Bioactive Compounds, Pharmacological Actions, and Pharmacokinetics of Genus Acacia

Plants are a promising source of bioactive compounds that can be used to tackle many emerging diseases both infectious and non-infectious. Among different plants, Acacia is a very large genus and exhibits a diverse array of bioactive agents with remarkable pharmacological properties against different diseases. Acacia, a herb found all over the world, contains approximately more than 1200 species of the Fabaceae family. In the present review, we have collected detailed information on biochemical as well as pharmacological properties. The data were retrieved using different databases, such as Elsevier, PubMed, Science Direct, Google Scholar, and Scopus, and an extensive literature survey was carried out. Studies have shown that Acacia possesses several secondary metabolites, including amines, cyanogenic glycosides, flavonoids, alkaloids, seed oils, cyclitols, fluoroacetate, gums, non-protein amino acids, diterpenes, fatty acids, terpenes, hydrolyzable tannins, and condensed tannins. These compounds exhibit a wide range of pharmaceutical applications such as anti-inflammatory, antioxidant, antidiarrheal, antidiabetic, anticancer, antiviral, liver protective effects, and so on. Thus, the literature shows the tremendous phytochemical impact of the genus Acacia in medicine. Overall, we recommend that more research should be conducted on the medicinal value and isolation and purification of the effective therapeutic agents from Acacia species for the treatment of various ailments.


Introduction
With more than 1200 species, the genus Acacia is the second largest in the Leguminosae (Fabaceae) family. The genus is distributed throughout warm tropical and temperate regions of the world, with the greatest number of species (about 957) in Australia and a significant number (around 185) in America, Africa (144 species), and Asia (89 species). [1]. Many pharmacological molecules have been isolated from diverse species of Acacia. The root, leaves, pods, and bark of Acacia hold the uppermost quantity of tannin and phenolic compounds, such as gallic acid, dicatechin, quercetin, robidandiol, β-amyrin, hentriacontane, betulin, sitosterol, kaempferol-3 chlorogenic acid, and glucoside isoquercetin [2]. A. nilotica (L.) Willd. Ex Del., which is recognized as a medicinal tree, belongs to the family Mimosaceae and has been identified as being abundant in phenolic substances involving saponins, 2,4-dinitrophenyl salicylic acid Antifilarial, Antidiabetic [28,29] Acacia pennatula Pods Methanol 4-nitro-Ophenylenediamine Antioxidant, Antimutagenic [30] Acaciacatechu Leaves Aqueous, Cytotoxic, Antiviral [31] Acacia aroma Leaves Ethanol

Chemical Components Isolated from Acacia
Acacia is a varied genus including a variety of bioactive components such as alkaloids [33], flavonoids [8], terpenoids [34], phenolic compounds, and tannins [35,36], which are accountable for various pharmacological and biological properties such as antibacterial, anti-inflammatory, antihypertensive, antiplatelet, hypoglycaemic, anti-atherosclerotic, analgesic, and anticancer, owing to their higher free radical scavenging and antioxidant properties [37]. The phytochemical analysis of the A. nilotica leaf extracts revealed that it contains volatile oil, saponins, hydrolysable tannin, flavonoids, tannins, triterpenoid, phenol, alkaloids which are actual important compounds when regarding the pharmacologically bioactive phytochemicals in the plant [38]. Members inside the genus A. sensu lato were documented to enclose cyclitols, cyanogenic glycosides, amines, essential oils, diterpenes, simple alkaloids, fatty acids of the fluoroacetate, seed oils, triterpenes, amino acids, saponins, phytosterols, gums, flavonoids, and hydrolyzable reduced tannins as well. Deboshree Biswas and M.G Roymon reported that the bioactive principles found in methanolic bark and leaf extracts of A. arabica were investigated using an HPLC/MS/MS. Oleic acid (C 18 10 ), were also found in the leaf extracts (C 8 H 8 O 5 ). 3,4,5-trihydroxybenzoate was one component isolated from a bark extract (C 7 H 6 O 5 ). Overall, this genus (and other mimosoid legumes) looks to be deficient in acetylenes, coumarins, phenylpropanoids, anthraquinones, naphthoquinones, lignans, glucosinolates, stilbenes, and uncommon fatty acids. However, only a small number of species have been specifically examined for these substances; thus, undoubtedly, the phytochemicals of only a small portion of Acacia species have been examined yet. Various phytocompounds from different Acacia species are shown in Table 1.

Alkaloids and Amines
In most of the taxa comprising the genus A. sensu lato, both relatively simple alkaloids and amines are present. They are particularly plentiful in the seeds from the subgenus Aculeiferumsection monacanthea of the Neotropical species, and also the species of Africa, including A. kraussiana, A. schweinfurthii, A. caesia, A. brevispica, and A. pentagona. Moreover, many of the non-protein amino acids that are present in other plants are missing and habitually have N-methyltyramine [39]. Amines are also found in the vegetative parts of these plants in a majority [39]. Once sheep eat the fodder of the species of subgenus guajillo, Aculeiferumis A. berlandieri, from North America over prolonged periods, N-methyl-β-phenethylamine (PEA) produces hind-limb ataxia [40]; this compound may also decrease the fertility of male Angora goats [33]. N-Methyl-β-PEA (1) co-exist with β-PEA, N-methyltyramine in the vegetative material of guajillo [40], and three additional amines (hordenine, tyramine, and N-methyltyramine) [33]. Nonetheless, additional sensitive investigation using GC/MS showed the existence of minor quantities of almost 33 other alkaloids and amines, including mescaline, methylamphetamine, amphetamine, mimosine methyl esters, isoquinoline alkaloids, nicotine, and nornicotine [33]. A. roemeriana and A. greggii have both been shown to contain N-Methyl-PEA; however, it is not limited to that subgenus. This component also occurs in A. angustissima of series Filicinae, A. rigidula, A. constricta, and A. schottii. Tyramine is established in A. angustissima, A. roemeriana, and A. greggii [40]. B-PEA and the associated amines have been correspondingly described in certain Australian species of subgenus Phyllodineae involving A. cultriformis, A. hakeoides, A. harpophylla, A. floribunda, A. kettlewelliae, A. adunca, A. linifolia, A. lunata, A. podalyriaefolia, A. longifolia, A. pravissima, A. suaveolens, and A. prominens [41]. N-methyltryptamine likewise N, N-Dimethyltryptamine, and other N-methylated tryptamines are present in A. maidenii, A. simplicifolia, and A. phlebophylla bark [42]. Inside the root bark of A. spirorbis and leaves of A. harpophylla, hordenine exists, while N-α-cinnamoylhistamine is present in A. polystacha, A. argentea, leaves, and A. spirorbis fresh fruit bark [41].

Cyanogenic Glycosides
Several Acacia species possess substances of cyanogenic glycoside nature and are able to deliver hydrogen cyanide once the plant tissue is attacked. For this to happen, the β-glycosidases and the glycosides must be together. Of the identified cyanogenic species, plants have been defined as either devoid of both the enzyme and the substrate, possessing both of them, or having either one of them. Animals may be poisoned by the latter variety. Cyanogens have been discovered in Acacia plants in over 70 species [43], including 45 of the subgenus Phyllodineae and 25 of the subgenus Acacia. A small number of taxa in the subgenus Aculeiferum have been shown to contain cyanide. Cyanogens of the Acacia subgenus are a group of aliphatic components originated from leucine, isoleucine, valine, and, in particular, linamarin, proacipetalin, lotaustralin, epiproacipetaline, proacaciberin, heterodendrin, and 3-hydroxyheterodendrin [44]. Australian species (Almost 96%) in the subgenus Phyllodineae have been explored in a survey. The results showed that 45 species were found to be positive for cyanogenicity, and most of them lie in the Juliflorae group [45]. In these, the cyanogenic glycosides include prunasin (6) and sambunigrin (7). However, two species, i.e., A. pulchella var. reflexa and A. exilis, of the Phyllodineae subgenus have been shown to contain heterodendrin, an aliphatic cyanogen [46]. Generally speaking, cyanogenic species in the Phyllodineae subgenus lack the enzymes required to hydrolyze the compounds rapidly. Though the cyanogenic species of Acacia are widely distributed in Australia, few reports of poisoning livestock attributed to Acacia species exist [45]. The African species A. hereroensis and A. caffra of the subgenus Aculeiferum also encompasses the aromatic cyanogens, sambunigrin, cyanogens, and prunasin. In addition, herbarium specimens of A. welwitschia, A. klugii, and A. chariessa were weakly positive for the release of hydrogen cyanide following the Feigl-Anger test.

Gums
Gum arabic, also known as gum Acacia, is seen as the main exudate extracted, with desired properties, generally from a particular African species, such as A. senegal (Ac-uleiferum). This gum is produced artificially in Sudan by injuring trees and gathering gum tears [56]. Approximately 250 g/tree/year is the average yield, and the whole annual production is close to 60,000 tons [57]. This component is hydro-soluble up to 50% by weight, resulting in a transparent mucilaginous solution with a low viscosity. Gums are produced in response to injury, stress, bacteria, insects, or fungal attacks on the plant as dispersible complex carbohydrates. [58]. Gums are usually released from damaged sites into fissures and fractures in the bark or appear as uneven masses or "tears" on the surface of branches or trunks. Even though the configurations of naturally occurring vegetal gums differ widely, several containing gum arabic have backbones of d-galactopyranose units linked 1 → 3, and many contain four sugars: l-rhamnose, d-glucuronic acid and l-arabinose, and d-galactose. They comprise the cations Mg 2+ , Ca 2+ , and K + [56]. Gums [60]. Several species of Acacia subgenus Phyllodineae are able to produce large amounts of gums [61]. Amongst the species formerly used as commercial gums, Australian black wattle (A. dealbata, A. decurrens, A. pycnantha, A. homalophylla, or A. sentis,) belong, and the gum of an unnamed wattle species too [62]. In the early 1900s, A. rivalis gum provided the foundation for a commercial gum manufacturing industry in South Australia [63]. Nevertheless, a large number of these Australian commercial gums are known to have poor quality; strong in taste, were dark reddish brown vis à vis the color was more likely to alter in gels than in mucilage with water. Gums grown east of the Great Dividing Range are mostly not soluble in water; however, the ones with dry inner are likely to be more water-soluble [64]. In other new investigations, the chemical and physical characteristics of many wattle gums have been studied [59]. Though the initial investigations showed that gums from the species of the Phyllodineae subgenus were described with a low rhamnose percentage, low acidity, high galactose/arabinose ratio, and low intrinsic viscosity, advanced studies have shown much more dissimilarity in several parameters than those firstly observed [59]. The characteristics of common gums from the Acacia species are shown in Table 2.

Tannins
Some Acacia species, including those in the subgenera of Aculeiferum and Acacia, as well as those in the series Filicinae and other mimosoid legumes, contain hydrolyzable tannins [44]. Using the potassium iodate method for gallotannins, the leaves of various species and, to a lesser extent, their bark were found to contain between 1 and 8% hydrolyzable tannins [35]. The chemical 1,3-di-O-galloyl-4,6-hexahydroxydiphenoyl-glucopyranose has been found in the leaves of A. raddiana [97].

Pharmacological Activities
Many studies on the pharmacological properties of Acacia species have been conducted as a result of their widespread use in disease care. Secondary metabolites from the Acacia species have a variety of biological actions, including antibacterial, antifungal, antioxidant, anticancer, antiparasitic, antidiabetic, immunomodulatory, and cytotoxic properties ( Table 1).

Anti-Hypertensive and Anti-Spasmodic Activity
A methanol (MeOH) extract from A. nilotica pods inhibited the rate and force of spontaneous shrinkages in the atria of paired guinea pigs. The activity of the pod extract is thought to be promoted by the calcium channel barrier since it suppressed K-induced contractions in rabbits. The extract's potential was investigated using phentolamine and atropine. Although phentolamine inhibited nor-vasoconstrictor epinephrine's action, the pretreatment of the extract with animal models had no influence on the NE effect, ruling out the role of adrenoceptor blocking. [9]. A methanol extract from the bark of Acacia leucophloea was investigated for potential spasmolytic effects on a rabbit jejunum preparation that spontaneously contracted due to its historical use as a gastrointestinal medication. The findings indicated that the spontaneous contractions were inhibited, pointing to a spasmolytic activity of Acacia leucophloea [108].

Anticancer and Anti-Mutagenic Properties
Plant-derived drugs have demonstrated the greatest impact in the antitumor field, with drugs such as vinblastine, vincristine, taxol, and camptothecin improving chemotherapy for some cancers [109]. A realistic and promising strategic approach to cancer prevention is the continuous search for new anticancer compounds in plant medicines and traditional foods [110]. Therefore, the quest for anticancer molecules in plant biodiversity continues, and Acacia species have not yet escaped this wave of research into natural anticancer molecules. A. modesta has a variety of pharmacological properties, including anticancer. In a study, the anticancer activity of the liver cancer cell line HepG2 was evaluated. In A. modesta plant extracts, HPLC analysis revealed the presence of phytochemicals, such as steroids, alkaloids, phenols, flavonoids, saponins, tannins, anthraquinone, and amino acids. The A. nilotica extract and its components exhibited antimutagenic/antiproliferative effects. The key agents are believed to be flowers and gums. In the investigation of [111], the anticancer potential of the gum (aqueous (Aq.) extract), leaves, and flowers were accessed on papillomagenesis, induced by 7,12-dimethylbenz(a) anthracene (DMBA). The total chromosomal was reduced in mice fed with an Aq. extract via oral gavage, in addition to the significant decrease in the occurrence of micronuclei to combat Dalton's ascetic lymphoma (DAL); the mice models were pretreated with an A. nilotica extract with 10 mg/kg.b.w (14 successive days). The extract significantly reduced tumor expansion compared to the control group. The histopathological effects of the pre-treatment completed with the A. nilotica extract against acetaminophen-induced liver injury in rats showed that the injuries produced by acetaminophen were considerably reduced by owing to its ability to decrease the oxidative stress of acetaminophen-induced hepatocellular impairment [112]. The MeOH had a dose of 5 mg/plate, and the methanol extract from the bark reduced the UV-induced mutagenicity in E. coli WP-2. This decrease could be due to an enzymatic action that reversed pyrimidine dimmer synthesis. [113]. Furthermore, catechin-rich A. catechu extracts demonstrated anticancer activity against the human breast adenocarcinoma cell line (MCF-7) by inhibiting the expression of the transcription factors NF-B, p53, and AP-1, as well as nitric oxide levels [114]. The anticancer activities of A. catechu have already been well summarized previously [115]. Other species with anticancer properties are shown in Table 1.

Analgesic and Anti-Pyretic Activity
Several pathological diseases are triggered by inflammation and pain. The synthetic drugs used to treat these conditions have extremely toxic side effects. Global efforts are underway to introduce novel medicinal plants in order to develop effective, affordable, and safe drugs. Afsar and his colleagues investigated the anti-inflammatory, antipyretic, and analgesic activity of A. hydaspica methanol extract and its active fraction. The findings suggest that the existence of bioactive chemicals in A. hydaspica may be responsible for the pharmacological activities, validating the indigenous value of A. hydaspica towards inflammatory illnesses [12]. The analgesic effects of A. nilotica were evaluated in addition to the acetic-acid-mediated discomfort in rats (with 150 and 300 mg/kg b.w. as dose levels). The effective activity was displayed comparably to a standard drug, acetylsalicylate [116]. The hot-plate method was used to evaluate the analgesic effect compared to 1 mL of aspirin (100 mg/Kg) as a positive control. Organic acids, polysaccharides, and flavonoids were reported to be the inducers of the extract activity [117]. In an additional study, the analgesic and antipyretic effects were evaluated using brewer's yeast (15%) with hot-plate methodology using Wistar Albino rats). The dose of the extract was 400 mg/kg b.w. and the results showed a reduction in the temperature of the rectum from 39.0070.25 • C to 37.7070.15 • C after administration (23 h) [118]. Furthermore, in another study, the analgesic, antipyretic activity, and anti-inflammatory potential of the methanolic extract obtained from A. cyanophylla were evaluated [119]. By using the hot-plate method, the analgesic activity showed a maximal activity of 36.98%, and similar patterns were seen for antipyretic activity.

Anti-Inflammatory
Many studies have proposed the anti-inflammatory activities of different species of Acacia. Eldeen and his coworkers [120] investigated the anti-inflammatory properties of acassane diterpene niloticane extracted from an ethyl acetate bark extract of Acacia nilotica subsp. Kraussiana. The results showed that in the cyclooxygenase test, niloticane possessed activity with IC50 values of 28 and 210 microM against COX-1 and COX-2, respectively. Moreover, the anti-inflammatory potential of using TPA-induced ear edema in mice was presented by the bioactive compounds obtained from aerial portions of Acacia nilotica [121]. The outcomes of the inhibitory activities of the pretreatment undertaken with A. nilotica extract (Aq.) on yeast-induced pyrexia and carrageenan-induced paw edema in rats (with a dosage of 100 mg/Kg b.w.) exhibited a reduction in the edema of the paw (20%), relatively less than that shown by 1 mL aq. aspirin solution (47%) [117]. Aq. pod extracts (50 and 100 mg/kg b.w.) were investigated in rats for carrageenan-induced edema, and the cotton pellet-induced granuloma models and the results showed a maximum inhibition of 64.41 percent and 25.62 percent, respectively [122]. Other groups of researchers investigated the anti-inflammatory properties of extracts from the heartwood of A. confuse. They found that A. confusa heartwood extracts or derived phytocompounds have a high potential for preventing diseases induced by the increased production of reactive oxygen species, including inflammatory diseases [13]. In an additional study, A. tortilis, an Algerian Sahara plant, was evaluated for its phenolic composition and biological activities. The biological activity of the A. tortilis extract was noteworthy, and the phenolic compounds discovered were proposed to be a useful starting point for the creation of cytotoxic and anti-inflammatory medicines [14]. Previous research has also shown that the pharmaceutical properties of A. hydaspica might be attributed to its indigenous value against inflammatory diseases [12]. The extracts of Acacia modesta also showed potent anti-inflammatory, antipyretic, analgesic, antidepressant, and anticoagulant activities, which conclude that the bark of A. modesta has significant therapeutic potential [123].

Anti-Microbial Activity
The species of Acacia have broad-spectrum antibacterial properties against a variety of diseases. A. ataxacantha is a pharmacological species widely used in the traditional medicine of the Benin Republic to treat infectious disorders. Three chemicals (1-3) were isolated and identified from the bark of A. ataxacantha using chromatographic and spectroscopic techniques. Three triterpenoids were isolated during a phytochemical analysis of A. ataxacantha (Fabaceae) (lupeol (1), betulinic acid (2), and betulinic acid-3-trans-caffeate (3). Compound 3 had a higher MIC value of 12.5 g/mL against Staphylococcus epidermidis and Candida albicans. The overall findings of this investigation showed that compound 3 isolated from A. ataxacantha has antimicrobial activity towards Gram-positive and Gramnegative bacteria and yeast, particularly Candida albicans [16]. A. plicosepalus yielded a novel flavanocoumarin, loranthin (1), as well as catechin (2), quercetin (3), rutin (4), gallic acid (5), and methyl gallate (6). Loranthin has the unusual flavanocoumarin skeleton, which connects the flavan and coumarin moieties via C-7/C-8 of both moieties. Loranthin's antibacterial activity was tested against many pathogens, and it was found to have a substantial impact against Staphylococcus aureus [18]. The other Acacia, i.e., A. farnesiana, has been shown to exhibit antibacterial activity against Vibrio cholerae. By using nuclear magnetic resonance (NMR) methods ((1) H NMR and (13) C NMR), the active component was extracted from A. farnesiana and identified as methyl gallate. Methyl gallate degraded cell membrane integrity, resulting in a reduction in cytoplasmic pH (pHin, from 73 to 30) and membrane hyperpolarization, and the treated cells no longer generated ATP [19]. Cavazos and his coworkers evaluated the antibacterial and antioxidant activity of the extracts of A. berlandieri and A rigidula leaves (acetone, methanol, and acetic acid) [23]. A. rigidula leaf extracts exhibited antibacterial activity against Pseudomonas alcalifaciens, Pseudomonas aeruginosa, Y. enterocolitica, E. coli, S. aureus, and E. faecalis, while A. berlandieri displayed minimal inhibitory effects against P. alcalifaciens, P. aeruginosa, and Y. enterocolitica; thus, highlighting the significance of the species as a antimicrobial agent. The microbial inhibition of A. nilotica (leaf extract) on E. coli was proposed to be associated with the antibacterial activity, with a minimum inhibitory concentration of 70 mg/mL. This demonstrated the plant's potential for treating Campylobacter-related microbial infections. [38]. The susceptibility of Campylobacter to the extract is of great interest seeing the common antibiotic resistance phenomena of the organism [38]. The aqueous extracts of A. catechu also exhibited an antimicrobial effect against Staphylococcus aureus, Pseudomonas aeruginosa, Proteus mirabilis, E coli, and Klebsiella pneumonia with a diameter of zone of inhibition (ZoI) of 17.66 ± 1.52, 16.66 ± 1.15, 14.0 ± 2.0, 8.33 ± 0.57, and 8.0 ± 0.0 mm, respectively [124]. Many other studies proposed the potent antimicrobial activity of A. catechu [125][126][127]. Thus, the data suggest that A. catechu, which is abundant in bioactive secondary metabolites, may be a promising source of compounds for the development of new antimicrobial drugs.

Antioxidant Activity
Acacia species contain a high concentration of polyphenolic chemicals, which have significant antioxidant capabilities and help to reduce the risk and treatment of oxidative stressrelated disorders, such as cardiovascular, neurological, and cancer. Several publications have extensively studied the antioxidant activity of Acacia species in vitro, utilizing radicals such as 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis[3-ethylbenzothiazoline-6sulphonic acid] (ABTS) [128]. A. hydaspica is a natural shrub that has a variety of medicinal characteristics. Afsar et al. evaluated A. hydaspica polyphenol-rich ethyl acetate extract against cisplatin (CP)-induced lung-damaged rats. The results showed that because of its inherent antioxidant capacity and polyphenolic components, A. hydaspica extract might serve as a possible adjuvant that reduced CP-induced lung damage [17]. Lotfi Ghribia and his coworkers investigated the anti-acetycholinesterase and antioxidant potential activity of compounds and extracts from A. cyanophylla. In the DPPH test, the ethanolic extract of the flowers exhibited the highest antioxidant effect (67.26 µg/mL). The isolated compound, Isosalipurposide 1, also showed a significant antiradical power [21]. Next, five Acacia heartwood methanolic extracts, including A. mangium, A. auriculiformis, A. crassicarpa, A. leucophloea, and A. deccurens, were tested for antioxidant activity using three different in vitro assays. The A. crassicarpa extracts exhibited the highest antioxidant activity, which was accompanied by high phenolic and hydrolyzable tannin concentrations [22].
Many countries around the world, including Pakistan, consider soil salinity to be a severe environmental issue. A. stenophylla and A. albida were studied in a hydroponic experiment to investigate distinct mechanisms of salinity resistance. According to the findings of this study, A. stenophylla is more salinity-tolerant than A. albida because it maintains better ionic balance and stronger antioxidant enzyme activities, resulting in increased biomass production [129]. Additionally, the flower extracts of A. dealbata were investigated during three stages of flowering. The results indicated that the hydroethanolic extracts performed well for all of these biological activities, including antioxidant activity, and the results varied according to the maturity status of the flowers, with the early stage being the most active, which can be attributed to the chalcones content [25]. These first results suggested that A. dealbata could be a good source of natural antioxidants, which may be used to stabilize free radicals that induce oxidative stress.
In another study, during the MeOH extract fractionation of the A. nilotica extract, the AN-2 fraction was isolated and recognized using spectroscopic methods, i.e., mass spectroscopy and NMR, to be a derivative of coumarin (umbelliferone). The anti-oxidative properties in vitro, comprising the deoxyribose, DPPH, reducing power, lipid peroxidation, and chelating power assays, were performed. The results showed that the anti-oxidative activity of umbelliferone was dependent on the concentration, almost 100 µg/mL, and leveled off later with no more activity enhancement. This shows the first document for the antioxidant activity exhibited by umbelliferone isolated from A. nilotica [38]. In the study, the two extraction techniques were evaluated for radical scavenging power. The results showed that the consecutive extraction was efficient in concentrating the bioactive agents in the extract when compared with the maceration. The investigation indicated that the extract of ethanol has high quantities of flavonoid and phenolic compounds and had effective and significant antioxidant potential. The antioxidant activity of the extract (ethanolic) may be attributed to its ability to donate electrons or hydrogen, as well as its direct radical scavenging abilities [130]. Similarly, different studies reported the antioxidant potential of A. catechu. Aryal et al. found that both ethanol and methanol extracts of A. catechu barks exhibit antioxidant potential, assessed by DPPH radical scavenging assay [131]. Additionally, DPPH radical and ABTS radical scavenging assays, ferric reducing power assays, super-oxide radical scavenging assays, and lipid peroxidation with an IC50 of 48.65-54.44 mg of equivalents/g powder demonstrated the antioxidant capacity of methanol and aqueous extracts of A. catechu [132].

Anti-Filarial and Antidiabetic Activity
Diabetes is one of the world's five main causes of death. Many herbal medications have been advocated for the treatment of diabetes in addition to the currently available therapeutic options [128]. Previously, authors have documented Acaciaside (both A and B), glucuronic, and methylglucuronic acid, rhamnose, galactose, and arabinose isolated from many parts of A. auriculiformis (Fabaceae) [133]. Acaciaside A and B, which was isolated from the funicles, displayed anti-filarial property both in vitro and in vivo vis à vis bovine filarial parasite Setaria cervi [134,135]. The A. auriculiformis ethanolic extract was found to be effective against microfilaria and tested on dogs infected with Dirofilaria immitis [28]. Acaciaside A also has anti-cestocidal activity [136]. It is also documented to possess antiplasmodial activity [137]. The A. nilotica ssp. Indica was found to display hypoglycemic properties and the blood sugar levels dropped by almost 25.05% in normal rats nourished for one week; however, it did not exhibit significant hypoglycemic activity in alloxanised diabetic rats. The hypoglycaemic property of the legumes was owing to the indirect or direct stimulation of the β-cells of islets of Langerhans to release more insulin [138]. The other study suggests that a hydroethanolic leaf extract of A. auriculiformis possesses good antioxidant and enzyme inhibitory potential, which, in turn, might be responsible for its antidiabetic effects [29]. Similarly, A. catechu extracts showed an antidiabetic activity towards porcine pancreatic α-amylase, [139] with an IC 50 of 49.9 µg/mL. Ethyl acetate, dichloromethane, aqueous fractions, and a crude methanolic extract of the bark of A. catechu showed the inhibitory activity of α-glucosidase and α-amylase, with IC50 ranges of 9-115 g/mL, in another investigation [131]. Kumar et al. studied the antidiabetic potential of an aqueous extract of A. tortilis polysaccharide from gum exudates and its role in the comorbidities associated with diabetes in STZ-nicotinamide-induced diabetic rats [140]. The administration of 500 and 1000 mg/kg doses of the extract showed a significant reduction in fasting blood glucose level compared to diabetic control after 7 days, thus, revealing the potential of A. tortilis for the treatment of T2DM and its comorbidities. Furthermore, chloroform extracts of A. arabica bark significantly decreased the elevated serum glucose levels in alloxan-induced diabetic albino rats [141].

Antiviral and Nematicidal Activity
The crude extract of the plant's leaves presented antiviral effects against the Turnip mosaic virus in vitro. The reduction was found in a number of lesions on the host's C. album (80.2%) and Chenopodium amaranticolor (93.77%), and the lesions decreased once the extract was present on the leaves of the host. The potato virus was repressed by the bark extract [142]. The nematicidal activity was observed by the Aq. leaf extract of the plant and A. senegal as well against Meloidogyne incogenita by the inhibition of its hatching [143]. DNA viruses, viruses belonging to Herpesviridae, Poxviridae, and Papillomaviridae were targeted using V. nilotica, and resulted in anti-bovine herpes virus and direct virucidal activity against goatpox virus. The meta-analysis inferred that V. nilotica could be a promising source of anti-hepatitis C virus drug leads with the ability to prevent its long-term sequelae while promoting immune competence [144]. Additionally, another study aimed to assess the cytotoxic and antiviral activity of an aqueous leaf extract of A. catechu against the new castle disease virus (NDV) on human peripheral blood mononuclear cells (PBMC). Variable doses of the aqueous leaf extract of A. catechu (0.5-30 mg/mL, 50 L; diluted in phosphatebuffered saline, PBS) were tested, and the results showed that at higher concentrations, the aqueous leaf extract of A. catechu suppressed NDV proliferation and also decreased CD14 monocyte surface marker with or without NDV [31].

Pharmaceutical Preparation That Have Acacia its Main Molecules
The prospective, placebo, randomized, and positively controlled test was intended to assess the clinical properties of an existing gel enclosing A. arabica for decreasing gingival inflammation and plaque in gingivitis patients. Ninety individuals diagnosed with chronic general gingivitis were included, and then they were arbitrarily distributed (into three groups): Group I, constituted the placebo; Group II, gumtone; Group III, chlorhexidine (1%). A clinical assessment was carried out using the plaque index at baseline and the gingival index of Loe and Silness. Gumtone gel presented substantial clinical enhancement against the index of plaque and gingival scores in comparison to Group I, with a placebo-containing gel. The enhancement was similar to 1% chlorhexidine (gel). Dissimilar to chlorhexidine gel, the gumtone gel was not related to unpleasant taste or the discoloration of teeth [145,146]. This combines the ordinary teeth whitening fiber, PEELU, which exhibits invigorating and astringent characteristics of NEEM, as well as other roots, barks, flowers, and plants that were valued by Ayurvedic Professionals for centuries for their distinct and combined efficacy in maintaining superior hygiene. Polishes and cleans teeth to their whitest, refreshes and soothes sensitive gums, and purifies the breath and mouth naturally. Ingredients: Immunity maintenance supports intercellular interactions, which are offered through the glyconutrient blend and eight sugar immune enhancers. Glyconutrient Blend is a branded blend of ingredients. It contains eight immune-boosting glyconutrients derived from the whole coffee bean, as well as other natural ingredients. These nutrients are known as vital components for cellular network signaling, as well as playing particular functions in immune responses. ImmunEnhancer™ (a polysaccharide) is derived from a Larch known as Arabinogalactan. The basis of good health is built upon a strong responsive immune system. Arabinogalactan's effects on NK Cells have been shown i to maintain a healthy immune system in scientific investigations. Organic Acacia Fiber Powder is a dietary fiber made from the gum of the Acacia tree; it is pure, natural, and soluble. Research has indicated that soluble fiber in the diet can aid in improving bowel regularity. The powder also exhibits tremendous prebiotic potential, as it is able to support healthy intestinal flora. Since it reduces fermentation and decreases bloating and gas problems, Acacia powder is well tolerated. This powder can be taken on a daily basis and does not contain any gastrointestinal irritant stimulants [147]. To date, scientists are looking for new alternatives and ways to increase the value of the various products derived from A. nilotica. The by-products of the species A. nilotica have been explored for their full use in diverse fields. The multipurpose value of A. nilotica as a source of fodder, fence posts, fuel, wood, shade, gums, and tannin has provoked the researchers with further directions for investigation. The gum obtained from the trunk has already been part of the cosmetic, textile dyeing, printing, food, and pharmaceutical industries [148]. The leaves have also been used to remove hazardous synthetic colors and heavy metals from wastewater as bio-adsorbents. It can also be used as a bio-indicator to monitor pollution from heavy metals, copper, and cobalt.

Herb-Drug Interaction
To date, research based on drug-herbal interactions has generally been limited to case reports and limited systematic reviews. Meanwhile, for the treatment of several medical conditions, supplements of herbal drugs are used around the world. These are used in combination with drugs or used alone [149]. In some cases, the combined use of herbs and drugs may alter the pharmacokinetic profile of drugs [150]. The simultaneous usage of herbal medicines may increase, oppose, or stimulate the activity of drugs. Clinically, the lack of efficacy might be the consequence of these interactions, as well as toxic reactions, and unexpected side effects. Thus, healthcare professionals should remain vigilant for the potential interactions between herbal medicines and prescribed drugs, especially when drugs with a narrow therapeutic index are used. The data show that the Acacia gum obtained from A. rabi, reduced the absorption of drugs, such as amoxicillin [151]. The findings indicate that the coexistence of amoxicillin and gum rabic in the upper gastrointestinal tract resulted in a pharmacokinetic interaction that significantly decreased the absorption of amoxicillin. The other study proposed that black catechu can significantly alter theophylline pharmacokinetics in vivo, possibly due to the inhibition of CYP1A and P-glycoprotein activity; thus, precaution should be exercised when administering black catechu with CYP1A substrate [152].

Conclusions
Ethnopharmacology is the field that involves the detailed study of plants to identify new medications and the development of advanced drugs. Genus Acacia includes a group of plants with promising pharmacological properties. This review summarizes the presence of phytoconstituents in different Acacia species with diverse and potent pharmacological properties, including anti-inflammatory, analgesic, antioxidant, antimutagenic, antiproteolytic, antiviral, nematicidal activity, and so on. Mainly, polyphenols are responsible for the antioxidant potential of different extracts and the said pharmacological potential. The use of Acacia extracts and their active agents in different herbal formulations further demonstrated the medicinal value of this genus. Due to the promising therapeutic role of different species of Acacia, further studies should be carried out in order to develop multifunctional drugs and describe their bioavailability, pharmacokinetics, physiological pathways, and importance to human health in sufficient detail.