Naturally Occurring Xanthones and Their Biological Implications

Xanthones are chemical substances in higher plants, marine organisms, and lower microorganisms. The most prevalent naturally occurring sources of xanthones are those belonging to the families Caryophyllaceae, Guttiferae, and Gentianaceae. Structurally, xanthones (9H xanthan-9-one) are heterocyclic compounds with oxygen and a γ-pyrone component. They are densely packed with a two-benzene ring structure. The carbons in xanthones are numbered from their nucleus and biosynthetic construct. They have mixed shikimate-acetate (higher plants) and acetate-malonate (lower organisms) biosynthetic origins, which influence their classification. Based on the level of oxidation of the C-ring, they are classified into monomers, dimers, and heterodimers. While based on the level of oxygenation or the type of ring residue, they can be categorized into mono-, di-, tri-, tetra-, penta- and hexa-oxygenated xanthones, bis-xanthones, prenylated and related xanthones, xanthonolignoids, and other miscellaneous xanthones. This structural diversity has made xanthones exhibit considerable biological properties as promising antioxidant, antifungal, antimicrobial, and anticancer agents. Structure-activity relationship studies suggest C-1, C-3, C-6, and C-8 as the key positions that influence the biological activity of xanthones. Furthermore, the presence of functional groups, such as prenyl, hydroxyl, glycosyl, furan, and pyran, at the key positions of xanthones, may contribute to their spectrum of biological activity. The unique chemical scaffolds of xanthones, their notable biological activities, and the structure–activity relationships of some lead molecules were discussed to identify lead molecules as possible drug candidates.


Introduction
Xanthones are a heterocyclic class of secondary metabolites that are mostly found in lichen, fungi, and higher plant groups.They are formed from dibenzo-γ-pyrone, which is γ-pyrone condensed with two benzene rings (Figure 1A,B) [1,2].The term "xanthone" was first used by J.C. Robert in 1961.Since these metabolites are typically formed as yellow solids, the word "xanthone" comes from the Greek word "xanthos", which means yellow tint.The first documented xanthone derivative to be extracted from Gentiana lutea roots was gentian in 1821.The chemical formula of xanthone is C 13 H 8 O 2 , and its IUPAC designation is 9H-xanthen-9-one [3].
Lichens, fungi, plants (Polygalaceae, Moraceae, Gentianaceae, and Guttiferae families), and ferns all contain these tricyclic secondary chemicals.These metabolites are widely distributed in nature and because of their chemical makeup and position of the substituent groups on the aromatic ring, they have a variety of biological actions.Derivatives of xanthones come from two main sources: the marine environment (lower organisms) or naturally occurring sources of higher plants, which can be manufactured and extracted [4,5].Researchers have been motivated to extract, separate, and purify these heterocyclic metabolites from their natural origins to prepare them as prospective candidates for drug development due to their unique structural architecture and known pharmacological effects.In the past twenty years, researchers have concentrated on understanding the structure-activity relationship of xanthones to use them effectively in medicine.Numerous xanthone derivatives, both natural and artificial, have been examined and found to offer major health benefits [6].Xanthones and their derivatives can bind to several protein receptors involved in the etiology of diseases, making them have a wide range of biological activities, including antidiabetic, antioxidative, anti-inflammatory, anticancer, antibacterial, and antithrombotic effects [7][8][9][10][11][12].Lichens, fungi, plants (Polygalaceae, Moraceae, Gentianaceae, and Guttiferae families), and ferns all contain these tricyclic secondary chemicals.These metabolites are widely distributed in nature and because of their chemical makeup and position of the substituent groups on the aromatic ring, they have a variety of biological actions.Derivatives of xanthones come from two main sources: the marine environment (lower organisms) or naturally occurring sources of higher plants, which can be manufactured and extracted [4,5].Researchers have been motivated to extract, separate, and purify these heterocyclic metabolites from their natural origins to prepare them as prospective candidates for drug development due to their unique structural architecture and known pharmacological effects.In the past twenty years, researchers have concentrated on understanding the structure-activity relationship of xanthones to use them effectively in medicine.Numerous xanthone derivatives, both natural and artificial, have been examined and found to offer major health benefits [6].Xanthones and their derivatives can bind to several protein receptors involved in the etiology of diseases, making them have a wide range of biological activities, including antidiabetic, antioxidative, anti-inflammatory, anticancer, antibacterial, and antithrombotic effects [7][8][9][10][11][12].

Methodology
The study involved an extensive literature search through various scientific databases (including Google Scholar, PubMedCentral, SciFinder, Scopus, and Web of Science) for information on naturally occurring xanthones.For the literature review, the following were the inclusive criteria: naturally occurring xanthones, history of xanthones, classes of xanthones, biosynthesis of xanthones, biological activities of xanthones (antifungal, antibacterial, anticancer, coagulant, antioxidant, anti-inflammatory, and anti-HIV/AIDS effects), and structure-activity relationship of xanthones.Exclusive criteria included a search for classes of compounds other than xanthones.All chemical structures were drawn using ACD/ChemSketch (Freeware) version 2021.1.1 (Advanced Chemistry Development, Inc., Toronto, ON, Canada).

History of Xanthones
De Koning and Giles discovered bikaverin, a wine-red pigment that was separated from many species of the fungi Fusarium, Gibberella, and Mycogone, in 1988 [30].Bikaverin contains a quinone moiety, which may be responsible for its biological properties, such as antiprotozoal and antitumor activities [31,32].The first report of natural xanthone, Gentisin (1,7-dihydroxy-3-methoxyxanthone), came from the higher plant Gentiana lutea in 1821, while the first prenylxanthone derivative, tajixanthone, was isolated from the fungus, Aspergillus stellatus in 1970 [33].
In 1971, Bikaverin and norbikaverin were discovered by Kjaër and associates [34].Using trifluoroacetic anhydride (TFAA) in combination with the synthesized naphthalene derivative (I) and the aryl acid (II), de Koning et al. [30] first introduced the carbonyl bridge to form the xanthone nucleus (Figure 2).This resulted in the intended product being produced as a single regioisomer (III) in a 51% yield.Palladium on carbon in the presence of hydrogen under pressure was then used to deprotect the compound, affording the phenol (IV) an 80% yield.Using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to oxidize the phenol (IV) resulted in the surprise production of the spiro compound (V) in a 61% yield.With the use of aqueous trifluoroacetic acid (TFA), the spiro compound was hydrolyzed to the required trione (VI) in a 94% yield.Pyrolytic isomerization of the trione (VI) resulted in a 93% yield of the xanthone-based chemical.The mechanism of the DDQ-facilitated reaction that results in the creation of the spiro compound has not been thoroughly explored since this synthesis.Investigating this innovative synthesis's versatility was also necessary, especially regarding more electron-poor precursors.Owing to the wide diversity of biological activities exhibited by xanthones, it is critical to identify a flexible synthetic strategy that can support a variety of xanthone ring structures.
yield.With the use of aqueous trifluoroacetic acid (TFA), the spiro compound was hydrolyzed to the required trione (VI) in a 94% yield.Pyrolytic isomerization of the trione (VI) resulted in a 93% yield of the xanthone-based chemical.The mechanism of the DDQ-facilitated reaction that results in the creation of the spiro compound has not been thoroughly explored since this synthesis.Investigating this innovative synthesis's versatility was also necessary, especially regarding more electron-poor precursors.Owing to the wide diversity of biological activities exhibited by xanthones, it is critical to identify a flexible synthetic strategy that can support a variety of xanthone ring structures.
Xanthone is structurally described as 9H-xanthen-9-one, a heterocyclic compound having a dibenzo-γ-pyrone moiety, with a basic molecular formula of C 13 H 8 O 2 [3,35].They are categorized based on their structural characteristics as xanthone monomers and xanthone dimers/heterodimers, and further into four subclasses based on the level of oxidation of the xanthone C-ring: fully aromatic-, dihydro-, tetrahydro-, and hexahydroxanthones (Table 1).The xanthone nucleus is numbered according to the mixed biosynthetic origins of the carbons in plants, which is in line with the IUPAC recommendations [36].

Parent Class Structural Example Natural Source (Family) Reference
Based on the level of oxidation of the C-ring Monomers 1 (Xanthones) are categorized based on their structural characteristics as xanthone monomers and xanthone dimers/heterodimers, and further into four subclasses based on the level of oxidation of the xanthone C-ring: fully aromatic-, dihydro-, tetrahydro-, and hexahydroxanthones (Table 1).The xanthone nucleus is numbered according to the mixed biosynthetic origins of the carbons in plants, which is in line with the IUPAC recommendations [36].

Isomangiferin
Mangifera indica (Anacardiaceae) [59] Biosynthetically, xanthones from higher plants are derived from mixed shikimateacetate origin [14], while those from fungi and other lower organisms are often acetatederived [3,36], as presented in Figure 3A,B.In higher plants, the xanthone nucleus is of mixed biosynthetic origin, with the A-and C-rings giving rise to acetate and shikimic acid pathways, respectively (Figure 3A).The biosynthetic pathways for eliciting xanthones from Gentiana lutea are presented in Figure 3A,B.Here, 3-hydroxybenzoic acid derived from phenylalanine is coupled with three acetate units to form a polyketide.Aromatization of the side chain occurs, leading to a freely rotating benzophenone intermediate, which undergoes divergent oxidative phenolic coupling to give two different products, the 1,3,7-trihydroxyxanthone and the 1,3,5-trihydroxyxanthone mediated by xanthone synthase, a membrane-bound enzyme associated with cytochrome P450 [60].In lower organisms, xanthones are biosynthesized from eight acyl groups, connected to each other to form 1,3,5,7,9,11,13,15-octaketonic intermediate.The octaketonic intermediate can cyclize to form benzoquinone and benzophenone intermediates.The benzophenone intermediate further transformed to produce ravenelin [3] (Figure 3C).

Isomangiferin
Mangifera indica (Anacardiaceae) [59] Biosynthetically, xanthones from higher plants are derived from mixed shikimateacetate origin [14], while those from fungi and other lower organisms are often acetatederived [3,36], as presented in Figure 3A,B.In higher plants, the xanthone nucleus is of mixed biosynthetic origin, with the A-and C-rings giving rise to acetate and shikimic acid pathways, respectively (Figure 3A).The biosynthetic pathways for eliciting xanthones from Gentiana lutea are presented in Figure 3A,B.Here, 3-hydroxybenzoic acid derived from phenylalanine is coupled with three acetate units to form a polyketide.Aromatization of the side chain occurs, leading to a freely rotating benzophenone intermediate, which undergoes divergent oxidative phenolic coupling to give two different products, the 1,3,7trihydroxyxanthone and the 1,3,5-trihydroxyxanthone mediated by xanthone synthase, a membrane-bound enzyme associated with cytochrome P450 [60].In lower organisms, xanthones are biosynthesized from eight acyl groups, connected to each other to form 1,3,5,7,9,11,13,15-octaketonic intermediate.The octaketonic intermediate can cyclize to form benzoquinone and benzophenone intermediates.The benzophenone intermediate further transformed to produce ravenelin [3] (Figure 3C).

Biological Activities of Natural Xanthones with Structure-Activity Relationship (SAR) Insight
Xanthones have been linked to a number of biological characteristics, including antifungal, antibacterial, anticancer, coagulant, antioxidant, anti-inflammatory, anti-HIV/AIDS, and insecticidal effects.

Biological Activities of Natural Xanthones with Structure-Activity Relationship (SAR) Insight
Xanthones have been linked to a number of biological characteristics, including antifungal, antibacterial, anticancer, coagulant, antioxidant, anti-inflammatory, anti-HIV/AIDS, and insecticidal effects.

Antifungal Activity
Three xanthones isolated from the dichloromethane extract of Hypericum brusiliense stems and roots, 5-hydroxy-1-methoxyxanthone (1), 6-deoxyjacareubin (2), and 1,5-dihydroxyxanthone (3), have been reported to demonstrate notable inhibition against the activity of the pathogenic fungus, Cladosporium cucumerinum.Based on the thin-layer chromatography (TLC)-bioautographic assay method, the minimum amounts of compounds 1-3 needed to inhibit the growth of the fungus were 3, 3, and 0.25 µg/mL, respectively, while propiconazole (standard drug) showed activity at 0.1 µg/mL [61].Considering the structural configuration of these xanthones, it may not be far-fetched to attribute their considerable antifungal activities to the tricyclic xanthone nucleus and complete oxidation (aromatization) of the C-ring.Additionally, the presence of 1,5-dihydroxyl group in 3 might have contributed to its best activity, while an extra pyran ring seemed to have caused a notable reduction in the activity of 2 (Figure 4A).In another related study using the TLC bioautographic method, the antifungal activity of six xanthones, 2-deprenylreediaxanthone B (4), 5-O-methyl-2-deprenylrheediaxanthone B (5), calcinoxanthone D (6), roeperanone (7), 5-O-demethylpaxanthonin (8), and 5-O-methylisojacareubin (9), isolated from H. roeperanum, was evaluated against Candida albicans and Cladosporium cucumerinum [62].The xanthones 4-8 showed selective inhibitory activity against Candida albicans at a minimum of 1 µg/mL, which was comparable to amphotericin B (standard drug = 1 µg/mL) but lower in activity than miconazole (standard drug = 0.001 µg/mL).However, the least active xanthone was 9, requiring a minimum of 5 µg/mL for inhibition [62].By structurally relating these xanthones to their antifungal activities, again, one could attribute the least potency of 8 to its extra pyran moiety (Figure 4B).On the other hand, the xanthone nucleus with a hydroxyl group at positions C-1 and C-6 might have contributed majorly to the similar antifungal activity displayed by 4-8, while the presence of a furan ring attached to the C-ring of 4 and 5, prenyl (lavandulyl) substituent at position C-4 of the xanthones 6 and 7, as well as the cyclized terpene moiety attached to position C-2 of 8, might not have contributed much to the antifungal activity of the respective xanthones (Figure 4B).It is worthy of mention that the presence of γ-pyrone and phenolic hydroxyl moieties as characterized by flavonoids and xanthones, enhances antimicrobial activity by increasing the hydrophilicity of the pathogen cell to cause leakage of ions out of the cytoplasm, leading to increased osmotic pressure in the cytoplasm, thereby resulting in cell lysis [63].
Future studies may include evaluating the potency of 1,5-dihydroxyxanthone (3) and that of xanthones 4-8 on clinical isolates of fungi, elucidating their molecular mechanisms of action, and obtaining more active analogs that can be optimized as antifungal drug candidates.

Antibacterial Activity
Some natural xanthones have been reported to show broad-spectrum antibacterial activities.For instance, the young fruits and flowers of Garcinia cowa afforded nineteen xanthones, with antibacterial activity exhibited against Bacillus cereus, B. subtilis, Staphylococcus aureus, S. typhimurium, Escherichia coli and Pseudomonas aeruginosa at a minimum inhibitory concentration (MIC) range of 2-128 µg/mL [64].All 19 xanthones showed complete oxidation, that is, their C-ring was aromatized.However, based on the SAR study, six of the xanthones: garciniacowone E (10), fuscaxanthone A (11), 7-O-methylgarcinone E (12), α-mangostin (13), rubraxanthone (14), and garcinianone B (15), showed varying level of activity, as presented in Figure 4.It was revealed that prenylation and oxygenation of the xanthone's dibenzo-γ-pyrone core influence their antibacterial activity.There was an improvement in the activity of α-mangostin (13) against B. subtilis (MIC = 8 µg/mL) compared to 10 (MIC = 128 µg/mL).This could be attributed to the presence of prenyl substituent at positions C-2 and C-8 as well as the tri-oxygenation (trihydroxy substituent) at positions C-1, C-3 and C-6.Furthermore, the best activity (MIC = 2 µg/mL) displayed by garcinianone B (15) could be linked to the presence of a geranyl (C 10 ) unit at position C-8 and the 1,3,6-trihydroxy substituent.Conversely, the presence of an extra pyran ring depleted the antibacterial activity, as revealed in garciniacowone E (10) with MIC of 128 µg/mL (Figure 5).Previous studies have shown that in addition to the ion-solubilizing properties of the phenolic groups, prenylation of xanthones and other flavonoid derivatives may help to alter the hydrophilicity-lipophilicity properties of the peptidoglycan lipid bilayers of the periplasmic membrane of the bacteria, making the membrane permeable for cell lysis [63,65].In summary, the chemical diversity of xanthones provides an opportunity to elucidate their SARs, highlighting the importance of prenylation (geranyl) at position C-8 and hydroxylation at C-6 for optimal antibacterial activity.However, in vivo studies are required to determine further the safety and efficacy of lead xanthones such as rubraxanthone ( 14) and garcinianone B (15) for possible drug candidates against bacterial infections in the future.

Antibacterial Activity
Some natural xanthones have been reported to show broad-spectrum antibacterial activities.For instance, the young fruits and flowers of Garcinia cowa afforded nineteen xanthones, with antibacterial activity exhibited against Bacillus cereus, B. subtilis, Staphylococcus aureus, S. typhimurium, Escherichia coli and Pseudomonas aeruginosa at a minimum inhibitory concentration (MIC) range of 2-128 μg/mL [64].All 19 xanthones showed complete oxidation, that is, their C-ring was aromatized.However, based on the SAR study, able for cell lysis [63,65].In summary, the chemical diversity of xanthones provides an opportunity to elucidate their SARs, highlighting the importance of prenylation (geranyl) at position C-8 and hydroxylation at C-6 for optimal antibacterial activity.However, in vivo studies are required to determine further the safety and efficacy of lead xanthones such as rubraxanthone (14) [64] with copyright permission from © American Chemical Society (Washington, DC, USA) and American Society of Pharmacognosy (Northbrook, IL, USA).

Anticancer Activity
. Antibacterial activity of some xanthones of Garcinia cowa against Bacillus cereus [64].The bioactive moieties are illustrated in red and blue.

Anti-Inflammatory Activity
In the search for natural anti-inflammatory agents, it is critical to look for lead compounds that have one or more of the following pharmacological actions: (1) suppress transcription control of genes encoding enzymes responsible for prostaglandin (PG) biosynthesis or inflammatory cytokines; and (2) prevent the release of PGs, the major chemical mediators in the regulation of inflammation, by directly inhibiting the enzymes responsible for arachidonic acid (AA) and PG biosynthesis, including phospholipase A2 and cyclooxygenase-2 (COX-2) [79].The anti-inflammatory properties of five xanthone compounds-demethylpaxantonin, patulone, garcinone B, tripteroside, and 1,3,5,6-tetrahydroxyxanthone-purified from an H. patulum callus tissue culture were evaluated according to Yamakuni et al. [80].Two of the xanthones demonstrated considerable activity: patulous (41), which inhibits COX-1 activity and A23187-induced PGE2 release, possibly having an anti-inflammatory effect, and garcinone B (42), which inhibits both A23187-induced prostaglandin E2 (PGE2) release and lipopolysaccharide (LPS)-induced necrosis factor kappa β (NF-κβ)-dependent transcription.According to these findings, 42 may find use as a neuropharmacological instrument in the investigation of intracellular signaling networks related to inflammation [80].A great cellular model for researching synoviocyte physiology in connection to the onset and management of rheumatoid arthritis (RA) is the human fibroblast-like synoviocyte rheumatoid arthritis (HFLS-RA) [81].In an HFLS-RA cell-based assay involving α-Mangostin (13), it was discovered that 10 μg/mL of the Figure 8. Xanthones from Polygala japonica with their in vitro ferric-reducing antioxidant power [78].Functional groups indicated in blue and red are presented to show the structure-activity relationship.

Anti-Inflammatory Activity
In the search for natural anti-inflammatory agents, it is critical to look for lead compounds that have one or more of the following pharmacological actions: (1) suppress transcription control of genes encoding enzymes responsible for prostaglandin (PG) biosynthesis or inflammatory cytokines; and (2) prevent the release of PGs, the major chemical mediators in the regulation of inflammation, by directly inhibiting the enzymes responsible for arachidonic acid (AA) and PG biosynthesis, including phospholipase A2 and cyclooxygenase-2 (COX-2) [79].The anti-inflammatory properties of five xanthone compounds-demethylpaxantonin, patulone, garcinone B, tripteroside, and 1,3,5,6tetrahydroxyxanthone-purified from an H. patulum callus tissue culture were evaluated according to Yamakuni et al. [80].Two of the xanthones demonstrated considerable activity: patulous (41), which inhibits COX-1 activity and A23187-induced PGE2 release, possibly having an anti-inflammatory effect, and garcinone B (42), which inhibits both A23187-induced prostaglandin E2 (PGE2) release and lipopolysaccharide (LPS)-induced necrosis factor kappa β (NF-κβ)-dependent transcription.According to these findings, 42 may find use as a neuropharmacological instrument in the investigation of intracellular signaling networks related to inflammation [80].A great cellular model for researching synoviocyte physiology in connection to the onset and management of rheumatoid arthritis (RA) is the human fibroblast-like synoviocyte rheumatoid arthritis (HFLS-RA) [81].In an HFLS-RA cell-based assay involving α-Mangostin (13), it was discovered that 10 µg/mL of the compound inhibited the nuclear translocation of the transcriptional inflammatory protein, p65, and suppressed the production and activation of important proteins in the NF-κβ pathway to inhibit the inflammatory process [82].It is worth mentioning that the anti-inflammatory α-Mangostin (13), patulone (40), and garcinone B (41) have their position C-8 substituted with prenyl and pyrano moieties with hydroxyl group at positions C-1, C-3, and C-8 (Figure 9).This underscores the importance of these functional groups on the overall anti-inflammatory activity of xanthones.Further in vivo studies, including mechanistic analysis, would help to establish the anti-inflammatory potency of xanthones and their definitive impact on their structural moieties in combating inflammatory conditions.
Molecules 2024, 29,4241 19 of 27 compound inhibited the nuclear translocation of the transcriptional inflammatory protein, p65, and suppressed the production and activation of important proteins in the NF-κβ pathway to inhibit the inflammatory process [82].It is worth mentioning that the antiinflammatory α-Mangostin (13), patulone (40), and garcinone B (41) have their position C-8 substituted with prenyl and pyrano moieties with hydroxyl group at positions C-1, C-3, and C-8 (Figure 9).This underscores the importance of these functional groups on the overall anti-inflammatory activity of xanthones.Further in vivo studies, including mechanistic analysis, would help to establish the anti-inflammatory potency of xanthones and their definitive impact on their structural moieties in combating inflammatory conditions.

Anti-HIV/AIDS Activity
Significant advancements have been made over the last three decades in identifying therapeutic approaches for the human immunodeficiency virus (HIV), which causes the acquired immune deficiency syndrome (AIDS).Replication of the virus is inhibited by blocking reverse transcriptase-catalyzed deoxyribonucleic acid (DNA) polymerization from viral ribonucleic acid (RNA), as reverse transcriptase is necessary early in proviral synthesis [83].Reverse transcriptases are thought to be promising targets for chemotherapy because they may be unique to certain viruses [83].Natural xanthones have demonstrated action against the human immunodeficiency virus (HIV) in recent times.Many xanthones have secondary therapeutic activities against fungal infections in immunecompromised HIV/AIDS patients in addition to their direct antiviral activity [83].Swertifrancheside (42), a flavone xanthone glycoside (xanthone dimer) from Swertia franchetiana has been reported to show a considerable level of activity in inhibiting HIV reverse transcriptase [84].Two prenylated xanthones, macluraxanthone B (43) and macluraxanthone C (44), isolated from Maclura tinctoria bark have been reported to show considerable anti-HIV activity [85].After passing an initial anti-HIV screening stage, 43 and 44 demonstrated good potential with EC50 values of 1.1-2.0μg/mL.With IC50 levels ranging from 2.2 to 3.7 μg/mL, the catechol functionality (6,7-dihydroxylbenzoyl and 5,6-

Anti-HIV/AIDS Activity
Significant advancements have been made over the last three decades in identifying therapeutic approaches for the human immunodeficiency virus (HIV), which causes the acquired immune deficiency syndrome (AIDS).Replication of the virus is inhibited by blocking reverse transcriptase-catalyzed deoxyribonucleic acid (DNA) polymerization from viral ribonucleic acid (RNA), as reverse transcriptase is necessary early in proviral synthesis [83].Reverse transcriptases are thought to be promising targets for chemotherapy because they may be unique to certain viruses [83].Natural xanthones have demonstrated action against the human immunodeficiency virus (HIV) in recent times.Many xanthones have secondary therapeutic activities against fungal infections in immune-compromised HIV/AIDS patients in addition to their direct antiviral activity [83].Swertifrancheside (42), a flavone xanthone glycoside (xanthone dimer) from Swertia franchetiana has been reported to show a considerable level of activity in inhibiting HIV reverse transcriptase [84].Two prenylated xanthones, macluraxanthone B (43) and macluraxanthone C (44), isolated from Maclura tinctoria bark have been reported to show considerable anti-HIV activity [85].After passing an initial anti-HIV screening stage, 43 and 44 demonstrated good potential with EC 50 values of 1.1-2.0µg/mL.With IC 50 levels ranging from 2.2 to 3.7 µg/mL, the catechol functionality (6,7-dihydroxylbenzoyl and 5,6-dihydroxylbenzoyl moieties) of the xanthones appears to give increased HIV inhibitory activity, but they also demonstrate substantial toxicity against CEM-SS host cells [85].Thus, it may not be far-fetched to attribute the anti-HIV activity of 42-44 to the xanthone's dibenzo-γ-pyrone nucleus, the C-ring (C-1 and C-3) substitution with a hydroxyl group, and the presence of flavone glycoside at position C-6 (Figure 10).
Molecules 2024, 29, 4241 20 of 27 dihydroxylbenzoyl moieties) of the xanthones appears to give increased HIV inhibitory activity, but they also demonstrate substantial toxicity against CEM-SS host cells [85].Thus, it may not be far-fetched to attribute the anti-HIV activity of 42-44 to the xanthone's dibenzo-γ-pyrone nucleus, the C-ring (C-1 and C-3) substitution with a hydroxyl group, and the presence of flavone glycoside at position C-6 (Figure 10).

Antidiabetic Activity
The antidiabetic properties of some natural xanthones, such as γ-mangostin (25) and mangiferin (39), have been potentiated [86].Mangiferin is a xanthoneglycoside primarily found in the fruits, peels, stembarks, and leaves of Mangifera indica, while γ-Mangostin has been reported in the fruits of Garcinia mangostana [87,88].The study showed that xanthones could enhance insulin sensitivity, regulate glucose metabolism, and inhibit oxidative stress and inflammation through the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs) signaling pathways.Based on in vitro studies, it was demonstrated that natural xanthones such as γ-mangostin (25) from Garcinia mangostana and mangiferin (39) from Mangifera indica inhibit α-amylase and αglucosidase enzymes, with IC50 values of 3.2 μM and 5.6 μM, respectively, showcasing their potential to improve glucose metabolism [86,89].Further in vivo studies on 39 in streptozotocin-induced diabetic rats have shown its ability to lower fasting blood glucose levels and improve HDL levels, which may help in the overall glycemic control and lipid profiles [90].

Antidiabetic Activity
The antidiabetic properties of some natural xanthones, such as γ-mangostin (25) and mangiferin (39), have been potentiated [86].Mangiferin is a xanthoneglycoside primarily found in the fruits, peels, stembarks, and leaves of Mangifera indica, while γ-Mangostin has been reported in the fruits of Garcinia mangostana [87,88].The study showed that xanthones could enhance insulin sensitivity, regulate glucose metabolism, and inhibit oxidative stress and inflammation through the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs) signaling pathways.Based on in vitro studies, it was demonstrated that natural xanthones such as γ-mangostin (25) from Garcinia mangostana and mangiferin (39) from Mangifera indica inhibit α-amylase and α-glucosidase enzymes, with IC 50 values of 3.2 µM and 5.6 µM, respectively, showcasing their potential to improve glucose metabolism [86,89].Further in vivo studies on 39 in streptozotocininduced diabetic rats have shown its ability to lower fasting blood glucose levels and improve HDL levels, which may help in the overall glycemic control and lipid profiles [90].
Based on the discussed biological activities of natural xanthones with their structural features, it can be summarized that xanthones are a unique class of compounds with a wide range of biological applications owing to their tricyclic dibenzo-γ-pyrone nucleus.It is worthy of mention that some xanthones from the mangosteen plant (G.mangostana), are known to display dual bioactivity.For instance, garcinone E (50) is a potent dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) [98].Also, α-mangostin (13), γ-mangostin (25), and 8-deoxygartanin (31) showed considerable multitarget actions against the digestive enzymes, α-amylase (IC 50 = 33.3µM), α-glucosidase (IC 50 = 69.2µM) and pancreatic lipase (164.4 µM) [99].These enzymes are known to play an important role in the metabolism of carbohydrates and lipids Thus, the mangosteen xanthones could further be exploited in the search for attractive therapeutic targets for the treatment of type 2 diabetes and obesity Therefore, further pharmacological assessment of these xanthones may be worthwhile.
Molecules 2024, 29, 4241 22 These enzymes are known to play an important role in the metabolism of carbohyd and lipids Thus, the mangosteen xanthones could further be exploited in the searc attractive therapeutic targets for the treatment of type 2 diabetes and obesity There further pharmacological assessment of these xanthones may be worthwhile.Finally, the distinct chemical scaffold of xanthones, such as prenylation at th position, including the geranyl (C-10) substituent, the presence of hydroxyl group a sitions C-1, C-6, and C-7, as well as the attachment of furan ring to the C-ring, may c interesting biological activities on xanthones.Thus, having compounds with such s tural construct, as in the proposed 8,8-Bis-(3,7-dimethyl-octa-2,6-dienyl)-1,6,9,10-tet droxy-1,2,3a,7a,8,12c-hexahydro-furo[3′,2′:4,5]furo [2,3-c]xanthen-7-one (51) (Figure 1 is expected that xanthones and their derivatives will continue to attract much inter drug discovery.(50).[The functional group may be involved in the bioactivity are in multicolor, including the green notation to highlig catechol group].

Conclusions and Future Prospects
Naturally occurring xanthones have been discussed through this review to show their natural abundance and distinct biosynthetic pathways, giving rise to unique ch cal scaffolds with notable biological activities, including antifungal, antibacterial, cancer, coagulant, antioxidant, anti-inflammatory, anti-HIV/AIDS, antidiabetic, an secticidal activities.Guttiferae, Gentianaceae, and Polygalaceae are among the h plant families with abundant xanthone sources, while Aspergillaceae is prominent am  (50).[The functional groups that may be involved in the bioactivity are in multicolor, including the green notation to highlight the catechol group].

Conclusions and Future Prospects
Naturally occurring xanthones have been discussed through this review to showcase their natural abundance and distinct biosynthetic pathways, giving rise to unique chemical scaffolds with notable biological activities, including antifungal, antibacterial, anticancer, coagulant, antioxidant, anti-inflammatory, anti-HIV/AIDS, antidiabetic, and insecticidal activities.Guttiferae, Gentianaceae, and Polygalaceae are among the higher plant families with abundant xanthone sources, while Aspergillaceae is prominent among the families of lower plants containing this unique chemical class.From the structure-activity relationship viewpoint, the effect of prenylation, oxygenation (hydroxyl group), and glycosylation, as well as furan and pyran substitutions of the dibenzo-γ-pyrone nucleus of xanthones, on the biological activities have been discussed.Therefore, having xanthones characterized by these chemical substituents at positions C-1, C-3, C-6, and C-8 may help to generate more active analogs as possible drug candidates.Among the promising xanthones highlighted in this study are γand α-mangostins, norathyriol, mangiferin, and isomangiferin, sterigmatocystin, while the structure, 8,8-Bis-(3,7-dimethyl-octa-2,6-dienyl)-1,6,9,10-tetrahydroxy-1,2,3a,7a,8,12c-hexahydro-furo[3 ′ ,2 ′ :4,5]furo [2,3-c]xanthen-7-one, which may offer greater biological effect, has been proposed though this study.However, the available biological data on xanthones is still limited.There is, therefore, a need for further investigation of the promising xanthones through efficacy and safety studies.With this, there would be enough in vivo and clinical data to sufficiently decipher the specific pharmacological actions of the promising compounds and their molecular mechanism of action for lead optimization.

Figure 1 .
Figure 1.Chemical structure of xanthone, showing its (A) basic nucleus/tricyclic ring system and (B) the different oxidation states of the C-ring.The carbon numbers are indicated in blue color.

Figure 1 .
Figure 1.Chemical structure of xanthone, showing its (A) basic nucleus/tricyclic ring system and (B) the different oxidation states of the C-ring.The carbon numbers are indicated in blue color.

Figure 2 .
Figure 2. Reaction scheme to produce xanthone-based compounds [34].Structures are drawn with copyright permission from © RSC Publishing.

Figure 4 .
Figure 4. Antifungal activity of some naturally occurring xanthones showing the structure-activity relationships (colored moieties) against (A) Cladosporium cucumerinum; and (B) Candida albicans.Structures redrawn according to Rocha et al.[61] and Rath et al.[62] with Copyright permission from © Elsevier Science Ltd., Amsterdam, The Netherlands.

Figure 6 .
Figure 6.Some natural anticancer xanthones show the structure-activity relationships in red and blue.

Figure 7 .
Figure 7.Some xanthones from Garcinia mangostana showing their structure-activity relationships based on CDK4 inhibition.Functional groups in blue and red influence anticancer activity.Structures redrawn with copyright permission from © 2019 Bhaskar Vemu et al. [77].

Figure 7 .
Figure 7.Some xanthones from Garcinia mangostana showing their structure-activity relationships based on CDK4 inhibition[77].Functional groups in blue and red influence anticancer activity.

Figure 8 .
Figure 8. Xanthones from Polygala japonica with their in vitro ferric-reducing antioxidant power.Functional groups indicated in blue and red are presented to show the structure-activity relationship.Structures redrawn with copyright permission from Li et al. [78].

Figure 9 .
Figure 9. Notable anti-inflammatory xanthones showing their active functional groups in blue and red.Structures redrawn according to Yamakuni et al. [80] and Zhuo et al. [82].

Figure 10 .
Figure 10.Anti-HIV xanthones from Swertia franchetiana [84] and Maclura tinctoria [85].[The functional groups that may be involved in the anti-HIV activity are in multicolor, including the green notation to highlight the catechol group].

Figure 10 .
Figure 10.Anti-HIV xanthones from Swertia franchetiana [84] and Maclura tinctoria [85].[The functional groups that may be involved in the anti-HIV activity are in multicolor, including the green notation to highlight the catechol group].

50 Figure 12 .
Figure 12.Chemical structures of some xanthones showing those with insecticidal activities (4 [93-97] and a proposed structure for possible biological evaluation (50).[The functional group may be involved in the bioactivity are in multicolor, including the green notation to highlig catechol group].

Figure 12 .
Figure 12.Chemical structures of some xanthones showing those with insecticidal activities (45-49) [93-97] and a proposed structure for possible biological evaluation (50).[The functional groups that may be involved in the bioactivity are in multicolor, including the green notation to highlight the catechol group].

Table 1 .
Classification of naturally occurring xanthones.

Table 1 .
Classification of naturally occurring xanthones.

Table 1 .
Classification of naturally occurring xanthones.

Table 1 .
Classification of naturally occurring xanthones.

Table 1 .
Classification of naturally occurring xanthones.

Table 1 .
Classification of naturally occurring xanthones.

Table 1 .
Classification of naturally occurring xanthones.
Based on the level of oxygenation/type of ring residueO OH Mammea americana
(15)garcinianone B(15)for possible drug candidates against bacterial infections in the future.
Figure 5. Antibacterial activity of some xanthones of Garcinia cowa against Bacillus cereus.The bioactive moieties are illustrated in red and blue.Structures redrawn according to Sriyatep et al.