A Medicinal Halophyte Ipomoea pes-caprae (Linn.) R. Br.: A Review of Its Botany, Traditional Uses, Phytochemistry, and Bioactivity

Ipomoea pes-caprae (Linn.) R. Br. (Convolvulaceae) is a halophytic plant that favorably grows in tropical and subtropical countries in Asia, America, Africa, and Australia. Even though this plant is considered a pan-tropical plant, I. pes-caprae has been found to occur in inland habitats and coasts of wider areas, such as Spain, Anguilla, South Africa, and Marshall Island, either through a purposeful introduction, accidentally by dispersal, or by spreading due to climate change. The plant parts are used in traditional medicine for treating a wide range of diseases, such as inflammation, gastrointestinal disorders, pain, and hypertension. Previous phytochemical analyses of the plant have revealed pharmacologically active components, such as alkaloids, glycosides, steroids, terpenoids, and flavonoids. These phytoconstituents are responsible for the wide range of biological activities possessed by I. pes-caprae plant parts and extracts. This review arranges the previous reports on the botany, distribution, traditional uses, chemical constituents, and biological activities of I. pes-caprae to facilitate further studies that would lead to the discovery of novel bioactive natural products from this halophyte.


Introduction
Ipomoea pes-caprae (Linn.) R. Br. is a widely distributed halophytic plant belonging to the family Convolvulaceae. This species trails and colonizes sand dunes along tropical and subtropical coastal beaches, preventing the erosion of dunes [1]. Moreover, I. pes-caprae occurs across coastal strands of tropical North and South America, Asia, East-and West-Central Africa, and Australia ( Figure 1) [2]. This plant is commonly called beach morning glory, bay hops, or railroad vine.
Traditionally, I. pes-caprae has been used for many medicinal purposes. For example, Australian Aborigines apply the heated leaves to wounds, skin infections, and inflamed sores, as well as to stings from poisonous fishes, manta rays, and insects [3]. In some parts of India, it is used in ritual baths to alleviate evil spirits. In Brazil, it serves an important role in traditional medicine to treat inflammation, gastrointestinal disorders, and pain [4]. Infusions of I. pes-caprae leaves have been recommended for treating hypertension and kidney ailments. At the same time, decoctions of the same plant are used to treat digestive disorders, internal and external pains, dysentery, inflammations, fatigue, strain, arthritis, and rheumatism [3]. Many natural product chemistry studies have been conducted on various parts of I. pes-caprae, which provides a scientific basis for certain uses of the plant in folk medicine. For instance, Pothula and Kanikaram evaluated the in vitro antimalarial activity of the root extracts of I. pes-caprae, which indicated that the methanolic extract possesses an excellent antimalarial activity with an half-maximal inhibitory concentration (IC 50 ) value of 15 µg/mL against Plasmodium falciparum strain 3D7 [5]. The phytochemical screening of the extracts of I. pes-caprae also revealed the presence of secondary metabolites, such as alkaloids, triterpenes, flavonoids, tannins, coumarins, carbohydrates, phenols, saponins, phlobatannins, and steroids [5]. The known uses of this plant in traditional medicine can be attributed to these secondary metabolites.
In general, secondary metabolites with various chemical scaffolds have been isolated from I. pes-caprae, exhibiting a wide range of biological activities. This review classifies and categorizes these isolated natural products from I. pes-caprae according to their biological activities from previous studies.

Botany
The root of I. pes-caprae is large and thick, about 3 m long, and 5 cm in diameter. The stem of this plant is succulent, running along the ground and rooting at the nodes [6]. The stem is green in color, herbaceous, prostrate, cylindrical, up to 30 cm height bearing numerous branches, and 0.3-0.4 cm in thickness; the odor and taste are characteristic with a smooth outer surface [7]. The leaves are simple, alternately arranged, dark green, and glabrous. The leaf shape can be variable but is typically ovate, orbicular, or oblong. The leaf base is truncate to shallowly cordate, and the apex is usually notched to deeply cleft but is sometimes rounded or truncated. The petioles vary in length, ranging from 2 to 15 cm. On young leaves, the petioles are commonly reddish, becoming yellowish-green as they age. There is a pair of nectar-producing glands on the underside of each leaf blade at its juncture with the petiole. These nectaries are red on new leaves, turning black with age, attracting ants, which defend the plant against herbivorous insects [6]. Its characteristic goat footprint-like leaf shape is a descriptive anatomical feature for naming the species. I. pes-caprae has characteristic pinkish lavender funnel-shaped flowers (6.4-7.6 cm wide) that bloom throughout the summer and fall [3]. The fruits are ovoid to flattened-globose, and capsules are dehiscent, usually measuring 1.3-1.9 cm long and wide. The seed is rounded to trigonous (three-sided), covered with dense, velvety hairs, and is 1.5-2.5 cm long [6].
I. pes-caprae found distributed on sandy beaches or in sunny roadside areas with a characteristic high-temperature and dry environment exhibits great salt tolerance and drought resistance [8]. As a typical halophyte, I. pes-caprae has a high-nutrient-utilization efficiency and plays important roles in sand fixation, wind resistance, landscape greening, and ecological restoration of the vegetation in tropical and subtropical coral islands and coastal zones [9]. The development of adventitious roots are important for the growth and survival of I. pes-caprae. When the stems are broken by a storm or when the stolons closer to the sea are washed away, they regrow quickly by vegetative reproduction [10]. The vines of I. pes-caprae easily sprout adventitious roots, and the depth of primary roots can reach 3 m, to make sure the plant is able to access water [11]. As a measure of reducing or eliminating osmotic stress and the toxic ions from seawater, I. pes-caprae accumulates large amounts of saline ions in vivo and has evolved a series of salt-tolerant mechanisms as an adaptive response to high-salt environments [12]. Additionally, the waxy and succulent leaf surface helps to prevent osmotic-stress damage. This characteristic allows I. pes-caprae to absorb water with ease and limit the stomata transpiration, and thus aid strong drought tolerance under high temperature and strong light [12]. I. pes-caprae is more tolerant to saline stress than to water stress, because its ability to accumulate solutes decreases at high-water-stress levels. Thus, it has a low inherent water-stress tolerance for long drought periods [13].

Establishment of I. pes-caprae in New Habitats
According to the Global Register of Introduced and Invasive Species, a few I. pes-caprae occur in Spain, Anguilla, and South Africa, as invasive species [14]. Similarly, there are reports of this species on Marshall Island, where it is referred to as 'topo' and considered an invasive species. Even though the plant is unknown to many in Marshall Island, the stems of this spreading vine are sometimes used for children's jump ropes and medicinal use, although not clearly defined.
Interestingly, there are a few reports on the occurrence of large populations of I. pescaprae in inland habitat, a plant originally known for colonizing sand dunes along coastal beaches [15,16]. Ridley stated that I. pes-caprae was never found inland, except in temporal cases where the seeds were dispersed in sand [17]. Contrary to this, in 2005, Devall and Thien revealed a wide population of I. pes-caprae growing inland on Lake Nicaragua's shores, believed to have been introduced inadvertently (conveyed by traveling ships to Granada), or purposefully due to its medicinal purpose [15]. However, the landward extent of the species is often limited by dispersal, competition, and shading by plants beyond the strand [1].

Traditional Uses
According to the literature, Ipomoea pes-caprae is widely used in folk medicine to treat several diseases. The use of this plant in traditional medicine has been documented in Brazil, Mexico, Thailand, Indonesia, Bahamas, Nigeria, Papua New Guinea, French Guiana, and India [3,[18][19][20][21][22][23]. Different parts of the plant, such as the leaves, roots, seeds, and stem sap, have been employed traditionally; however, the most used part of I. pes-caprae is the leaves -either the dried leaves or the fresh ones. For instance, the dried leaves of the plant are used to treat arthritis in Nigeria [21], while the young leaves are boiled in coconut oil to treat sores in Indonesia. There are similarities regarding the traditional use of this plant to treat diseases/disorders from one country to another.
For treating gastrointestinal-related disorders and symptoms, such as dysentery, ulcer, abdominal pain, and cramps, people from Mexico and Indonesia enhance the leaves of I. pes-caprae as infusion or decoction [24]. The roots are employed for their diuretic and mild laxative actions in French Guiana [1]. In Papua New Guinea, the leaves are chewed to relieve stomach aches while other plant parts, such as the seeds, are chewed with areca nut to soothe abdominal pains and cramps among the Thais [19]. In Mexico City, I. pes-caprae is available as a drug 'rinonina' in numerous herbal markets and healthfood stores where the infusions and decoctions are used to treat functional digestive disorders [3].
I. pes-caprae leaves are used in Thailand, Malaysia, China, Mauritius, and Australia for treating skin and joint diseases with associated pain and inflammations, such as dermatitis, boil, bedsores, and stings from jellyfish and stony fish, arthritis, and rheumatism [20,22,23]. Topical application of I. pes-caprae is used in this regard. Similar to the method used in Malaysia where the juice is squeezed from the leaves and applied to the area of the fish stings, the leaves are grounded and made into a paste form with distilled vinegar in Thailand. The liquid is eventually squeezed out and applied to the affected area [25]. The topical application of I. pes-caprae leaves is similar in Australia and Papua New Guinea, where the leaves are heated on fire and applied to the sores and stings [3]. Other plant parts, such as the stem sap, have also been used for treating sore eyelids, boils, and earaches.
To alleviate strain, fatigue, and physical weakness, decoctions of the plant are used as herbal baths [26] while an infusion of the leaves in hot water is taken orally in Bimini for the same purpose [1].
Other uses of I. pes-caprae have been reported. For example, the infusion of the leaves is used for treating hypertension and kidney ailments [3]. Ipomoea pes-caprae as "Vriddhadaru" in Ayurvedic medicine has been reported to be effective in the management of diabetes [27]. In Mauritius, people suffering from hemorrhoids either take a bath with a decoction of the plant or sit in a recipe containing a hot decoction so that the vapor reaches the hemorrhoids [20]. As a ritual bath, it is believed that the use of Ipomoea pes-caprae wards off evil spirits [28].
As a comment, the traditional use of I. pes-caprae to treat strain, fatigue, weakness, pain, and inflammation resulting from sting, arthritis, and rheumatism; intestinal disorders, such as ulcers, dysentery, and cramps; skin diseases, such as boils, bedsores, and dermatitis; and diabetes have been well documented in the literature. Meanwhile, the evident methods of herbal preparation used across these regions include infusion, decoction, herbal poultices, and herbal oils. In addition, these herbal forms are mostly administered either orally or topically.

Alkaloid
Calystegine B2 (1) (Figure 2) has been isolated from I. pes-caprae. This alkaloid is a member of nortropane alkaloid. Compound 1 is a tetrahydroxy congener that binds specifically to the active sites of glycosidases, inhibiting the enzymes [29,30].

Bioactivities of I. pes-caprae
Several studies have evaluated the extracts, fractions, and isolated compounds from Ipomoea pes-caprae for biological activities. Meanwhile, the major activities reported for this plant include antioxidant, anti-inflammatory, antinociceptive, antimicrobial, collagenase inhibitory, antispasmodic, anticancer, antitumor and antiproliferative, and multidrugresistance efflux inhibitory activities. The secondary metabolites associated with these activities are discussed in the following subsections.

Antioxidant Activity
The presence of excess free radicals in the human body has been implicated in the development of diverse human-related diseases. Secondary metabolites, on the other hand, play important roles by counteracting the effects of free radicals in the body. Such metabolites are often called antioxidants. Many antioxidant substances have been identified from natural sources in past years, including I. pes-caprae. Studies on the antioxidant activity of I. pes-caprae extracts have shown that it contains phytochemicals with the potential to scavenge free radicals [2]. In a study that evaluated the radical scavenging effects of medicinal halophytes, extract of Ipomoea pes-caprae showed strong radical scavenging and reducing power on a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical with IC 50 of 32.11 µg/mL, better than the synthetic antioxidants with IC 50 of 42.15 and 35.24 µg/mL for butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), respectively [41].
Quercetin (10), which was previously isolated by Krogh et al. from the methanol extract of I. pes-caprae aerial parts, is an effective free-radical flavonoid scavenger [24]. The presence of four hydroxyl (-OH) groups on its benzo-dihydropyran ring helps to eliminate the free radicals produced in the human body and helps the body to maintain a stable state. Low concentrations of 10 inhibited lipid peroxidation by increasing low-density lipoprotein receptor (LDL-R) expression, reducing proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion, and stimulating low-density lipoprotein (LDL) uptake [42]. Majewska et al. observed that 10 has the highest DPPH radical scavenging rate among some tested flavonoids, which included luteolin, rhamnetin, isorhamnetin, and apigenin. Compound 10 had an IC 50 value of 0.028 µM, stronger than the DPPH radical scavenging activity of standard antioxidants, vitamin C (0.111 µM), and trolox (0.15 µM), used in the experiment [43].
In another study, bioactivity-guided isolation of an acetone extract of the leaves of I. pes-caprae, which was collected from the Sarabanga riverbank, Omalur, Salem District, Tamil Nadu, India, afforded a coumarin, identified as 5,7-dihydroxy-4-phenyl-2H-chromen-2-one (4). Compound 4 expressed significant and dose-dependent activity on DPPH radicals (IC 50 = 0.032 µM) and hydroxyl radicals (IC 50 = 0.055 µM) [32]. This is the first report of the antioxidant activities of 4. However, coumarins have significant therapeutic potential and possess a wide spectrum of biological activities, which is attributable to the free-OH groups at C6, C7, or C8 positions [46].
Another antioxidant compound from I. pes-caprae is salicylic acid (26), an inhibitor of oxidative stress that acts by binding iron (Fe 2+ ) that produces OH − , peroxy, and alkoxy radicals in the process of lipid peroxidation [53]. Limonene (27), α-terpineol (28), α-copaene (29), 8-cedren-13-ol (30), and β-caryophyllene (46) are some of the major constituents of the essential oil from the fresh and dried leaves of I. pes-caprae, which were collected along Grand Gaube seashore, Mauritius [20]. Compound 27 has been reported in Citrus medica for its antioxidant activities [54]. The radical scavenging ability of 46, which was evaluated by the DPPH and ferric-reducing antioxidant power (FRAP) scavenging test, produced IC 50 values of 1.25 and 3.23 µM, respectively, compared to ascorbic acid with IC 50 of 1.5 and 3.8 µM, respectively [55]. Additionally, previous studies have reported the antioxidant potential of 28 and 29 [56,57]. The essential oil of Peucedanum longifolium is abundant in 30, where it exhibited a potent DPPH free-radical scavenging ability and inhibited lipid peroxidation [58]. The list of compounds from I. pes-caprae with antioxidant activity is summarized in Table 1.

Anti-Inflammatory Activity
The practice of using plants, their parts, or their extracts for anti-inflammatory purposes has been in existence for a very long time [59]. As previously mentioned, I. pes-caprae, for example, is used in Brazil to treat inflammation [4]. The fresh leaves of beach morning glory have been widely used to treat inflammation of toxic effects from jellyfish venoms and dermatitis. During the last decade, in vivo and in vitro studies have led to the discovery of various extracts and compounds with proven anti-inflammatory properties from natural sources [60]. In earlier studies, Pongprayoon et al. reported the inhibitory effect of Ipomoea pes-caprae extract (IPA), aspirin, and indomethacin on prostaglandin synthesis [61]. The extract showed a concentration-dependent inhibition of prostaglandin formation in vitro with IC 50 of 62.3 µg/mL, compared to aspirin and indomethacin with IC 50 values of 74.8 and 0.30 µg/mL, respectively. The IC 50 values of the IPA and aspirin are almost equipotent, but lower than indomethacin [34].  Further bioassay-guided separation of IPA yielded (-) mellein (11), eugenol (15), 4vinylguaiacol (16), and 2-hydroxy-4,4,7-trimethyl-1(4H)-naphthalenone (31). Compounds 15 and 16 were the most active with IC 50 values of 9.2 and 18 µM, respectively, while the IC 50 values for compounds 11 and 31 were 230 and 340 µM, respectively. The inhibitory effect of compounds 11, 15, 16, and 31 on prostaglandin formation partly explains the observed anti-inflammatory effect of IPA [34]. This represents the only report of the isolation of 31 as a natural product, although previously reported by Davis et al. as a minor product while investigating the biogenesis of tobacco isoprenoids [62]. Generally, phenolic antioxidants act by inhibiting tumor necrosis factor-α (TNF-α)-induced nuclear factor-kB (NF-κB) activation and by blocking cyclooxygenase (COX)-2 expression in lipopolysaccharide (LPS)-stimulated macrophages. Further studies have shown that 15 effectively modulates lung inflammation and remodeling in an in vivo acute lung injury model, by inhibiting TNF-α release and NF-κB activation [63].
Quercetin (10), previously isolated by Krogh et al. from the methanol extract of aerial parts of I. pes-caprae [24], is a known anti-inflammatory flavonoid. It has shown significant anti-inflammatory activities in human and animal cell types. Experiments conducted by Li et al. on animal models revealed the ability of quercetin to inhibit LPSinduced TNF-α production in macrophages and human lung cancer A549 cell lines [64]. Additionally, compound 10 can inhibit the COX and lipoxygenase (LOX) enzymes that produced inflammation [42]. The evaluation of the inhibitory effect of 10, engeletin, and astilbin, isolated from Smilax corbularia on LPS-induced nitric oxide (NO) production, TNFα, and prostaglandin E2 (PGE2) release in RAW 264.7 cells revealed that 10 showed the best inhibitory effect on TNF-α and NO production with IC 50 values of 4.14 and 37.1 µM, respectively. Interestingly, compound 10 showed higher IC 50 values for the inhibition of NO production and TNF-α release than indomethacin, which was used as the positive control, except for PGE2 release. The inhibitory effects of indomethacin on NO, TNF-α, and PGE2 release were 56.8, 143.7, and 2.8 µM, respectively [65].
Both caryophyllene oxide (33; sesquiterpenoid oxide) and α-pinene (34; monoterpene)major components of the essential oil of fresh and dried leaves of I. pes-caprae-have been reported for their anti-inflammatory activities in other studies. Compound 33, previously isolated from Annona squamosa bark extract, exhibited significant anti-inflammatory activities [66]. From the acetic acid-induced writhing test in mice, 33 inhibited the writhing response by 75.19% at 25 mg/kg body weight, almost to the same degree as aspirin (74.41%) at 100 mg/kg body weight [66]. Other studies have also confirmed the anti-inflammatory potential of 34 [67].

Antinociceptive Activity
Another traditional importance of beach morning glory is for treating dolorous processes. Pain is an unpleasant sensation associated with tissue damage. Generally, drugs used to treat pain are in high demand worldwide, either as opiates or non-steroidal antiinflammatory drugs (NSAIDs). Nowadays, much attention has been paid to screening analgesics from natural origins due to their lower side effects compared to opiates and NSAIDs [70]. Among such studies, Maria De Souza et al. examined the antinociceptive actions of a methanol extract and fractions from I. pes-caprae aerial parts [71]. The methanol extract produced an half-maximal infective dose (ID 50 ) of 33.8 mg/kg i.p. (writhing test) and also inhibited both the first and second phases of pain (neurogenic and inflammatory) in the formalin test, with ID 50 values of 37.7 and 12.5 mg/kg i.p., respectively [71].
Krogh et al. described the isolation of antinociceptive-active compounds from the methanol extract of I. pes-caprae [24]. Among the identified metabolites, isoquercetin (6), α-and β-amyrin acetate (37 and 38), betulinic acid (39), and glochidone (40) produced significant antinociceptive properties of 34.5, 54.4, 88.1, and 75.5% inhibition, respectively, against aspirin with 35.0% inhibition at 10 mg/kg i.p. in an acetic acid-induced abdominal constriction test. These findings supported the widespread use of I. pes-caprae to treat dolorous conditions [24]. Both 37 and 38 are derivatives of α-amyrin (35) and β-amyrin (36), respectively. Compounds 35 and 36 have been previously isolated from the resin of Protium kleinii where they showed significant antinociceptive activity against acetic acid-induced visceral pain in mice. The study suggested that the mechanism of action involves the inhibition of protein kinase A-and C-sensitive pathways [72]. In addition to the antinociceptive activity of 39 above, studies on 39 using the abdominal contortions model induced by acetic acid also proved its significant antinociceptive activity [73].
α-Terpineol (28), p-cymene (41), and (E)-nerolidol (42) are some of the major essential oils identified from the fresh and dried I. pes-caprae leaves in Mauritius [20]. These oils have shown considerable antinociceptive actions in the literature. For example, the evaluation of the antinociceptive actions of three monoterpenes by acetic acid-induced writhing and formalin-induced nociceptive tests in mice showed that 41 has the best in vivo and in vitro antinociceptive effect compared to (+) camphene and geranyl acetate in experimental models, reducing nociception in both phases of the formalin test [74]. The antinociceptive activities of the monoterpene 28 and the sesquiterpene alcohol 42 have been reported in other works [19,57]. Sericic acid (53), which was previously isolated from Vochysia divergens Pohl., also possesses antinociceptive properties [24]. The antinociceptive compounds identified in beach morning glory are listed in Table 3.

Antimicrobial Activity
Several studies have been conducted on I. pes-caprae, confirming its use in folklore medicine to treat diseases caused by microorganisms. For instance, the evaluation of the antibacterial activity of different solvent extracts of I. pes-caprae whole plant against some Gram-positive and Gram-negative bacteria revealed interesting activities in the ethyl acetate and the acetone extract only with minimum inhibitory concentrations (MIC) of 12.5 and 25 mg/mL, respectively, against Staphylococcus [75].
As previously mentioned, (-) mellein (11) was isolated from IPA oil, which was obtained from the steam distillation and extraction of dried I. pes-caprae leaves with petroleum ether [31]. Although this is not the first report of isolating this metabolite from natural sources, as it had been previously isolated from Aspergillus melleus and other microbial sources, it possesses antibacterial activity [34]. The diterpene, E-phytol Alagesan et al. isolated 5,7-dihydroxy-4-phenyl-2H-chromen-2-one (4) from the acetone extract of I. pes-caprae [32]. Compound 4 displayed maximum growth inhibition against E. coli and Shigella flexneri. This is the first report of the antimicrobial activity of this coumarin compound. Based on the previous studies, the carbon-7 (C7) free -OH group of coumarins is essential for inhibiting the growth of Gram-positive bacteria. This explains the observed activity of 4 since it contains free -OH groups at the carbon-5 (C5) and C7 positions [32]. Quercetin (10) is a broad-spectrum antibacterial and has significant fungal inhibitory activity. The antimicrobial activity of quercetin is achieved through diverse mechanisms of action, which include the prevention of bacterial adhesion, the inhibition of quorum-sensing pathways, the destruction or change of the plasma membrane, the inhibition of efflux pumps, affecting protein synthesis and expression, and the blockage of nucleic acid synthesis [42].
β-Sitosterol (55), which was identified from the methanol extract of I. pes-caprae aerial parts, is known for its antimicrobial properties. Another study that evaluated the effect of 55 on Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae found that 55 (0.048 µM) produced an antimicrobial activity almost equivalent to gentamicin (0.042 µM) [77].
Among the compounds identified by Gonçalves et al. from the methanolic fraction of a hydroalcoholic extract of I. pes-caprae aerial parts [33], chlorogenic acid (14) and caffeic acid (25) have been identified as antimicrobial agents [78,79]. Toyama et al. isolated 14 from Baccharis oxyodonta, which induced the destruction of many bacteria cells [80]. Zhang et al. stated that 14 acts by binding and disrupting the outer membrane, exhausting the intracellular potential, and therefore releasing the cytoplasmic macromolecules, which in turn leads to cell death [81]. In a different study, 14 effectively inhibited both Gram-positive and Gram-negative bacteria with MIC values of 0.226, 0.057, and 0.113 µM against E. coli, Shigella dysenteriae, and Salmonella typhimurium, respectively, while the MIC values were 0.057, 0.113, and 0.113 µM for Streptococcus pneumoniae, Staphylococcus aureus, and Bacillus subtilis, respectively [78]. On the other hand, compound 25, which is widely distributed in plant tissues, exhibits in vitro antibacterial activity [48]. In a study that evaluated the activity of 25 towards the staphylococcal strains using the standard microdilution liquid method, S. aureus ATCC 25293 was one of the most susceptible strains to 25 with a MIC value of 1.421 µM [79].
Sericic acid (53), another known metabolite from I. pes-caprae, demonstrated strong antifungal activity from studies conducted on Terminalia sericea and Vochysia divergens [24,84]. Against T. sericea (MIC of 0.135 µM), compound 53 had better activity than the standard drug clotrimazole (MIC of 0.261 µM) [84]. This finding correlates with Krogh et al. on the antifungal activity of 53 isolated from I. pes-caprae [24]. This may be due to the presence of conjugated carbons, some phenolic, hydroxyl, and carboxyl groups, and the number of acceptor atoms of hydrogen bonds in the compound, which are important structural descriptors for the antimicrobial activity of terpenes [85]. Xanthoxyline (92) is the main antifungal constituent isolated from Sebastiania schottiana [86]. It is also active against Cryptococcus neoformans and Aspergillus fumigatus with MICs of 0.255 and 0.382 µM, respectively [86]. The antimicrobial compounds from I. pes-caprae are summarized in Table 4.

Collagenase Inhibitory Activity
The depletion of collagen by collagenase enzymes is involved in various human pathologies, such as arthritis, cancer, cardiovascular diseases, and neurodegenerative diseases. This makes collagenase an important target for the pharmaceutical and cosmetic industry [87]. In a study conducted by Teramachi et al. to evaluate the collagenase inhibitory activity of the fractions from the methanolic extract of I. pes-caprae leaves from Khon Kaen, Thailand, the ethyl acetate-soluble fraction was the most active compared to others, which included n-hexane, n-butanol, and water-soluble fractions [35].  (Table 5). Phosphramidon with IC 50 of 0.6 µM was used as the positive control. The methyl ester 20 produced the best activity. In addition, a cytotoxicity test conducted for compounds 17, 18, 23, and 24 against Jurkat human T-cell leukemia cells showed that the compounds are almost non-cytotoxic (IC 50 value > 35 µM/mL). In the same study, caffeic acid (25) showed weak collagenase inhibition (IC 50 = 82.7 µM), whereas quinic acid was not active (IC 50 > 500 µM) [35].

Antispasmodic Activity
Antispasmodics are widely used to relieve breathing problems, muscle spasms, gastrointestinal cramps, and movement disorders associated with impaired contraction and smooth-muscle relaxation. The antispasmodic effect of several medicinal plants has been reported, including I. pes-caprae, due to tolerance and potential adverse effects associated with present drugs [88]. The evaluation of the antispasmodic properties of a lipophilic IPA obtained from I. pes-caprae collected along Bangsaen seashores, Thailand, showed a 23% inhibition at 31 µg/mL, which indicated the antispasmodic potential of the plant. [36]. As a continuation, both E-phytol (32) and β-damascenone (50) were obtained from the bioassay-guided fractionation of IPA by Pongprayoon et al. and were identified as possessing antispasmodic activity [36]. The result obtained showed that 0.105 µM of 32, 0.163 µM of 50, and 0.091 µM papaverine produced 41, 45, and 39% inhibitions, respectively, on submaximal contractions of guinea-pig ileal smooth muscle induced by histamine. The antispasmodic potencies of 32 and 50 were similar to papaverine-a spasmolytic agent. The interference with the contraction of the endothelial cell plays a role in IPA's observed anti-inflammatory activity [2]. Furthermore, compound 32 decreased vascular leakage by inhibiting the contraction of endothelial cells. Severe vascular contraction has been implicated in dermatitis caused by a jellyfish sting, leading to local vascular insufficiency and gangrene. As such, compounds with direct vasodilating activity, such as papaverine, have been recommended to treat toxin-induced dermatitis. The use of IPA is effective to treat toxin-induced dermatitis and has a non-specific antispasmodic action. Therefore, compounds 32 and 50 may be responsible for IPA's effectiveness toward jellyfish poison by inhibiting vascular smooth-muscle-cell contractions [36].
Isochlorogenic acid A (19), isolated from the ethyl acetate soluble fraction of a methanol extract of I. pes-caprae leaves also presents significant antispasmodic activities [89]. Xanthoxyline (92) is the main antispasmodic component isolated from Sebastiania schottiana Muehl. Arg. dried stem and leaves. From the study, the in vitro IC 50 of xanthoxyline against acetylcholine-induced contraction in guinea-pig ileum was 47 µM [90] (for details, see Table 6). Table 6. Antispasmodic activity of I. pes-caprae natural products.

(Xanthoxyline)
Inhibition of acetylcholine-induced contraction in guinea-pig ileum (IC 50 * = 47 µM) [90] 6.7. Anticancer, Antitumor, and Antiproliferative Activities The increase in the incidence of various types of cancer creates a need for new anticancer drugs. As a result, numerous anticancer compounds from plant sources have been/are being examined on various cancer cells and experimental animals, leading to a dynamic increase in newly discovered natural compounds with potent anticancer activities [91]. For instance, a comprehensive study revealed that I. pes-caprae methanol extract exhibited a better antitumor effect against melanoma than aqueous and petroleum ether extracts and swaras (fresh juice extracts), but lower than dacarbazine. The tumor volume inhibition of the extract on melanoma cells was significant (p < 0.01) and concentration dependent [28].
Six lipophilic glycosides have been obtained from the hexane-soluble extract of I. pes-caprae herbal drugs (aerial parts), which was purchased at a local healthfood store in Mexico City, through preparative-scale high-performance liquid chromatography (HPLC) separation. These glycosides are pescaproside A (56) and pescapreins I-IV (57-60), as well as stoloniferin III (61). The cytotoxicity of compounds 56-61 was tested against four human cancer cell lines-nasopharyngeal, squamous cell cervical, ovarian, and colon carcinomas-and a weak cytotoxicity with median effective dose (ED 50 ) range of 5-20 µg/mL was observed [3].
The antiproliferative activity of 5,7-dihydroxy-4-phenyl-2H-chromen-2-one (4) on human colon cancer cells HCT-116 was examined by MTT assay. In the study, 24 h of treatment of the HCT-116 cell with compound 4 decreased cell viability by about 30% (IC 50 = 0.055 µM). Molecular docking studies revealed that 4 is a good angiopoietin-2 inhibitor, thus confirming the significant antiproliferative activity of this secondary metabolite [32]. Quercetin (10) is another compound from I. pes-caprae whose antitumor potential has been proven in vivo and in vitro through various mechanisms from different studies. For instance, an evaluation of the effects of different concentrations of 10 on human leukemia cell lines HL-60 revealed that this compound inhibited HL-60 cell growth in a concentration-dependent manner, with an IC 50 value of about 7.7 µM after 96 h of treatment [92]. In another study, Chou et al. stated that 10 affected the regulation of tumor protein p53-related pathways in the tumor cell cycle by inducing endoplasmic reticulum (ER) stress, promoting p53 release, and inhibiting cyclin A, cyclin B, and cyclin dependent kinase-2 (CDK2) activities, thus causing the stagnation of MCF-7 breast cancer cells in the S phase [93].
Stigmasterol (54) is another anticancer and antiproliferative compound identified from the methanol extract of the fresh aerial part of I. pes-caprae [24]. Compound 54 inhibited the proliferation and colony formation potential of gastric cancer cells (IC 50 = 15 µM) by cell counting kit-8 (CCK-8) assay with no effect observed in untreated cells. Furthermore, 30 µM of 54 increased the percentage of apoptotic cells in gastric cancer SNU-1 cells from 1.75 to 43.66%. The apoptotic effects of 54 were also found to be concentration dependent. These results indicate the potential of 54 as an antiproliferative and anticancer metabolite [94]. Both α-amyrin (35) and β-sitosterol (55) have in vitro cytotoxic activities. In a study, the pentacyclic triterpene 35 was tested for its antiproliferative activity against cancer cell lines. The result showed an IC 50 value of 0.022 and 0.052 µM against A549 and human ovarian cancer cell lines A2780, in contrast to 0.00036 and 0.00058 µM for etoposide, respectively [95]. On the other hand, compound 55 remarkably inhibited the proliferation of human liver cancer cell lines HepG2 and human liver carcinoma cell lines Huh7 cells in a dose-dependent manner with IC 50 values of 0.017 and 0.021 µM, respectively, indicating that 55 exhibited cytotoxic effects through the induction of apoptosis and activation of caspase-3 and -9 in these cells. Camptothecin (positive control) produced similar results with IC 50 values of 0.011 and 0.012 µM for HepG2 and Huh7, respectively [96].

Compound
Pharmacological
Glucosidase inhibitors are promising therapeutic potential in treating diabetes, human immunodeficiency virus (HIV) infection, metastatic cancer, and lysosomal storage diseases [104]. Studies conducted on rat lysosomes suggested the presence of these inhibitors in I. pes-caprae. Contrary to Meira et al., which reported the presence of calystegine B1, B2 (1), B3, and C1 in I. pes-caprae [89], only the evidence of calystegine B2 (1) from I. pes-caprae exists from a reference found [29]. The polyhydroxylated alkaloid 1 was previously isolated from Ipomoea carnea and evaluated for the inhibition of rat epididymis glycosidases. From the result obtained, compound 1 proved potent by inhibiting lysosomal β-glucosidase with an IC 50 value of 0.75 µM, representing the best inhibitory activity among the tested calystegines, including B1, B3, and C1 [105]. Resin glycosides play important roles in the purgative properties of some Convolvulaceae species [106] (Table 9).

Materials and Methods
The information on the botanical description, traditional uses, and bioactivities of the secondary metabolites from Ipomoea pes-caprae were searched through a combination of databases, which include Google Scholar, PubMed, ScienceDirect, DOAJ, and SpringerLink. The data was updated until December 2021 using 'biological activities of Ipomoea pes-caprae,' 'Ipomoea pes-caprae natural products,' 'I. pes-caprae traditional uses,' 'invasive and introduced I. pes-caprae' and 'I. pes-caprae botany' as key search phrases. Publications were excluded from this review that did not or inadequately provide information on isolated and identified compounds from I. pes-caprae, geographical distribution, botanical description, traditional uses, and bioactivities of the extract. The study also excluded primary metabolites with no known biological activity from I. pes-caprae. Some of the components from the gas chromatography-mass spectrometry (GC-MS) analysis of I. pes-caprae leaves essential oil were included as secondary metabolites. The qantitative bioactivity information was selected to be included in the Tables.

Conclusions
Ipomoea pes-caprae is a widely distributed medicinal halophyte in tropical and subtropical regions, where it serves many uses in traditional medicine. I. pes-caprae is one of the most widely distributed beach plants across the world. The whole plant can be collected along coastal beaches, seashores, and sandy beaches, followed by proper identification and deposition of collected species in an herbarium. In some cases, the plant can be purchased and identified by a taxonomist or through comparison with an authentic sample collected in the herbarium. The plant samples of I. pes-caprae discussed in this review included collections from India, Brazil, Mexico, Mauritius, Thailand, Japan, and China, where the plant is used for food and therapeutic purposes. The biological activities of I. pes-caprae extract include antioxidant, anti-inflammatory, antinociceptive, antimicrobial, antispasmodic, anticancer, antitumor, antiproliferative, and multidrug-resistance inhibitory activities. The intrinsic biological potential and medicinal use of I. pes-caprae can be associated with many phytochemicals, such as alkaloids, norisoprenoids, phenols, terpenoids, steroids, and glycosides, contained in the plant.
For treating gastrointestinal-related disorders and symptoms, such as dysentery, ulcer, abdominal pain, and cramps, the leaves, seeds, and roots of I. pes-caprae are used. The use of this plant for this purpose can be attributed to the antispasmodic and antiulcerative effect of compounds, such as isochlorogenic acid A (19; yield 0.279 mg/g), E-phytol (32; yield 0.006 mg/g), β-damascenone (50; yield 0.0005 mg/g), and xanthoxyline (92; yield 0.003 mg/g). Either in isolation or synergy, the amount of these compounds contained in infusion or decoction of I. pes-caprae is enough to elicit effects capable of soothing abdominal pains and cramps and treating ulcers as used in traditional medicine. Furthermore, resin glycosides from the family Convolvulaceae are known for their purgative abilities, thus confirming the medicinal values of I. pes-caprae in traditional medicine for treating digestive disorders.
The use of I. pes-caprae for treating hypertension and kidney ailments has also been reported in the literature. Many anti-hypertensive drugs have good antioxidant properties, useful for improving vascular function and reducing blood pressure in animal models and humans. This study has shown that I. pes-caprae houses many compounds with proven antioxidant properties, such as 4, 6, 10, 14, 21, 23, 25, 36, 46, 54, and 55. The amount of these compounds in I. pes-caprae is enough to validate the effectiveness of this plant to treat hypertension traditionally. Furthermore, antibiotics serve as a therapy for kidney diseases, such as those caused by E. coli. Thus, compounds, such as 14, 25, 32, 46, 53, and 55, with good antimicrobial profiles might play important roles in the treatment of kidney ailments with the use of I. pes-caprae.
Ipomoea pes-caprae is a key component of Ayurvedic medicine, especially for the treatment of diabetes. The presence of the potent glucosidase inhibitor-calystegine B2 (1)-pexplains the therapeutic potential of this plant as used in traditional medicine for treating diabetes. Additionally, the antioxidant compounds from I. pes-caprae are also important for managing diabetes. I. pes-caprae is also used to treat hemorrhoids, which often present symptoms similar to digestive disorders accompanied by pain and discomfort. The identified compounds with digestive order and pain-soothing effects support using I. pes-caprae locally for this purpose.
The evaluation of the biological activity of I. pes-caprae was mostly conducted on the leaves and stems, while a dearth of information exists on other plant parts. Since different plant parts can show different biological activities, more studies should be conducted on other parts of I. pes-caprae, such as its flowers, fruits, seeds, or roots. Moreover, even though many studies have been conducted on I. pes-caprae, these studies are often limited to Asia, with a paucity of scientific evidence on the bioactivity of this plant from other regions, such as Africa, America, and Australia, where they are known to occur.
Although I. pes-caprae is considered a tropical plant growing around coastal areas, there are now pieces of evidence and report of the occurrence of I. pes-caprae as invasive species in areas outside the tropics, such as Spain, South Africa, Anguilla, and Marshall Island, spreading and gradually establishing itself by out-competing the native species. Large populations of this plant have been found growing in inland habitats, even though they are originally associated with coastal areas. The establishment of invasive species in these new habitats could be because the invasive species respond to climate change better than the native species. Therefore, the influence of climate change, most importantly global warming, cannot be overemphasized as having a key effect on the dispersal and establishment of I. pes-caprae into these new climatic regions.
This review provides insights that may facilitate the future study of the phytochemistry of this plant. I. pes-caprae is native to saline habitats, where the soil mixture contains organic nutrient material and inorganic nutrient salts flowing from the land and ocean, and are thereby expected to possess abundant biologically active secondary metabolites, such as vitamins, terpenoids (carotenoids and essential oils), and phenolics, due to these extreme conditions. Further evaluation of this halophyte for biological assays not suggested in traditional medicine is required. Research on I. pes-caprae has been restricted to the stems and leaves. Other I. pes-caprae parts, such as the flowers and fruits, should be further explored for more bioactive secondary metabolites. More studies should be conducted to evaluate the structure-activity relationship and mechanism of action for some identified compounds obtained from this species. This study has shown that I. pes-caprae contains important bioactive secondary metabolites. Finally, since climatic differences and habitat can influence the biosynthesis of secondary metabolites, this study strongly suggests that the further evaluation of the phytochemistry of both the invasive and inland species of I. pescaprae be conducted, to make possible the comparison of their respective phytochemicals with the reported studies.