ARTABOTRYS HEXAPETALUS (L. F.) BHANDARI: A PLANT WITH ENORMOUS BIOMEDICAL POTENTIAL

This review is intended to investigate the published report regarding phytochemical, ethnomedicinal, and pharmacological activities and put forth the therapeutic potential of Artabotrys hexapetalus (L. f.) Bhandari . ( A. hexapetalus ). It belongs to the family Annonaceae , one of the therapeutically important plants, broadly distributed throughout the world. An extensive review of the literature available in various recognized databases including logical writing and scientific literature, search engines such as Springerlink, ScienceDirect, SciFinder, PubMed, Scopus, Google Scholar, and BioMed Central as well as relevant books, websites, scientific publications, and dissertations were utilized as a source of information that provided an up-to-date review. Phytochemical profiling of these species revealed the presence of some imperative phytochemicals alkaloids, terpenoids, anthraquinones, butyrolactones, flavonoids, neolignans, phenolic compounds, and leucoanthocyanins as the basis of its valuable therapeutic properties. The other imperative phytoconstituents which contribute to the therapeutic properties are isoamericanin A, isoamericanol, americanin, artabotricinol and artabotriol, β-unsaturated-β-butyrolactones, arapetaloside taxifolin, apigenin-7-O-apiosylglucoside, glucoluteolin, and artabotrine. The pharmacological activities exhibited by Artabotrys hexapetalus as antimicrobial, antileishmanial, antioxidant, antifungal, antifertility, and anthelmintic properties are attributed to the presence of valuable bioactive phytoconstituents. Considering these facts an effort was made to present a comprehensive review enlightening the taxonomical, phytochemical, and pharmacological activities of plant Artabotrys hexapetalus. Future research can be directed to an extensive investigation about phytochemistry, clinical trials, pharmacokinetics, and acquiring safety data to add new dimensions to the therapeutic utilization of Artabotrys hexapetalus and other Artabotrys species.


INTRODUCTION
Artabotrys is a genus of woody trees, shrubs, and vines comprising about 130 genera and 2,300 species, which is distributed mainly in tropical and subtropical regions of the world, especially tropical Africa and Eastern Asia and the Indomalayan region [1,2]. Plants of Artabotrys genus are climbing herbs bearing recurved hooks borne on lateral branches and scandent shrubs are one of the largest genera of the custard-apple family [3]. Artabotrys hexapetalus (L. f.) (A. hexapetalus) Bhandari generally described as a folk drug that has a wide range of medicinal uses belonging to family Annonaceae. The family includes trees, shrubs, and lianas, found in almost all vegetation types. It is generally considered to be a natural family and one of the six members of Magnoliales [4]. It is an ornamental, medium-sized woody climber that produces aromatic flowers with fragrance. A. hexapetalus is native to India and widely distributed in the southern part of China, and is used in traditional Chinese medicine for the treatment of malaria [5]. It is a medium-sized climbing shrub, largely cultivated in India. Leaves are oblong, lanceolate, and glabrous. Flowers solitary or paired, often fragrant, usually on woody, hooked recurved branches (Peduncles) [6]. It is widely distributed throughout the southern part of China and also in the southern part of Asia. As a Chinese traditional folk medicine, its roots and fruits are used for treating malaria and scrofula, respectively [7]. The flower is acrid, bitter; useful in vomiting, diseases of the blood and the heart, leucoderma, headache. A decoction of leaves is given for cholera. Phytochemically it contains alkaloids, anthraquinones, butyrolactones, flavonoids, neolignans, phenolic compounds, leucoanthocyanins, terpenoids, and volatile oils [8][9][10]. Many phytochemicals in the form of flavonoids of A. hexapetalus possibly be modified or used as "lead" for developing more effective drug molecules. Hence, extensive pharmacological and phytochemical screening, together with the pharmacokinetic and toxicological assay can be aimed at future investigations. Hence an attempt is made to highlight selected phytochemical and biomedical potentials of A. hexapetalus species in this review.
A. hexapetalus probably native to South India and largely cultivated in India, Sri-Lanka, Burma, Southern China, and Taiwan. In different parts of the world, it is largely known as an ornamental plant. Within India, it is indigenous to South India and very commonly cultivated in gardens throughout the country for its fragrant flowers. Plant is propagated through stem cutting and seed. Group of fruits (usually 6) grow together at the end of the long peduncle [14].

Characteristics of plant A. hexapetalus
The plant is a climber with lateral branches straight, lenticellate, glabrous, dark brown when dry, young twigs sparsely pubescent shown in fig. 1.

Leaves
The leaves are simple, alternate, petiolated (3-8 mm), exstipulate, and distichously arranged. They are thinly pubescent; oblonglanceolate 6-10 mm long, shortly acuminate, elliptic, glabrous on both surfaces with a thinly coriaceous blade, and the base is acute cuneate. The colour of the leaves is pale green when dry. The midrib of the leaf is flat on the upper epidermis and raised at the lower epidermis with lateral anastomosing veins flat on both surfaces [15,16].

Inflorescence
It has a flat peduncle, solitary or in pairs that are sparsely pubescent with two branches; 1-2 flowers; bract elliptic to oblong and bud broadly ovoid.

Flowers
The flowers are bisexual and actinomorphic, possessing 3 whorls of perianth with 3 segments in each whorl. Entire parts of floral are distinct, yellow, solitary or in pairs, 3.2-3.8 cm long, pedicels 15-20 mm long, sepals are 6 cm long that erect to reflexed sparsely pubescent. Flowers are thinly fleshy, ovate, with acute apex and pubescent. The petals are fleshy, connate below, tips reflexed petals are lanceolate above the saccate base, clothed with apprised silky hairs. Inner petals are narrower, flat, 20-30 x 3-6 mm; torus convex; stamen are oblong. Apical possess a cylindrical carpels prolongation flat, obovoid, glabrous with 2-3 cm in diameter. The stamens are very short and tightly packed generally fertile with central anther portion, a distal pad of fleshy connective tissue, and a short fleshy basal portion [17,18].

Seed
Two large, ellipsoid oblong little flattened, deeply grooved on one side, more than 13 mm long. Sectioned seeds reveal channels or partitions in the ruminate endosperm [20]. Medicinal plants and traditional systems of medication is been continuously allied as the backbone of these systems. India has an ironic natural heritage of traditional systems of medicine. These traditional systems of medications with the perceptions of safety, efficacy, and quality will urge to protect the customary heritage [21]. The flowers of A. hexapetalus are tonic and stimulant. The fruits and the bark are used to treat fever, diarrhea, skin diseases, wounds, ulcers, inflammation, cough, asthma, and bronchitis. The leaves extract has antibacterial, antifertility, and antifungal activity [22]. The pulp of ripened fruits has been used traditionally in some parts of Assam for the fungal infections in the domestic animals the tribes of Malay Archipelago use a decoction of leaf for treatment of Cholera. Roots of this plant are used to treat Malaria according to Chinese traditional systems of medicine. The volatile oil from the flower in the Unani system of medicine is used in aromatherapy [23,24]. In Ayurveda and Siddha systems of medicines flowers used as tonic and stimulant. Fruit and bark are used to treat fever, diarrhea, flatulence, colic, constipation, skin disorders, wound healing, cough, and bronchial asthma. The decoction of leaves used as an antimicrobial, antifertility, muscle relaxant, and cardiac stimulant [25]. Flowers used as a flavoring in tea Southern India; Sri Lanka Used in perfumery as the source of essential oils. In Salem, Tamil Nadu, Southern India used in the preparation of stimulating tea-like beverages. In Java, Indonesia, Philippines, Southern China, India whole plant is used as an ornamental plant and for screen planting in large gardens. In traditional Chinese systems of medicine prescribed for the treatment of malaria and scrofula [26][27][28].

Phytochemical composition of A. hexapetalus
The literature proposes that A. hexapetalus possess important bioactive compounds, as shown in fig. 2.

Biological and pharmacological activities of A. hexapetalus
Herbal drugs have been playing a substantial role throughout the world in treating and preventing several diseases [42]. The essential oil of this plant has shown excellent antihelmintic property against tapeworms, earthworms, and roundworms [43]. Fruits of this plant are recoded as containing fixed and volatile oil, glycosides, and resins. Extracts are reported to show hypotensive and spasmogenic, as well as cardiac stimulating effects on some animals and a cardiac depressant on others [44]. Ethanolic and benzene extracts of leaves have shown irregular oestrus cycle in albino rats. Also used as a remedy to treat abdominal and kidney pains [45]. Decoction used in the treatment of cholera. It is used as a cardiotonic, cardiac stimulant, muscle relaxant, and uterine stimulant [46][47][48][49][50][51] (table 2).  [53]. Grainge M, et al. 1987 in this investigation tested leaf extracts of A. hexapetalus against Xanthomonas Campestris and Drechslera oryzae (Cochliobolus miyabeanus) and 10 other bacterial strains. The leaf extracts showed inhibition in the growth of X. campestris pv and campestris [54]. Haseena S, et al. 2019 reported the green synthesis of CuO nanoparticles using A. hexapetalus extract by co-precipitation method. The antibacterial ability of CuO nanoparticles was determined against gram-negative E. coli pathogen by the agar-agar diffusion method. Results revealed that CuO nanoparticles showed significant antibacterial activity against gram-positive E. coli strain [55].

Antileishmanial activity
Bajaj S, et al. 2018 evaluated the in vitro antileishmanial activity of extracts of A. hexapetalus against the Leishmania donovani (L. donovani) promastigotes. The plant extracts inhibited the growth of L. donovani in vitro after 24, 48, 72, and 96 h of incubation and had 50% inhibitory concentration (IC50). The lowermost concentration of extract showed inhibition of growth of L. donovani parasites it was measured as the maximum inhibitory concentration. This indicated after incubation at 24 and 48 h. all extracts showed antileishmanial activity in a dose-dependent mode [56].

Antioxidant activity
Manjula M, et al. 2011 reported screening of antioxidant and antimicrobial activity of A. hexapetalus flower extracts. 2,2,1diphenyl-1-picrylhydrazyl (DPPH) and reducing power method was utilized in the screening of antioxidant activity Results indicated reducing the power of extracts increased with increase in the concentration of extracts. DPPH free radical-scavenging of chloroform, methanol, aqueous extracts, and Gallic acid as standard with half-maximal inhibitory concentration IC50 values at the concentration range of 50-250μg/ml were determined as 378.73μg/ml,72.0μg/ml,118.49μg/ml and 68.75μg/ml respectively [57]. Satya K, et al. 2017 determined free radical scavenging activity of methanol extract of A. hexapetalus utilizing ascorbic acid as standard antioxidant. DPPH method was used for screening of antioxidant activity. A. hexapetalus extracts showed a 52.99% scavenging activity in the DPPH assay [58].  carried out in vitro free radical scavenging assays of A. hexapetalus flower extract. This assay was performed by determination of total antioxidant capacity, reducing ability Nitric oxide radical, and scavenging of hydrogen peroxide. A. hexapetalus flower extract effectively scavenged free radicals at all different concentrations and showed its potent antioxidant activity [59]. Bollapragada M, et al. 2018 determined in vitro antioxidant activity of methanolic extract of A. hexapetalus leaves. The antioxidant assay was determined using DPPH, ferric reducing antioxidant power, and total antioxidant capacity. The activity of methanolic extract at lower concentrations 10-50 μg/ml. IC50 values were 33.95 μg/ml in comparison to that of standard ascorbic acid 33.2μg/ml. The results demonstrated that the extract of A. hexapetalus had a significantly higher (p<0.05) value. Hydroxyl radical scavenging activity of methanolic extract of A. hexapetalus showed 200.3±3.11 μg/ml IC50 value [60].

Mosquito repellent activity
Rajabu A, et al. 2014 investigated mosquito repellent activity of their essential oils of leaves and stem bark of A. hexapetalus. The composition of oil from the stem bark and leaves showed both βcaryophyllene oxide and 11-hexadcyn-1-ol as the main components. Essential oil from the leaves of A. hexapetalus displayed strong activity with Repellent concentrations (RC50) values 1.81×10-5 mg/cm 2 and 2.79×10-5 mg/cm 2 . Against mosquitoes female Anopheles gambiae s. s. The repellency activity of essential oil in comparison to standard citronella oil used (RC50 = 4.1×10-6 mg/cm2) was found to be moderate [61]. Karthik Y, et al. 2012 evaluated the antifertility activity of hydroalcoholic extract of A. hexapetalus leaves in vivo on male Wistar rats and female Sprague Dawley rats and rabbits. In this study, male Wistar rats were orally fed with hydroalcoholic extract at a concentration of 200, 400, 600 mg/kg. p. o, for 45 d. This effect of the extract on reproductive organs, sperm count, serum testosterone, testicular cholesterol, and alkaline phosphates levels was noted and changes in testicular histology were compared with the control rats. Progestogenic activity assay was determined by pregnancy maintenance test in female Sprague Dawley rats. The result showed a decrease in weight of testis, seminal vesicles and sperm count, serum testosterone testicular cholesterol and alkaline phosphates level and the histological examination of testis demonstrated that decrease in the diameter of seminiferous tubule server hypercellularity of Leydig cells. The Pregnancy maintenance assay displayed non-progestogenic, progestational, or antiprogestational activities [62].

Hepatoprotective activity
Veena R, et al. 2016 screened the alcoholic extract of A. hexapetalus for in vivo hepatoprotective activity in rats, which were intoxicated by paracetamol. The hepatoprotective activity and oxidative stress of A. hexapetalus were determined using parameters like serum enzyme levels like SGOT, SGPT, ALP, ACP, Total Bilirubin, Direct Bilirubin, SOD, GSH, Vitamin C and catalase levels of the animals treated with hepato-toxic paracetamol. The alcoholic extract of A. hexapetalus overturned the hepatotoxicity that was induced by paracetamol in the rats, indicating their hepatoprotective action. This histopathological studies reveled structural damage occurred due to paracetamol, which was further supported by the DNA fragmentation studies that showed the absence of fragmentation of DNA in alcoholic extract-treated groups, indicating the hepatoprotective activity of A. hexapetalus [63].

Anthelmintic activity
Niaz M, et al. 2012 investigated the methanolic extract of bark of A. hexapetalus for in vitro anthelmintic and cytotoxic activities. Brine shrimp lethality bioassay was used for the evaluation of the cytotoxic activity. The methanolic extract presented noteworthy cytotoxic potential (LC50 value of 7.688 μg/ml) in comparison to standard vincristine (0.839 μg/ml). To evaluate anthelmintic activity where albendazole was used as the reference standard and methanolic extract of barks (50 mg/ml) showed paralysis of the worms at 68.33 min and death at 84.0 min. In comparison to the standard albendazole at the concentration of 10 mg/ml worms were paralyzed and killed at the respective 17 min and 48 min. Thus it confirmed the significant anthelmintic activities of bark extract of A. hexapetalus [64].  reported antipyretic activity of ethanolic extract of flowers of A. hexapetalus tested on yeast induced pyrexia in albino rats. To carry out screening of the antipyretic flower extract at oral doses of 100, 250, and 500 mg/kg was used. A significant reduction in body temperature on yeast induced pyrexia was observed at a dose of 500 mg/kg body weight when compared with standard Paracetamol drug (200 mg/ml). [65] CONCLUSION The present review comprises of a perspective to show current advances in the phytochemical and pharmacological activities of A. hexapetalus as a prognostic therapeutic agent. According to the literature review, it is uncovered that A. hexapetalus possesses valuable therapeutic uses as antimicrobial, antileishmanial, antioxidant, antifungal, antifertility, anthelmintic, mosquito repellent, hepatoprotective, and cytotoxic activity. It has a potent free radical scavenging property which sufficiently demonstrated in different assays. Its potential as an antioxidant and antimicrobial agent needs to be undermined in future research work. It may perhaps be advised that alkaloids, terpenoids, anthraquinones, butyrolactones, flavonoids, neolignans, phenolic compounds, and leucoanthocyanins might be valued as a principal molecule in the development of new drugs to treat various diseases. Various unique constituents in the form of flavonoids of A. hexapetalus can also be chemically modified or used as "lead" for developing more effective drug molecules. Therefore, extensive pharmacological and phytochemical screening, together with the pharmacokinetic and toxicological assay, will be a focus for forthcoming investigation. Furthermore, a well-designed study to measure its toxicity from its long-term use is another urgency. This review article emphasizes the potential of A. hexapetalus that can be employed in new therapeutic drugs and will offer the base for future research on the application of herbal medicines.

ACKNOWLEDGMENT
The authors would like to extend our gratitude to Mr. Albert W. D'Souza, Chairman Adel Education Trust and Dr.(Mrs.) Savita J. Tauro, Principal, St. John Institute of Pharmacy and Research, Palghar for the generous support, motivation, encouragement and providing necessary facilities to carry out inscription of this manuscript.

AUTHORS CONTRIBUTIONS
Abhijeet Puri: Being a single author, I carried out a compilation of literature, an inscription of a manuscript, read-through, revising, and improving the standard of the manuscript. No other co-author contributed to this work.