Natural Product Radiance, Vol. 8(2), 2009, pp.190-197 Review Paper

Kigelia africana (Lam.) Benth. — An overview Sangita Saini1*, Harmeet Kaur1, Bharat Verma2, Ripudaman1 and S K Singh3 1P.D.M. College of Pharmacy, Bahadurgarh 125 407, Haryana, 2Deptt of Forensic & Toxicology, All India Institute of Medical Sciences, Delhi-110 029, India 3Department of Pharmaceutical Sciences, Guru Jambeshwar University of Science & Technology, Hisar-125 001, Haryana *Correspondent author, E-mail: [email protected] Received 5 April 2008; Accepted 6 October 2008 Abstract perceived characteristics such as Our world harbours a rich source of medicinal which are used in treatment of bitterness, astringent taste or smell but wide range of diseases. The present review highlights the traditional uses, chemical constituents also because of forces that it seems to and pharmacological properties of africana (Lam.) Benth. syn. K. pinnata (Jacq.) emit in connection with its location, DC. This has great potential to be developed as drug by pharmaceutical industries but before orientation and association with other recommending its use in modern system of medicine, clinical trials are to be done. plants. It has a long history of use by rural Keywords: Kigelia, Kigelia africana, Kigelia pinnata, Cucumber , Sausage tree, and African countries particularly for Balmkheera, Isopinnatal, Kigelin, Chemical constituents, Medicinal properties. medicinal properties. Several parts of the IPC code; Int. cl.8 — A61K 8/97, A61K 36/18, A61P 1/12, A61P 17/00, A61P 25/00, plant are employed for medicinal A61P 29/00, A61P 31/00, A61P 33/00, A61P 35/00, A61P 39/06 purposes by certain aboriginal people9. In Introduction Savannah and riverine area3-6. The plant Malwi during famine the are roasted Nature has been a source of grows approximately 10 m high with to eat. Baked are used to ferment medicinal agents for thousands of years odd pinnately, composite opposite beer and boiled ones yield a red dye. Most and an impressive number of modern , leaflets are ovate to oblong in shape commonly traditional healers used it to drugs have been isolated from natural and 4-18 cm long. The are found treat a wide range of skin ailments like, sources, many of these isolations were in spring or summer season, hanging fungal infections, boils, psorasis and based on the uses of the agents in ancillary panicles up to 2 m long, corolla eczema. It also has internal application traditional medicines1. This plant-based of fused petals, irregularly bell shaped, including the treatment in dysentery, traditional medicine system continues to 9-13 cm long two lipped, yellowish ringworm, tape-worm, post-partum play an essential role in health care with on outside and purple on inside. Fruits haemorrhage, malaria, diabetes, 10 about 80% of the world’s inhabitants are oblong, hard 30-50 cm long, pneumonia and toothache . The tonga relying mainly on traditional medicines hanging on stalk for several month but women of Zambezi valley regularly apply for their primary health care2. Kigelia not split easily7, 8. The present review cosmetic preparation of Kigelia fruits to africana (Lam.) Benth. syn. K. highlights the contribution of their faces to ensure a blemish free 11 pinnata (Jacq.) DC. of K. africana in modern system of herbal complexion . In the folk medicine, the family is widely distributed in the South, medicine for new drug development. fruits of the plant are used as dressing for Central and West . It is known as There is correlation established between ulcers, purgative and to increase the flow 12 the cucumber or sausage tree because of the active constituents and their uses in of milk in lactating women . Roots are the huge fruits (average 0.6 m in length different fields. Some cosmetics said to yield a bright yellow dye. The Shona and 4 kg in weight), which hangs from preparations available in market are also people tend to use the bark or root as long fibrous stalks. It is also known as mentioned. powder or infusion for application to Balmkheera in Hindi and distributed all ulcers, drunk or applied in the treatment over India but found abundantly in West Traditional Uses of pneumonia, as a gargle for toothache, Bengal. It is found mostly in wetter areas The kigelia plant have medicinal and the leaves in a compound applied for 13 and spread abundantly across wet properties not only because of its backache . In West Africa, the root and

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Tree Leaves Fruits

Kigelia africana unripe is used as a vermifuge and as be norviburtinal and β-sitosterol. Gouda known compounds, stigmasterol and a treatment for haemorrhoids and et al isolated a furanone derivative, lapachol from the roots of this plant. rheumatism14. 3-(2'-hydroxyethyl)-5-(2″-hydroxypropyl)- Kigelin, β-sitosterol, 3-dimethyl kigelin The bark is traditionally used as dihydrofuran-2(3H)-one and four and ferulic acid has also been isolated a remedy for syphilis and gonorrhea. The iridoids, 7-hydroxy viteoid II, 7-hydroxy from its bark22. Five minor constituents fruits and bark ground and boiled in water eucommic acid, 7-hydroxy-10- isolated from root bark consisted of two are also taken orally or used as an enema deoxyeucommiol and 10-deoxyeucommiol known naphthaquinones and three new in treating children’s stomach ailments– together with seven known iridoids, aromatic monoterpenes23, 24. Two non- usually worms. Unripe fruit is used in jiofuran, jioglutolide, 1-dehydroxy-3,4- quinonoid aldehydes, norviburtinal and Central Africa as a dressing for wounds, dihydroaucubigenin, des-p-hydroxybenzoyl pinnatal were obtained from the root bark haemorrhoids and rheumatism. Venereal kisasagenol B, ajugol, verminoside and 6- by Joshi et al25. Biologically monitored diseases are commonly treated with the transcaffeoyl ajugol from the fruits19. They fractionation of the butanol extract from tree extracts usually in palm wine as oral also isolated a phenylpropanoid derivative stem bark led to the isolation of three medication15. identified as 6-p-coumaroyl-sucrose known iridoids: specioside, verminoside together with ten known phenylpropanoid and minecoside. All these irridoids were Chemical Constituents and phenylethanoid derivatives and a isolated earlier from root bark26, 27 and The K. africana plant has many flavonoid glycoside from the fruits20. The further characterized. All the compounds medicinal properties due to the presence structures of the isolated compounds were were identified by comparing their UV, IR of numerous secondary metabolites. These characterized by different spectroscopic and NMR data with the literature compounds include irridoids, flavonoids, methods. Govindchari et al isolated values28, 29. Table 1 summarizes some of and naphthoquinones and volatile kigelin as the major constituent of the the pharmacological activities of different constituent, etc16-18. Pinnatal and plant from the root heartwood21. The phytoconstituents of K. africana. isopinnatal were isolated from tropical structure of kigelin was established by that belongs to the plant family of chemical methods and spectroscopic Pharmacological Activities Bignoniaceae. Pinnatal was found in a techniques as 8-hydroxy-6, 7-dimethoxy- Antibacterial and Antifungal root bark extract of the plant. Thin layer 3-methyl-3, 4-dihydroisocoumarin and it A biologically monitored chromatography (TLC) examination of the was concluded that the absolute fractionation of the methanolic extracts most active fractions of both stem bark configuration at C-3 was R on the basis of of the root and fruits led to the isolation and fruits showed the presence of the same spectral analysis. They also isolated of the naphthoquinones, kigelinone, major components which were found to 6-methoxymellein together with two iso-pinnatal, dehydro-α-lapachone, and

Vol 8(2) March-April 2009 191 Review Paper lapachol and the phenylpropanoids, showed significant antimicrobial activity, support the traditional use of the plant in p-coumaric acid and ferulic acid as the which could be partially explained by the therapy of bacterial infections32. A disc compounds responsible for the observed activity of the iridoids present31. The fruits diffusion susceptibility test was used to antibacterial and antifungal activity30. The are a popular source of traditional screen concentrated extracts from the bark compounds isolated were tested for their medicine throughout Africa. But the stem of 3 medicinal plants (Alstonia boonei activity against Staphylococcus aureus, bark has been widely analysed for de Wild., Morinda lucida Benth. Bacillus subtilis, Corynebacterium pharmacological activity, yet knowledge and K. africana) for antimicrobial diphtheriae, Aspergillus niger, A. of the fruits is limited, despite more activity. Solvents with different polarity flavus, Candida albicans and extensive use in traditional remedies. were used for the extraction (methylene Pullularia pullularis (Aureobasidium Crude extracts of stem bark and fruits chloride, ethyl acetate, 95% ethanol sp.). The steroids and flavonoids are were prepared with distilled water, ethanol and acetonitrile), and the extracts hygroscopic and have fungicidal or ethyl acetate. In the microtitre plate were tested against Candida properties. bioassay, stem bark and fruit extracts albicans, Staphylococcus aureus, Chemical investigation showed showed similar antibacterial activity Enterococcus faecalis, Streptococcus that the aqueous extracts of the stem bark against Gram negative and Gram positive faecalis, Escherichia coli and of the plant contain iridoids as major bacteria. A mixture of three fatty acids Pseudomonas aeruginosa. The components. In the light of the traditional exhibiting antibacterial effects was patterns of inhibition varied with the plant uses of this plant, antimicrobial isolated from the ethyl acetate extract of extract, the solvent used for extraction and activities of the aqueous extracts and the fruits using bioassay-guided the organism tested. The largest zones of two major iridoids were tested fractionation. Palmitic acid, already inhibition were observed for ethanol against Bacillus subtilis, Escherichia known to possess antibacterial activity, was extracts of K. africana against S. coli, Pseudomonas aeruginosa, the major compound in this mixture. aureus and P. aeruginosa. S. aureus Staphylococcus aureus and Candida These results confirm antibacterial activity was the most inhibited microorganism. albicans. The crude aqueous extracts of K. africana fruits and stem bark, and No inhibitory effects were observed against

Table 1: Pharmacological activities of different phytoconstituents of Kigelia africana

Activity Irridoids Naphthoquinone Meroterpenoid Coumarin Lignans Sterols Flavonoids naphthoquinones derivatives

Anticancer + + + + + + + Mollusicidal + - - - - - + Syphilis and Gonorrhea + + - - - + + Antidiarrhoeal + - - - - - + Antiulcer + - - - - - + Antifungal - - + - + + + Antimalarial - - + - + - - Antiinflammatory/analgesic + + + - - + + Antibacterial + + + - + + - Postpartum Haemorrhage + - - + - + - Pneumonia + - - - - + +

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C. albicans. The extent of the inhibition analog of naphtha [2, 3-b] furan-4,9 to γ-sitosterol which is comparable to of the bacteria was related to the dione (furanonaphthoquinone [FNQ]) standard, lapachol39. concentration of the plant extract33. compounds, was isolated from the inner bark of the South American trumpet tree, Analgesic and Anti-inflammatory Antineoplastic Tecoma ipe Mart [syn. T. The analgesic effect of the stem The crude dichloromethane avellanedae Speg., Tabebuia bark of K. africana has not been extracts of stem bark and fruit showed impetiginosa (Mart. ex DC.) Standl., T. previously reported and the mechanism cytotoxic activity in vitro against cultured cassinoides (Lam.) DC.], or K. by which it occurs is mostly likely via the melanoma and other cancer cell lines africana, which is known to have inhibition of prostaglandin synthesis as using the Sulphorhodamine B assay, which antitumour activity35. Kigelia contains the indicated by its inhibition of acetic acid- was used for bioassay-guided fractionation. constituent lapachol that is effective in the induced mouse writhing. Also, it is known TLC examination of the most active treatment of solar keratosis, skin cancer that centrally acting analgesic drugs fractions of both stem bark and fruits and kaposi sarcoma (an HIV-related skin elevate the pain threshold of mice towards showed the presence of the some major ailment)36. Serial dilutions of standardised heat and pressure40, 41. The ethanolic components which were found to be water, ethanol, and dichloromethane extract was evaluated for analgesic norviburtinal and β-sitosterol. extracts of the stem bark and fruits of K. property using acetic acid induced mouse Norviburtinal was found to be the most africana were tested for their growth writhing and hot plate reaction time and active compound but had little selectivity inhibitory effects against four melanoma anti-inflammatory property using the for melanoma cell lines while isopinnatal cell lines and a renal cell carcinoma line carrageenan induced paw edema and its also showed some cytotoxic activity. (Caki-2) using two different (MTT and probable mechanism evaluated in mice β-Sitosterol was found to be SRB) assays. Lapachol, a possible and guinea pigs. The extract showed a dose comparatively inactive. HPLC analysis of constituent of these extracts, together with dependent significant reduction of the the crude extract showed that the amount known therapeutic antineoplastic agents, number of writhes (P<0.001) with 500 of norviburtinal present in the plant was also tested in the same way. The IC50 mg/kg body weight dose giving the highest material did not account for all of the of each extract was measured after extracts reduction. The extract showed an activity of the total extracts34. Investigation were diluted to 100 µg/ml in 1% ethanol insignificant elongation of the hot plate into the biological activity of K. africana or water. Significant inhibitory activity was reaction time (P>0.05). In the has focussed on its antibacterial activity shown by the dichloromethane extract of carrageenan induced paw edema, a dose and its cytotoxic effects against cancer cell the stem bark and lapachol (continuous dependent significant inhibition was lines. These are related to the traditional exposure). Moreover, activity was dose- observed (P<0.001) between the second uses of bark and fruit extracts for treating dependent, the extract being less active and fifth hour. It is clear that the ethanolic diseases caused by microorganisms and after one hour exposure. Chemosensitivity stem bark extract has significant analgesic as a remedy for skin cancer. Considerable of the melanoma cell lines to the stem and anti-inflammatory activity. Inhibition in vitro cytotoxicity has been bark was greater than that seen for the of the synthesis of prostaglandins and demonstrated by extracts of the fruits and renal adenocarcinoma line. In marked other inflammatory mediators probably barks and the iridoid-related compound contrast, sensitivity to lapachol was similar accounts for the analgesic and norviburtinal and the naphthoquinone amongst the five cell lines37. The antitumour anti-inflammatory properties42. isopinnatal have been shown to be two of activity of Bignoniaceae is probably due Chemical analysis of a polar extract of the compounds responsible. The mainly to its naphthaquinoids which among K. africana fruit indicated the presence compounds also show cytotoxicity against them, for example lapachol, have been of verminoside, an iridoid, as a mammalian cell lines. Kigelinone,5-or 8- considered as candidates for clinical use38. major constituent, and of a series of hydroxy-2-(1-hydroxyethyl) naphtha [2, 3- In vitro cytotoxic activity found in root polyphenols such as verbascoside. In vitro b] furan-4, 9 dione, a phytochemical bark extract of K. africana is attributed assays showed that it had significant

Vol 8(2) March-April 2009 193 Review Paper anti-inflammatory effects. Cytotoxicity and Anti-malarial and is superior to chloroquine and cutaneous irritation of the extract and of Four naphthoquinoids isolated quinine30, 46-49. compounds verminoside and verbacoside from root bark of the plant were assessed were investigated. The crude extract did in vitro against chloroquine-sensitive CNS stimulant not affect cell viability in vitro either in (T9-96) and chloroquine-resistant (K1) The ethanolic stem bark extract cells grown in monolayers (ML) or in the Plasmodium falciparum strains and of K. africana has a potential central reconstituted human epidermis (RHE, for cytotoxicity using KB cells. The most nervous system (CNS) stimulant effect that 3D) model; neither caused release of active 2-(1-hydroxyethyl) naphtha [2, 3- can be explored for therapeutic advantage pro-inflammatory mediators or b] furan-4, 9-dione showed good as an alternative treatment in medical histomorphological modification of antiplasmodial activity against both conditions associated with dizziness, 43, 44 RHE . strains; IC50 values were 627 nM for the drowsiness and sedation. CNS stimulant

Supercritical CO2 extracts of K1 and 718 nM for the T9-96 strains. The effect of the ethanolic stem bark extract

Kigelia have been shown to be more IC50 values were comparable to those of was studied in mice using the barbiturate effective than Indomethacin a potent related naphthoquinones isolated from induced sleeping time and the Rota rod synthetic anti-inflammatory (Table 2). K. africana and these compounds also bar to check the extract’s effect on muscle Two different anti-inflammatory assays: exhibited marked toxicity against coordination. The results showed that the inhibition of “oxidative burst” on human endothelial ECV-304 cells due to their extract at all doses tested reduced the neutrophils and inhibition of antiplasmodial effect. An antimalarial duration of sleeping time when compared cyclooxygenase (COX-2) were done. K. compound known as lapachol has been to the control group that received distilled africana extracts were tested against a extracted from the root. Another water. This difference in sleeping time was control (buffer, neutrophils and WST-1) compound (quinone) obtained from the significant (P<0.0001 at all doses tested) and against indomethacin45. Absorbance wood shows anti-malarial activity against and this was also found to be dose is measured at 450nm. drug resistant strains of P. falciparum dependent. Its effect was also compared with caffeine (a known stimulant) and the extract gave a shorter duration of sleeping I time compared to caffeine, (P<0.05 at o o o 400 mg/kg dose) indicating better o s o o o s N stimulant properties. In comparison with o o N N o s N diazepam the extract at all doses tested, o s o N N N N o reduced form of electron also gave a shorter duration of sleep mediator o Na N (P<0.0001). On the Rota rod, the extract o N o had no sedative effect as the animals o maintained their balance on the rod WST 1 WST 1- Formazan through the entire period of the experiment50.

Table 2 : COX-2 activity of mixtures containing Kigelia africana Antiprotozoal A fractionation of stem bark and Plant parts used Extract Cox-2 activity(µg/ml)(IC50) root bark extracts of the plant allowed the isolation of one furanonaphthoquinone, Fruit Chloroform/ethanol/water 0.8 2-(1-hydroxyethyl)-naphtho-[2, 3-b] Fruit Chloroform/methanol 0.8 furan-4, 9-quinone and three Indomethacin - 32 naphthoquinoids: isopinnatal, kigelinol,

194 Natural Product Radiance Review Paper and isokigelinol. Compounds 2-(1- activity was provided by the reduced fecal ingredients reduces wrinkle depth and hydroxyethyl)-naphtho-[2, 3-b] furan-4, output and protection from castor oil- fine lines leaves skin smooth, promotes 9-quinone and isopinnatal possessed a induced diarrhoea in the extract-treated tone elastic naturally lightens pronounced activity against both animals. The extract remarkably decreased pigmentation, reduces skin blemishes, Trypanosoma brucei brucei and T. b. the propulsive movement of the deep cleanses and eliminates impurities. rhodesiense bloodstream forms (IC50: gastrointestinal contents. On the isolated Tightens the delicate skin around the eyes. 0.12 µM and 0.045 µM, respectively for guinea pig ileum, the extract did not Refines the skin and stimulates naphthoquinones and isopinnatal 0.37 µM appreciably affect acetylcholine and circulation. Its fruit pulp and extracts can and 0.73 µM) with a certain selectivity histamine induced contractions, but be exploited in the nutraceutical, dietary/ compared to KB cells (IC50:3.9 µM and significantly reduced nicotine evoked herbal supplement, pharmaceutical, 14.8 µM for naphthoquinones and contractions. The i.p. (intra peritoneal) cosmeceutical and other products63-65. 51-53 isopinnatal, respectively) . Compounds LD50 of the extract in mice was estimated Specific products could include: (i) anti- kigelinol and isokigelinol had a to be 785.65 ± 24 mg/kg55. melanoma and after-sun applications, less potent antitrypanosomal activity anti-inflammatory agent, antioxidant with IC50 values. Although little Other activities agent and Cosmetic skin tightening active ethnopharmacological evidence exists, the De Santos et al56 and Sant’ana ingredient. naphthoquinones are active against several et al57 tested the activity of lapachol and protozoal species associated with disease. 2-hydroxy 3-alkyl naphthoquinones Conclusion Serial dilutions of extracts from the stem possessing nitrogenated alkyl chains K. africana is an interesting bark were tested for their growth against the snail Biomphalaria example of a plant, used in traditional inhibitory effects against Entamoeba glabrata lapachol and isolapachol medicine for many years, but which is now histolytica. Butanol extract of stem bark showed strong mollusicidal activity against attracting interest and use far beyond its exhibited in vitro antiamoebic activity. adult snail58, 59. The plant shows the potent original geographical range. Experiments Three known iridoids specioside, antioxidant effects due to caffeic acid into the effect of Kigelia extracts and some verminoside and minecoside were derivatives and compounds unique to of the pure compounds contained therein, isolated, purified and identified by Kigelia. An ethanol extract of kigelia has on microorganisms and cancer cells have comparing their spectral data with the been shown to possess some antioxidant shown that the traditional use of this plant literature values. These compounds were activity60, 61. The plant shows antidiabetic is given considerable justification. The tested against HK-9 strain of E. activity also62. chemical constituents of the plant provide histolytica for their in vitro antiamoebic molecules, which could be of immense evaluation and Metronidazole was used as Cosmeceutical Preparations medicinal applications. Considering the reference drug in all the biological The kigelia plant contains many medicinal purposes for which it is experiments. It is found that verminoside steroidal saponins and two flavonoids used, there is enormous scope for future has two fold antiamoebic activities as (luteolin and quercitin). Its fruit extract research on K. africana, and further compared to the standard drug while is useful to develop the bust and reinforce pharmacological investigation is specioside showed comparable activity the strength and stability of Breast collagen warranted. with metronidazole54. fibers. A cream made from fruit extract is used to remove sunspots known as ‘Solar References Antidiarrhoeal Keratosis’ particularly on the face and 1. Cordell GA, Biodiversity and drug discovery: a Aqueous extract of K. hands. A number of skin creams, scalp symbiotic relationship, Phytochemistry, africana was screened for antidiarrhoeal application and shampoos are derived 2000, 56, 463-480. activity using experimental animal from the fruit. Some common cosmetics 2. Farnsworth NR, Akerele O and Bingel AS, models. Evidence for antidiarrhoeal made from kigelia as one of the active Medicinal plants in therapy, Bull WHO, 1985, 63, 965-981. Vol 8(2) March-April 2009 195 Review Paper

3. Cragg GM and Newman DJ, Medicinals for medicinal and poisonous plants of Southern 26. El-Sayyad SM, Flavonoids of the leaves and the millennia, Ann NY Acad Sci, 2001, and Eastern Africa, Livingstone, London, fruits of Kigelia pinnata, Fitoterapia, 953, 3-25. 1962, p. 52. 1981, 4, 189-91. 4. Heine H, In: Flora of Tropical West Africa, by 16. Houghton PJ, The sausage tree (Kigelia 27. Houghton PJ and Akuniyli DN, Irridoids from J Hutchinson and JM Dalziel (Eds), 2nd Edn, pinnata): ethnobotany and recent scientific Kigelia Pinnata bark, Fitoterapia, revised by FN Hepper, 1963, Vol. 2, p. 385. work, South Afr J Bot, 2002, 68 (1), 1993, 64, 183-186. 14-20. 5. Sofowara A, The present status of knowledge 28. El- Naggar SF and Doskotch RW, Specioside: of the plants used in traditional medicine in 17. 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