A Review on Bioactive Phytochemical Constituents and Pharmacological Activities of Aegiceras corniculatum : A Pharmaceutically Important Mangrove Plant

Aegiceras corniculatum , commonly referred to as Khalsi, is a member of the mangrove Myrsinaceae family. Te various parts of this plant have been used in traditional medicinal systems for their potential therapeutic efects in conditions such as asthma, microbial infections, diabetes, pain relief, infammation, cancer, and arthritis. A diverse array of bioactive phytochemicals such as favonoids, benzoquinones, triterpenes, polyphenolic acids, stilbenes, tannins, and macrolides have been identifed in diferent parts of this plant. Te aim of this review was to summarize the bioactive phytoconstituents reported from this plant that are accountable for the observed diferent pharmacological efects of the plant and further elucidate the possible underlying mechanisms by which these chemicals exert their actions. Te search was conducted on various widely used database platforms, including Google Scholar, Scopus, Web of Science, SciFinder, and PubMed. Articles published until July 2023 were extracted and all the information was sorted based on the inclusion and exclusion criteria. Te data revealed that anti-infammatory compounds from this plant suppress iNOS, myeloperoxidase, COX, LOX, and cytokines (like TNF-alpha, IL-1 ß , LTB 4 , IL-12, and IL-6) to reduce infammation. 5-O-Butyl-embelin, 2-hydroxy-5-ethoxy-3-nonyl1, 4-benzoquinone, 5-O-methylembelin, 5-O-methyl-rapanone, s-saponin, and 5-O-ethylembelin are some phytochemicals of A. corniculatum with anticancer properties, although their mechanism is unclear. A. corniculatum has antibacterial, parasitic, and antifungal efects, but no antiviral efects were reported. Te plant-isolated coumaric acid and fatty acids interact with bacterial DNA/RNA and limit protein formation, making them antibacterial. Gallocatechin, epicatechin, epigallocatechin-3-O-gallate, epigallocatechin, and other tannins, as well as favonoids like kaempferol, quercetin, and isorhamnetin, are some of the compounds in A. corniculatum that may depolarize and change bacterial membranes, showing antibacterial efect. Tese phenolic chemicals also reduce oxidative stress and help treat cancer and other infammatory diseases. Te extract of this plant activates the κ -opioid receptor, causing central antinociception. Catechol components, such as epigallocatechin-3-O-gallate, protect against CNS illnesses including Parkinson’s disease and amnesia. Despite numerous studies demonstrating various pharmacological advantages of this plant and its constituents, the number of clinical trials conducted on humans remains signifcantly limited.


Introduction
Since ancient times, in pursuit of a cure for their illness, humans have sought to nature for drugs.Te initial usage of medicinal plants was instinctual, similar to that of animals.Over time, it became clear why people were turning to diferent plants for the treatment of diferent illnesses; as a result, the practice of using medicinal plants to combat disease moved away from an empirical basis [1].Te global market for herbal medicines was assessed at a fnancial value of 170 billion United States dollars in the year 2022 and calculations indicate that this market is anticipated to expand to USD 600 billion by the year 2033, exhibiting a compound annual growth rate (CAGR) of 15% during the period spanning from 2023 to 2033 [2].Natural product utilization in medicine is an important resource for pharmaceutical businesses worldwide that are working to fnd new therapies [3].Approximately 6,500 plant species are believed to inhabit Bangladesh, and among them, over 500 species are recognized for their medicinal properties, with 250 routinely employed in the formulation of healthcare remedies.Yet, most of these plants are not being investigated chemically, pharmacologically, or toxicologically to fnd out what parts of them are useful [4].
Mangrove and mangrove associates have long been widely used as medicinal and nonmedicinal purposes throughout the world.Tere are reports of extracts from plants of mangrove origin to have proven activity against human, animal, and plant pathogens [5].Te diversity in activity of these plants could be due to the peculiar environment (high moisture, large tidal diference, high salinity, etc.) in which they exist, producing stressful conditions, which might change their morphology, physiognomy, and biosynthetic pathways to survive [5].Bangladesh has the largest single block of Sundarbans mangrove forests in the world, which is a globally signifcant ecosystem rich in plant biodiversity [5].However, the scientifc information about the biological efects of these plants and active substances is scarce and poorly documented.Aegiceras corniculatum, a Myrsinaceae mangrove plant, is called Khalsi in Bengali and grows in India, China, Singapore, Australia, Papua New Guinea, and Singapore.Traditional medicine has used the plant's fruits, leaves, and stem bark to treat asthma, arthritis, diabetes, infammation, cancer, hepatic diseases, and many others [6].In diferent portions of this plant such as leaves, bark, root, stem, and twig, researchers have identifed a number of bioactive secondary metabolites.Tese metabolites include, but are not limited to, favonoids, polyphenolic chemicals, terpenoids, tannins, alkaloids, and various glycosides [7][8][9][10][11][12][13][14][15][16][17].Tese compounds may be accountable for the plant's antimicrobial, antidiabetic, analgesic, anti-infammatory, anticancer, and antiarthritis efects.As a part of our continuing search for new insight of Bangladeshi traditional medicinal plants, here we report the bioactive phytoconstituents and pharmacological potential of A. corniculatum as well as the possible mechanism of action behind the pharmacological efects.

Methodology for Conducting the Search.
For the start of this review, a thorough literature search was undertaken on 11th March 2023.Te search was conducted on various widely used database platforms, including Google Scholar, Scopus, Web of Science, SciFinder, and PubMed.Te search terms employed were "Aegiceras corniculatum" along with "pharmacological use," "folk medicinal uses," "mechanism of action," and "isolated compounds."

Te Process of Study
Selection.Tis review encompassed various types of investigations.Te research encompasses various methodologies, including (a) investigations conducted on animal models (in vivo), (b) studies conducted in a controlled laboratory environment (in vitro), (c) computational studies that use computer models and simulations, (d) investigations that examine the pharmacological efects of plant extract and various phytochemicals derived from A. corniculatum, (e) studies that provide information on the specifc concentrations, doses, and routes of administration for the extract and its individual compounds, and (f ) investigations that elucidate the underlying mechanisms of action of the isolated phytochemicals.

Te Process of Extracting Information.
Te articles that were examined underwent a comprehensive evaluation process that considered various factors such as the surname of the frst author, the year of publication, the specifc substance being studied, the experimental framework employed, the observations made, the outcomes observed, the proposed mechanism of action, and the concentrations that were evaluated.Te searches revealed 949 records, of which around 84 studies met the criteria and rest of others are excluded.Tis document presents an overview of the fundamental stages involved in conducting a data search, including the processes of data exclusion and inclusion, as well as other pertinent details.

Pharmacological Efects of
•OH) generation and detoxifcation in cells and tissues causes oxidative stress which arises as by-products of metabolic processes in biological systems [30,31].A study found that extracts derived from A. corniculatum, namely, nhexane, EtOAc, and MeOH (Table 2), demonstrated profciency in efciently neutralizing diferent free radicals (like O 2 •−, H 2 O 2 , •OH) in more than one in vitro experimental tests [27].Te potential explanation for the antioxidant property of A. corniculatum leaves may be attributed to their comparatively higher total phenolic content [38].A noteworthy correlation was observed between the total phenol content and the outcomes of various antioxidant assays, including the DPPH and ABTS radical scavenging assays, as well as the FRAP and phosphomolybdenum assays (Table 2) [32].Te key phenolic constituents (Figure 1) found in 2 Journal of Chemistry

Anti-Infammatory.
Diseases including diabetes, cardiovascular disease, cancer, and asthma all are involved with infammation in some way [39].Infammation is a sophisticated immunological response that causes the consecutive release of proinfammatory cytokines.Terefore, the mitigation of infammation-associated ailments can be achieved by suppressing the excessive production of infammatory mediators, particularly proinfammatory cytokines such as IL-1b, IL-6, and TNF-alpha [40].Based on a recent study, it was observed that the administration of A. corniculatum extracts at dosages of 250 and 500 mg/kg resulted in a signifcant reduction in paw edema in Swiss albino mice [6].By combining diferent in vivo and in vitro models (Tables 2 and 3), a study indicates that extracts obtained from A. corniculatum, specifcally methanol and ethyl acetate extracts, exhibit notable inhibitory efects on the chronic infammatory phase and these efects are observed through the suppression of mononuclear cell infltration, fbroblast proliferation, collagen fber production, and connective tissue formation, all of which contribute to the development of granuloma [45].Carrageenan-induced pleurisy is a very common method used to test anti-infammatory therapeutics [49].Methanol and ethyl acetate extract of A. corniculatum protects against acute lung infammation by lowering nitrate/nitrite concentrations and MPO enzyme levels and also decreases neutrophils and mononuclear infltration at a higher dose (100 mg/kg) in a mice model of pleurisy [47] (Table 3).Diferent classes of phytochemicals are isolated from diferent parts of A. corniculatum (Table 4) which is the potential causative factor for the observed anti-infammatory efect [51,52].In accordance with the outcomes of a research, it has been found that the ethyl acetate extract of plant demonstrates inhibitory efects on the production of eicosanoids like LTB 4 (IC 50 : 0.86 ± 0.03 g/ml), 5-HHT (IC 50 : 3.4 ± 0.04 μg/ml), and 12-HHT (IC 50 : 0.08 ± 0.002 μg/ml), with only a minor efect on 12-HETE (IC 50 : 8.0 ± 0.18 μg/ml), thus demonstrating that it has comparatively strong binding preference towards the 5-lipoxygenase and cyclooxygenase-1 in relation to the 12-lipoxygenase [43].Te ethyl acetate extract derived from plants contains a diverse range of triterpenes and phenolic compounds (like favonoids), which have the potential to exhibit anti-infammatory properties [14,28,32,43].

6
Journal of Chemistry selectivity of hexane extract towards lipoxygenases [16,43,57,58].Oxidative stress plays a signifcant role in the development of chronic infammation [59].Current research aimed to replicate the anti-infammatory response to oxidative stress in an in vivo model of glucose oxidase-induced paw edema in mice revealed that extracts derived from A. corniculatum possess the ability to inhibit the production of proinfammatory mediators in the presence of oxidative stress, owing to their capacity to scavenge OH radicals [27].Tus, it can be inferred that n-hexane, EtOAc, and MeOH extracts derived from the A. corniculatum possess anti-infammatory properties that are exerted through various mechanisms of action (Figure 3).Hence, A. corniculatum, a species of mangrove plant, has been employed for numerous years in the management of various infammatory and autoimmune conditions, such as coronary artery disease, rheumatoid arthritis, and allergies and asthma, and its utilization as a traditional remedy has garnered signifcant recognition.

Antiproliferative.
Cancer indicates a signifcant global public health concern, exerting a considerable infuence on nations across the spectrum of development.In the year 2018, there was a global estimation of approximately 18.1 million newly diagnosed cases of cancer and it is projected that by the year 2030, this fgure will increase to reach approximately 23.6 million cases [60].Te signifcance of identifying medicinal plants with notable cytotoxic potential for the advancement of cancer therapies has experienced a notable increase in the past decade, and progress in this domain is currently expanding [61].Te methanolic extract obtained from A. corniculatum demonstrated pronounced cytotoxic efects on healthy, colon, and breast cancer cells, as evidenced by IC 50 values ranging from 0.02 to 0.66 mg•mL −1 .However, the cytotoxicity against gastric cancer cells was notably low [62].Diferent classes of phytochemicals are isolated from diferent parts of A. corniculatum (Table 1) which may be responsible for anticancer or cytotoxic efect [51,52].
Te benzoquinone derivatives, namely, 5-O-ethylembelin and 5-O-methylembelin (Table 4), which have been extracted from A. corniculatum, have been found to induce cell cycle arrest in HL-60 cells specifcally in the G 1 /G 0 phase, and this efect is believed to be mediated through their interaction with microtubular proteins [16,65].However, the precise mechanism underlying this interaction remains to be elucidated.Higher levels of reactive oxygen species (ROS) produced through persistent aerobic glycolysis, subsequent pyruvate oxidation in mitochondria, receptor and oncogene activation, and activation of growth factor-dependent pathways or oxidizing enzymes contribute to the induction of genetic instability [66].Various studies have proposed that the protective efect of antioxidants against cancer is manifested through the inhibition of the generation of carcinogenic metabolites [67,68].Also, epigallocatechin-3-O-gallate inhibits DNA methyltransferase activity and controls histone acetylation, which increases apoptosis and also activates mitogen-activated protein kinases to boost anticancer action [69].Terefore, A. corniculatum has anticancer benefts against various cancers through a variety of methods and may serve as a future source of anticancer drugs.

Analgesic.
A study suggested that A. corniculatum's ethanolic and water-soluble extracts (200 and 400 mg/kg, p.o.) had a substantial analgesic efect, increased latency in Eddy's hot plate, and reduced the writhing caused by acetic acid in a dose-dependent way [70].According to another investigation, the extract derived from A. corniculatum demonstrated notable inhibition of writhing impulse (Table 3).Specifcally, at doses of 250 mg/kg and 500 mg/kg body weight, the extract exhibited inhibitory efects of 54.78% and 75.60%, respectively, and these fndings indicate that the extract's potency is comparable to that of a 25 mg/kg dose of diclofenac sodium [6].Te potential mechanism underlying the antinociceptive efect of methanol plant extract appears to involve the activation of the κ-opioid receptor.On the other hand, the n-hexane extract may exert its efects by acting as an opioid agonist on the peripheral opioid receptor, thereby counteracting withdrawal abstinence syndrome through the GABAB receptor.In contrast, the neurogenic analgesic action of the EtOAc extract was not found to be mediated by the opioidergic system.Instead, it is possible that the extract exerts its efect by inhibiting the biosynthesis of proinfammatory PGs [41].Diferent investigations found that favonoids, favonols, benzoquinones, triterpenes, polyphenolic acids, stilbenes, and others are some naturally occurring chemical constituents isolated from plant extract and may be responsible for reducing both central and peripheral pain efect through diferent mechanisms [27][28][29]71].

Antimicrobial. Several investigations have demonstrated that
A. corniculatum possesses antimicrobial properties against diferent microorganisms (Table 2) Alloxan-induced diabetic male albino rats ACEt extract of A. corniculatum leaves (25, 50, and 100 mg/kg body weight) for 60 days Oral Te activity of hexokinase has been observed to be elevated, while the activities of glucose 6-phosphatase and fructose-1,6-bisphosphatase have been found to be reduced [42] Carrageenan-induced rat paw edema and glycogen-induced peritonitis models Journal of Chemistry  (2 (2) Sakurasosaponin methyl ester (1) Gallocatechin Tannin DPPH radical scavenging By scavenging free radicals [25] (2) Epigallocatechin  Fatty acid Antimicrobial assay of fatty acids through using disk difusion method using S. aureus, E. coli, K. pneumonia, and P. aeruginosa Due to the metabolic oxidation products of fatty acids [20] (2) Linoleic acid 12 Journal of Chemistry [7,20,36,55].An antimicrobial refers to any substance that has the ability to eliminate microorganisms or inhibit their proliferation or development.Tere are primarily four types of antimicrobial drugs, including antibacterial, antifungal, antiviral, and antiparasitic drugs [72,73].An in vitro study found that A. corniculatum stems are used to inhibit adult earthworms (Pheretima posthuma) showing anthelmintic efect [36].Also methanol extract of polyherbal mixture containing A. corniculatum and Chaetomorpha antennina demonstrated a suppressive efect of approximately 63.50 ± 0.408% on P. falciparum, a parasite that causes malaria, when tested at a concentration of 1.5 mg/ml [44].

Journal of Chemistry
Te plant contains various benzoquinones (embelin), including 2,5-didehydroxy-6-methylembelin, embelin, 5-O-ethylembelin, and 5-O-methylembelin (Table 4).Tese have exhibited antimalarial activity in laboratory tests against both chloroquine-sensitive (3D7) and resistant (K1) strains of the malaria parasite [24].Benzoquinones are the most cytotoxic substances presumably because of their higher electrophilicity and autooxidation potential [74].Tese fndings suggest potential antimalarial activity of A. corniculatum's phytoconstituents.Methanol extract derived from A. corniculatum exhibits in vitro inhibitory efects on the growth of Fusobacterium nucleatum, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans in the disk difusion method, and the observed efect can be attributable to the existence of (−) epicatechin and coumaric acid within the extract [55].Tere  Journal of Chemistry is a possibility that coumaric acid can bind to the phosphate anion present in the DNA double helix.Moreover, it can potentially insert itself into the groove of the DNA double helix, and these interactions have the potential to afect the production of proteins and the growth of bacteria [75].A recent study has demonstrated that the EtOAc fraction exhibited the most potent antituberculosis activity, with a minimum inhibitory concentration (MIC) of 6.25 μg/ml, with the highest total phenolic content and antioxidant activity.A clear correlation was observed between the amounts of phenolic content and the efectiveness of the antituberculosis activity [28].Diferent extracts of A. corniculatum contain phenolic compounds (Figure 1) such as polyphenolic acid (like gallic acid and coumaric acid); tannins (such as gallocatechin, epicatechin, epigallocatechin-3-O-gallate, and epigallocatechin); and favonoids (like kaempferol, quercetin, and isorhamnetin) which may be responsible for antimicrobial activity [11,25,38,43,55,76].Te existing literature suggests that the inhibition of pathogenic bacteria by phenolic compounds is attributed to the depolarization and alteration of membrane fuidity [77].Moreover, the fatty acids derived from the pneumatophore of A. corniculatum exhibited signifcant efcacy against GNB Klebsiella pneumoniae and a medium efcacy against GPB Staphylococcus aureus.Te results suggest that the ability of the fatty acid fractions to kill bacteria depended on the presence of long-chain unsaturated fatty acids [20].Possible mechanisms by which antibacterial fatty acids exert their efects include the potential to hinder DNA/RNA replication, impede cell wall formation, disrupt the integrity of the cytoplasmic membrane, and interfere with metabolic pathways [78].Macrolides such as isocorniculatolide A; 11-Omethylisocorniculatolide A; 11-O-methylcorniculatolide A; 12-hydroxy-11-O-methylcorniculatolide A; and corniculatolide A are isolated from A. corniculatum which may show antibacterial activity through their ability to bind the bacterial 50S ribosomal subunit causing the inhibition of bacterial production of protein [12,79].Tese fndings point to the possibility of antibacterial action on the part of the phytoconstituents found in A. corniculatum.Two compounds, called as Acornine 1 and Acornine 2 (Table 4), were extracted from A. corniculatum, and both of them demonstrated growth inhibitory activity against the fungus T. clypeatus [7].Both of the Acornines are triterpenoid saponins, which have been found to possess the ability to disrupt the structural integrity of the cell membrane, resulting in the release of cellular contents and afterwards inhibition of fungal growth [7].Terefore, it is obvious that this plant is efective against a wide spectrum of microorganisms through diferent mechanisms.
3.2.6.Efect on CNS Diseases.Phenolic compounds capable of traversing the blood-brain barrier have been observed to elicit benefcial health outcomes within the brain [80] [25,84].A study also shows that strong antioxidant activities in A. corniculatum have been shown to improve cognitive performance in both adult and elderly rats and can be used to treat amnesia [48].Furthermore, it has been reported that the methanol plant extract elicits a central antinociceptive efect by activating the κ-opioid receptor [41].Only a few studies have been carried out on the central nervous system (CNS) to explore the neuropharmacological impacts of this specifc plant.Further research is required to investigate the neuropharmacological activity of this plant and elucidate its mechanism of action.

Antidiabetic Efect.
According to a research study, it was discovered that the ACEt extract derived from the leaves of A. corniculatum exhibits antidiabetic properties in male albino rats.Tis efect is achieved by enhancing the activity of hexokinase (Table 3) while simultaneously reducing the activities of glucose 6-phosphatase and fructose-1,6bisphosphatase [42].Alpha-glucosidase inhibitors reduce postprandial blood glucose and insulin by inhibiting small intestine carbohydrate absorption in diabetic patients [85].
Te results of an in vitro study demonstrated that the ethyl acetate portion and water portion extracts derived from the leaves of A. corniculatum exhibited inhibitory efects on the alpha-glucosidase enzyme.Te IC 50 values for the ethyl acetate portion and water portion were determined to be 40.59µg/mL and 60.79 µg/mL, respectively [37].Further research is warranted to identify the specifc molecules underlying the antidiabetic efect and to comprehensively understand the precise mechanism of action, and this necessitates a comprehensive investigation utilizing both in vivo and in vitro approaches.

Conclusion
Te primary sources for the development of medical drugs are active ingredients derived from medicinal plants.Different classes of compounds, including favonoids, benzoquinones, tannins, triterpenes, polyphenolic acids, stilbenes, and macrolides, are present in A. corniculatum that are responsible for a wide range of pharmacological efects.Quercetin, (3β, 16α, 20α)-3,16,28-trihydroxyolean-12-en-29-oic acid 3-{O-β-D-glucopyranosyl (1 ⟶ 2)-O-[β-Dglucopyranosyl (1 ⟶ 4)]-α-L-arabinopyranoside}, isorhamnetin, aegicoroside A, kaempferol, and (−)-epicatechin are some of the chemicals isolated from this plant that may be responsible for anti-infammatory activity.Te compounds present in this plant exhibit inhibitory efects on iNOS, myeloperoxidase, COX, and LOX enzymes and additionally reduce the production of various cytokines including TNF-α, IL-1ß, IL-6, and LTB4, resulting in an anti-infammatory response.A specifc substance called Ssaponin, derived from this plant, has been identifed to induce cell death through mitochondrial-mediated pathways in both androgen-dependent and castration-resistant cells, by modulating androgen receptor (AR) mechanisms.Also -Oethylembelin are some of the other phytochemicals of A. corniculatum showing anticancer efect, but their exact mechanism is still unknown.Multiple studies have revealed that A. corniculatum exhibits antimicrobial properties against a variety of microorganisms, including both types of bacteria, parasites, and fungi.However, no evidence of antiviral efects has been observed.Diferent in vitro and in vivo studies found that diferent extracts of A. corniculatum are used to inhibit adult earthworms (Pheretima posthuma) showing anthelmintic efect and inhibit P. falciparum showing an antimalarial efect.Plantisolated coumaric acid and fatty acids have the capacity to interact with bacterial DNA/RNA and to inhibit protein production through a variety of mechanisms and can show antimicrobial efect.Macrolides from A. corniculatum may inhibit bacterial protein production by binding the bacterial 50S ribosomal subunit.Gallocatechin, epicatechin, epigallocatechin-3-O-gallate, epigallocatechin, and other tannins, as well as favonoids like kaempferol, quercetin, and isorhamnetin, constitute some of the phenolic compounds found in A. corniculatum that may be responsible for antibacterial activity by depolarizing and changing the fuidity of bacterial membranes.Tese phenolic compounds are also responsible for acting as antioxidants by reducing oxidative stress which will assist to diminish a variety of infammatory disorders (such as asthma and arthritis), cancer, and various other ailments.Two triterpenoid saponins, Acornine 1 and Acornine 2, were isolated from A. corniculatum, and both exhibited growth inhibitory action against T. clypeatus.One possible explanation for this is the capacity of the triterpenoid saponin to limit fungal development by compromising the structure of the cell membrane.Evidence has been discovered supporting the idea that this particular plant possesses a central antinociceptive efect through the activation of the κ-opioid receptor.In addition, the neuroprotective properties of this plant against several central nervous system (CNS) disorders like Parkinson's disease and amnesia could potentially be ascribed to the existence of catechol compounds, including epigallocatechin-3-O-gallate.In addition, certain scholars have also discovered the plant's potential antidiabetic properties through the inhibition of the alpha-glucosidase enzyme.However, additional investigation is necessary to determine the exact neuropharmacological and antidiabetic efects.In summary, A. corniculatum exhibits a diverse range of pharmacological Journal of Chemistry properties, including antibacterial, antioxidant, anticancer, anti-infammatory, antidiabetic, analgesic, and neuroprotective efects.Tis fnding provides evidence for the utilization of this botanical species as a traditional remedy.

Table 2 :
In vitro pharmacological efect of A. corniculatum extract.

Table 3 :
In vivo pharmacological efect of A. corniculatum extract.

Table 4 :
Pharmacological efect of compounds reported from A. corniculatum.
Figure 3: Proposed mechanism of action for A. corniculatum extracts in reducing infammation.