentiation of the antibiotic against multidrug-resistant strains of E. coli and S. aureus (Viera et al., 2010, Bento et al., 2013, Solomon-Wisdom et al., 2014). Ethanolic extracts from stem and bark of A. muricata also showed antiviral activity in vitro against the Herpes simplex virus (Padma et al., 1998). Antimicrobial bioactivity of A. muricata extracts is attributed to flavonoids, steroids and alkaloids present in the plant extracts (Radji et al., 2015). The mechanism of action is probably due to a synergism of these compounds. It has been reported that some alkaloids have the ability to bind with DNA of microorganisms and inhibit RNA synthesis (Roger et al., 2015), and have shown antimicrobial activity by glycosidase inhibition (Mohanty et al., 2008). It has also been reported that flavonoids act by inhibiting both cytoplasmic membrane function and DNA synthesis, such as quercetin that binds to GyrB subunit of E. coli DNA gyrase and inhibits the enzyme ATPase activity. Phenylphenol was reported to bind to membrane protein or hydrogen with vital proteins such as microbial enzymes and inhibit and change their functions (Radji et al., 2015). With respect to antiviral bioactivity, it is known that plant extracts interfere with HIV-I replication at an early step of the virus. In the first step, plant extracts interfere with virus entry into the host cell by reduction of input viral RNA and by interfering with the function of the envelope proteins that diminish the infectivity of viral particles. This indicates that plant extracts have virucidal activity and act before the interaction with the host cell. Also, plant extracts inhibit attachment of virus to the host cell. It is demonstrated that antiviral activity of plant extracts is mediated by polyphenol compounds (Helfer et al., 2014). 4.2. In vivo studies of extracts and isolated compounds The most encountered in vivo studies were hypoglycemic, anti-tumorigenic, hepato and gastro protective studies. The pharmacological activities of A. muricata extracts evaluated in vivo are summarized in Table 4. Table 4. Pharmacological activities of A. muricata extracts evaluated in vivo. Activity Plant part Solvent Dose Test model and results References Hypoglycemic Leaf H2O 100 mg/kg p.o. by 25 days Reduction of blood glucose (4.7 mmol/l) in diabetes mellitus rats Adewole and Caxton-Martins (2006) H2O 100 mg/kg p.o. by 25 days Increase of serum insulin glucose (12.2 μU/ml) in diabetes mellitus rats MeOH 100 mg/kg, daily for two weeks Reduction of blood glucose (4.22 mmol/l) in diabetes mellitus rats Adeyemi et al. (2009) H2O 100 mg/kg, daily for 28 days Reduction of blood glucose (80.75 mg/dl) in diabetes mellitus rats Florence et al. (2014) Stem bark EtOH 100 mg/kg, daily for 14 days Reduction of blood glucose (187 mg/dl) in diabetes mellitus rats Ahalya et al. (2014) Anti-cancer Leaf EtOH 100 mg/kg/4 wk Restoration of colon total protein in cycas-induced colorectal carcinogenesis in rats Okolie et al. (2013) Leaf EtOAc 500 mg/kg/8 wk 72.5% of ACF inhibition in AOM induced colorectal carcinogenesis in rats Moghadamtousi et al. (2015c) Anti-tumorigenic Dried fruit H2O:Cet 50% 200 mg/kg/35 wk 32% growth inhibition (weight) of breast tumor induced by MDA-MB-468 cell in rats Dai et al. (2011) Leaf/ Stem H2O 50 mg/kg/35 days 59.8% growth inhibition of pancreatic tumor induced by CD18/HPAF cell in rats Torres et al. (2012) Leaf EtOH/H2O 30 mg/kg bwt 0% of incidence of initiation and promotion of tumors induced in mouse skin Hamizah et al. (2012) Anti-diarrhea Leaf MeOH 25 a 200 mg/kg, vo 13.94% of inhibition of activated charcoal transit in mouse Salinas et al. (2011) Gastroprotective Leaf EtOH 80% 300 mg/kg 92.8% of inhibition of total area of gastric lesion in rats Roslida et al. (2012) Leaf EtOAc 400 mg/kg Reduction of ulcer index in ethanol-induced ulcerogenesis in rats Moghadamtousi et al. (2014) Hepato-protective Leaf H2O 400 mg/kg twice daily for 7 days: Reduction of bilirubin level (5.68 μmol/l) in rats hyperbilirubinemia induced Arthur et al.(2012a) Leaf H2O 50 mg/kg 97% of protection versus hepatotoxicity induced in rats by CCl4 Arthur et al. (2012b) Leaf H2O 100 mg/kg 100% of protection versus hepatotoxicity induced in rats by acetaminophen Anti-inflammatory Leaf H2O 1.5 mg/kg 71.12% reduction of plant edema induced in mouse model Poma et al. (2011) Leaf EtOH 400 mg/kg Reduction of volume (0.47 ml) of carrageenan-induced paw edema in rats Sousa and Vieira (2010) Anti-nociceptive Leaf EtOH 80% 10 mg/kg op 53.92% prolongation of reaction time of mice exposed to the hot plate Roslida et al. (2012) Leaf EtOH 80% 300 mg/kg 95.3% inhibition of abdominal writhes of mice induced by 0.6% acetic acid Leaf EtOH 80% 100 mg/kg 47.36% of reduction time spent licking on formalin-induced in mice Leaf EtOH 400 mg/kg 41.41% inhibition of acetic acid-induced writhing in mice Sousa and Vieira (2010) Leaf EtOH 400 mg/kg Increase the latency time (13.25 min) in mice Leaf EtOH 400 mg/kg 45% inhibition of formalin-induced nociception in mice Anxiolytic-like effect Leaf EtOH 40% 0.5 g/kg, vo: 45% reduction of time reaction in Albino mice/elevated plus maze Oviedo et al. (2009) Hypotensive Leaf H2O 48.53 mg/kg Reduction of blood pressure (57.7 mm Hg) in rats Nwokocha et al. (2012) Wound healing Stem bark EtOH 4% in ointment/12 days 88.58% reduction of area of open wound produced in rats Padmaa et al. (2009) Leaf EtOAc 10% in cream, two applications a day per 15 days 77% of wound closure in rats Moghadamtousi et al. (2015b) NR, Not reported; EtOH, ethanol; H2O, water; MeOH, methanol; EtOAc, ethyl acetate; Cet, cetone; CCl4, carbon tetrachloride; wk, week; ACF, aberrant crypt foci; AOM, azoxymethane. 4.2.1. Hypoglycemic activity A. muricata leaf extracts showed hypoglycemic activity in murine models (Adewole and Caxton-Martins, 2006). In these studies, the effect of aqueous and methanolic extracts of A. muricata leaves on reducing the concentration of blood glucose in rats with diabetes induced with streptozotocin (STZ) was evaluated, and the histology and biochemistry of the pancreas were observed. Pancreatic β-cells in rats that were administered with extracts of A. muricata did not show the alterations that are normally found in diabetic rats. An increase in the antioxidant enzymatic activity and insulin content in pancreatic serum was reported. Near normal blood glucose levels, body weight, food and water intake, lipid profile and oxidative defense were achieved after a month of daily treatment with A. muricata extract, which could prevent the deleterious effect of STZ by its antioxidant and protective effect of pancreatic β-cells (Florence et al., 2014). It has also been reported that there is a positive correlation between tannins, flavonoids and triterpenoids content and the inhibition of α-glucosidase. Flavonoids inhibit α-glucosidase through hydroxylation bonding and substitution at β ring (Hardoko et al., 2015). This inhibition decreases carbohydrate hydrolysis and glucose absorption, and inhibits carbohydrates metabolism into glucose (Hardoko et al., 2015). Additionally, glycemic index (GI) and glycemic load (GL) have been reported for A. muricata fruit. GI indicates the effect of the content and type of carbohydrates of a food on blood glucose content, while GL estimates how much the food will raise blood glucose level after eating it. GI and GL are considered low for A. muricata, which agrees with its hypoglycemic potential (Passos et al., 2015). 4.2.2. Anti-cancer activity Ethyl acetate extract of A. muricata leaves showed chemopreventive properties on azoxymethane-induced colonic aberrant crypt foci in rats (Moghadamtousi et al., 2015c). As acetogenins, the extract downregulates PCNA and Bcl-2 proteins, upregulates Bax protein and restores the levels of the antioxidant enzymes. An excessive ROS generation results in the production of lipid radicals such as malondialdehyde (MDA), and an elevated concentration of MDA was observed in patients suffering from colorectal cancer (Moghadamtousi et al., 2015c). A. muricata extract treatment reduced MDA formation in colon tissue, confirming its protective effect against oxidative stress. 4.2.3. Anti-tumorigenic activity Anti-tumoral activity has been reported for extracts and some isolated acetogenins of A. muricata. Hamizah et al. (2012) reported that the ethanolic extract of A. muricata leaves showed greater anti-tumor activity in murine models than curcumin, a known natural chemopreventive. This extract has shown protective effect in biochemical events and in morphological changes in induced colorectal carcinogenesis. Aqueous extract of commercial powder capsules containing leaf and stem of A. muricata also showed anti-tumorigenic and anti-metastatic activities on pancreatic tumors in murine models (Torres et al., 2012). Breast tumor in rats was reduced by treatment for 5 weeks with A. muricata fruit extract (Dai et al., 2011). The mechanism of action suggests the inhibition of multiple signaling pathways that regulated metabolism, metastasis, induction of necrosis and cell cycle arrest (Torres et al., 2012, Dai et al., 2011), has been shown in cytotoxic mechanism. Antitumor activity was also reported for two acetogenin isolates of A. muricata (Ko et al., 2011, Wang et al., 2002). Ko et al. (2011) reported that bullatacin at doses of 400 mg/kg was able to reduce a tumor induced in rodents 300 times better than the commercial drug Taxol (paclitaxel). Meanwhile, annonacin at doses of 10 mg/kg reduced tumor size induced in murine models comparable to the commercial drugs cisplatin and adriamycin (Wang et al., 2002). A study by Yang et al. (2015) demonstrated that crude leaf extract showed more in vitro inhibition of prostate cancer proliferation and more effect on tumor growth-inhibition than flavonoid-enriched extract. This report suggests that the effectivity of crude extract is probably due to a synergistic interaction between flavonoids and acetogenins. 4.2.4. Hepatoprotective and gastroprotective activities Arthur et al., 2012a, Arthur et al., 2012b studied the hepatoprotective activity of the leaf aqueous extract of A. muricata. They reported that the extract was effective against hyperbilirubinemia or jaundice with similar effect to silymarin (Silybum marianum). The extract reduced the harmful effect and preserved the hepatic physiological mechanism of the liver damaged by a hepatotoxin such as paracetamol (Acetaminophen), a drug widely used as antipyretic and analgesic, which can cause liver damage if taken in excessive (Arthur et al., 2012b). This study suggests that soursop extract reduces bilirubin levels due the glucosides present in the extract, which might be converted into glucuronic acid, conjugating with bilirubin for excretion, or because the extract active regulators increase the activity of enzymes, synthesis of transporter, and steps related to bilirubin clearance pathway (Arthur et al., 2012b). Ethyl acetate and ethanol extracts from leaf of A. muricata showed protective gastric effect like omeprazole in ethanol-induced ulcerogenesis in rats (Moghadamtousi et al., 2014, Roslida et al., 2012). Antiulcer potential of A. muricata is probably through its antioxidant compounds that increase the mucosal nonprotein sulfhydryl group content (Roslida et al., 2012). The excessive production of gastric acid in patients with ulcers can reduce the level of gastric wall mucus (GWM). A. muricata extract caused attenuation in gastric acidity and retrieved the loss in GWM like proton pump inhibitors drugs as omeprazole but in less proportion. Additionally, the antioxidant effect of A. muricata extract can play an important role in the gastroprotection. The ROS produce oxidative damage to the gastric mucosa. A. muricata extract restores the activity of enzymes such as glutathione (GHS), catalase (CAT), nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA) and prostaglandin E2 (PGE-2) that reduces cellular ROS. Histopathological analysis showed that the extract protects the gastric tissue from hemorrhagic lesion associated with attenuation of leukocyte infiltration and submucosal edema (Moghadamtousi et al., 2014). 4.2.5. Anti-inflammatory and anti-nociceptive activities Anti-inflammatory activity similar to the activity presented by indomethacin, which is a nonsteroidal anti-inflammatory, has been reported (Poma et al., 2011, Sousa and Vieira, 2010). The antinociceptive effect of ethanolic and hydroalcoholic extracts of A. muricata has been reported using various chemical and thermal nociceptive models. A. muricata produced antinociception action of activity in both neurogenic and inflammatory phases (Roslida et al., 2012). Metabolites of arachidonic acid (called icosanoids) are involved in inflammation process (Poma et al., 2011). These metabolites are produced via cyclooxygenase and lipoxygenase when a cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. It has been proposed that the mechanism of antinociception may be by inhibition of cyclooxygenase (COX) and lipoxygenases (LOX) and other inflammatory mediators by flavonoids present in the plant extract (Poma et al., 2011). 4.2.6. Anxiolytic and anti-stress activities The anxiolytic and the anti-stress effects were more effective in the alkaloid fraction than in the crude hydroalcoholic extracts (Oviedo et al., 2009). It is possible to attribute this bioactivity to the alkaloid compounds; especially because two of the isolated alkaloids (anonaine and asimilobine) have relaxing activity. These compounds can influence the central nervous system via the 5HT1A receptor. The 5HT1A receptor binds with the endogenous neurotransmitter serotonin and is involved in the modulation of emotion (Hasrat et al., 1997a, Hasrat et al., 1997b). This bioactivity can validate the reason for the traditional use of A. muricata as sedative. 4.2.7. Hypotensive activity Leaf extract of A. muricata caused a dose-dependent reduction in mean arterial pressure (MAP) in normotensive rats (Nwokocha et al., 2012). The suggested hypotensive mechanism of action of aqueous extract of A. muricata did not involve the endothelial or nitric oxide-dependent pathways. Studies suggested that plant extracts lower blood pressure through the blockage of calcium ion channel, and this Ca+ antagonism is further demonstrated by its ability to relax high K+ induced contractions (Nwokocha et al., 2012). The hypotensive effect has been attributed to alkaloids such as coreximine, anomurine, and reticulin, and some essential oil components such as β-caryophyllene (Nwokocha et al., 2012). 4.2.8. Wound healing Bark and leaf extracts showed elevation in wound contraction compared with wound without treatment (Padmaa et al., 2009, Moghadamtousi et al., 2015b). Wound healing consists of four complex phases: coagulation, inflammation, proliferation and maturation. A. muricata accelerates some of these phases. In inflammatory phase the protein expression of heat shock proteins (Hsp70) is important for healing due to their role in cell proliferation. A. muricata induced upregulation of Hsp70 in wound tissues. In this phase the inflammatory cells produce cytokines and free radicals that in great quantity can produce lipid peroxidation in wound. Tissues treated with A. muricata extracts showed elevated activity of CAT, GPx and SOD that protect tissue against oxidative damage to accelerate the wound healing process. Additionally, A. muricata extracts reduce MDA, the biomarker of lipid peroxidation that can cause defect in endothelial cells, fibroblast and collagen metabolism necessary for wound healing. During the maturation phase, the collagen accumulation and fibroblast proliferation occurred. A. muricata extracts elevated the deposition of collagen fibers in the wound as observed in histological analysis (Moghadamtousi et al., 2015c). 4.3. Clinical studies Ethanolic extracts of A. muricata leaves have been clinically evaluated in relation to their hypoglycemic activity. Arroyo et al. (2009) conducted a randomized, parallel grouped, double blind phase II clinical trial, in patients with type 2 diabetes mellitus. Groups of patients were given 1, 2 or 3 capsules of ethanol extract from A. muricata leaves (180 mg) plus 5 mg of glibenclamide for 30 days, and another group only received glibenclamide. The results of this study showed a decrease in the blood glucose or glycemia level in patients receiving extract of A. muricata compared to patients who did not receive it. Side effects were reported in 11% of patients (five patients) receiving A. muricata extract. Two of them mentioned burning pain in epigastrium, one was associated with nausea, and the remaining three reported nausea (Arroyo et al., 2009). Compounds responsible for the hypoglycemic activity found in the A. muricata leaf extracts could be flavonoids and alkaloids, which are present in the leaves and the fruit (Table 2). Additional to the clinical study described above, two cases of anticancer evaluations have been reported (Hansra et al., 2014, Yap, 2013). In one of them, tumor markers showed that a breast cancer patient has been stable and had no side effects after therapy for 5 years (Hansra et al., 2014). Therapy consisted in taking 227 gm of leaves decoction of A. muricata (10–12 dry leaves in water for 5–7 min) daily and Capecitabina (2500 mg PO) 2 weeks on one week off (Hansra et al., 2014). The other case of study involves the disappearance of the malignancy with substantial regression of colon tumor cells in a patient who combined lifestyle modifications with the intake of some herbal extracts and nutraceuticals. The therapy included the daily ingestion of 5 g of powered leaf and seed of A. muricata extract (Yap, 2013). 5. Toxicology Considerable information, both formal and informal, is available on the relation of the consumption of A. muricata with the appearance of an atypical Parkinson’s disease (Caparros-Lefevre et al., 2002, Lannuzel et al., 2006). The toxicity reported for the extracts is variable depending on the plant part used, and the solvent employed (Table 5). Table 5. Neurotoxicity and mutagenicity of acetogenins and alkaloids of A. muricata. Activity Compound Dose Test model and results References Mutagenicity Annonacin Squamocin 1000 μg/plate: No mutagenic according Ames test Guadaño et al. (2000) Neurotoxicity Coreximine Reticuline Annonacin EC50: 13 μM EC50: 304 μM EC50: 0.018 μM Viability reduction of mesencephalic dopaminergic neurons Lannuzel et al. (2003) and Hôllerhage et al. (2009) Annonacin 50 nM Induced concentration-dependent neuronal cell loss, reduction brain ATP levels in rat striatal neurons cell Escobar-Khondiker et al. (2007) Solamin Annonacin Annonacinone Isoannonacin EC50: 1210 nM EC50: 60.8 nM EC50: 189.7 nM EC50: 121.3 nM Viability reduction of rat striatal neurons cell Hôllerhage et al. (2009) Annonacin 3800 and 7600 μg/kg for 28 days Reduction brain ATP levels, neuronal cell loss and gliosis in the brain stem and basal locomotive ganglia in rats Champy et al. (2004) Annonacin 7600 μg/kg/day for 28 days Neurodegeneration in male Lewis rats Lannuzel et al. (2006) EC50: Median effective concentration 5.1. Acute toxicity Aqueous extracts showed a LD50 > 5 g/kg, while methanolic and ethanolic extracts of leaves, flowers and pulp had a LD50 of > 2 g/kg (Sousa and Vieira, 2010), which are considered non-toxic according to the guidelines of OECD (http://www.oecd.org/chemicalsafety/testing/oecdguidelinesforthetestingofchemicals.ht). The median lethal dose of aqueous extract of leaves is above the expected consumption for a human, which is about 211 mg/kg per day, considering that an average person consumes one cup of tea three times per day (Arthur et al., 2011). Therefore, for a human to reach the lethal dose of consumption of soursop leaf infusion would require consuming more than 71 cups of tea a day. For toxicity in organs, Arthur et al. (2011) reported that doses greater than 5 g/kg of aqueous extract might cause kidney damage, unlike the 1 g/kg dose that showed hypoglycemic and hyperlipidemia properties. The most toxic extracts that have been reported are methanol extracts of pericarp, fruit pulp or seed (Boyom et al., 2011). A. muricata pulp consumed for 28 days showed no effect in blood hematology and serum biochemistry (Syahida et al., 2012). A study that evaluated the toxicity of crude leaf extract and its flavonoid and acetogenins enriched extracts shows that acetogenins-enriched extract was more toxic than others (Yang et al., 2015). This study suggested that whole extract could pose similar bioactive properties of its fractions or isolated constituents, but without their toxicity. 5.2. Neurotoxicology The association of the consumption of fruit and homemade preparations of A. muricata with the appearance of atypical Parkinsonism in the Caribbean Island of Guadeloupe is based on a case study published in 1999 (Caparros-Lefevre et al., 2002). This association has also been reported in New Caledonia and Caribbean patients living in London (Shaw and Höglinger, 2008). From these studies, assessment of the neurotoxic effect of the main bioactive compounds of A. muricata alkaloids and acetogenins was initiated. It was evident that some of the isolated compounds induce neurotoxicity and neurodegenerative diseases in murine models (Table 5). The reticuline and coreximine alkaloids and solamin, annonacinone, isoannonacinone and annonacin acetogenins were shown to be toxic to dopaminergic cells by impairing energy production (Escobar-Khondiker et al., 2007, Hôllerhage et al., 2009, Lannuzel et al., 2002, Lannuzel et al., 2003, Lannuzel et al., 2006). Annonacin toxicity was greater than the toxicity of the pesticide rotenone, which was used as a positive control. Champy et al. (2005) and Lannuzel et al. (2006) reported that in murine models annonacin enters the brain parenchyma, decreases ATP levels and induces neurodegeneration in the basal ganglia. According to these authors, this neurodegeneration induced no change in the behavior or locomotor activity in rodents. Regarding the neurotoxicity, seven acetogenins have been evaluated using mesencephalic dopaminergic neurons, rat striatal neurons cells and laboratory rats (Table 5). Champy et al. (2005) reported that annonacin and reticuline, which are the most abundant acetogenin and alkaloid in A. muricata, respectively, are neurotoxic. Annonacin is about 1000 times more toxic for neuronal cell cultures than reticuline, and 100 times more potent than 1-methyl-4-phenylpyridinium (MPP), a known neurotoxin that causes Parkinsonism in humans and animal models. This study was conducted by administering isolated annonacin to laboratory rats intravenously. The amount administered to rats was determined by estimating the amount of annonacin a human would consume by ingesting fruit or canned nectar daily for one year. Neurotoxicity studies of annonacin suggest that there is a need for a long exposure to this molecule to observe the effect in murine models, while pharmacokinetic studies estimated low bioavailability of this compound. In this regard, AVIS (l’Agence Francaise de Sécurité des Aliments) in 2010 issued a statement which concluded that on the basis of available experimental data, it is not possible to say that cases of atypical parkinsonian syndromes observed in Guadeloupe are linked to consumption of species belonging to Annonaceae family. 6. Conclusions A. muricata is widely used in traditional medicine to treat illness such as diarrhea, dysentery and fever, pain, respiratory and skin illness, internal and external parasites, bacterial infections, hypertension, inflammation, diabetes and cancer. Decoctions of bark, root, seed or leaf are the most widely used preparations. In vitro and in vivo studies support the majority of the traditional uses but lack clinical validation. Among the traditional uses that have not shown scientific validation yet are the effectivity in treating respiratory tract, heart and kidney affections, treatment to animal bites and stings, and obesity treatments. More than 200 phytochemicals have been identified in this plant, mainly acetogenins, alkaloids and phelos. These phytochemicals have shown pharmacological activities such as antimicrobial, antiprotozoan, antioxidant, insecticide, larvicide, selective cytotoxicity to tumoral cells, anxiolytic, anti-stress, anti-ulceric, wound healing, anti-icteric, hepatoprotective, and hypoglycemic. New phytochemicals are been identified in soursop. Mechanisms of action of the plant extracts and phytochemicals have been proposed. Cytotoxicity implies the disruption of mitochondrial membrane to arrest cells in G0/G1 phase, and the induction of apoptosis, the inhibition of multiple signaling pathways that regulate metabolism, induction of metastasis and necrosis of cancer cells. Mechanism of action of antioxidant activity is by hydrogen donation, while antimicrobial action is because of some phytochemicals having the ability to bind with DNA and inhibiting RNA synthesis and by glycosidase inhibition lacking cytoplasmatic membrane function. Mechanisms of action of antinociception may be by inhibition of cyclooxygenase and lipoxygenase enzymes and other inflammatory mediators. Hypotensive mechanism is thought to be through the blockage of calcium ion channel. Mechanisms of action of other bioactivities have not been completely elucidated, such as anxiolytic, anti-stress and hypoglycemic activities. Some phytochemicals, such as acetogenins, have shown neurotoxicity in vitro and in vivo studies. More research is needed to quantify the amount of neurotoxic compounds and to determine the level of human exposure. 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