Chiral Derivatives of Xanthones with Antimicrobial Activity

According to the World Health Organization, the exacerbated use of antibiotics worldwide is increasing multi-resistant infections, especially in the last decade. Xanthones are a class of compounds receiving great interest in drug discovery and development that can be found as natural products or obtained by synthesis. Many derivatives of xanthones are chiral and associated with relevant biological activities, including antimicrobial. The aim of this review is to compile information about chiral derivatives of xanthones from natural sources and their synthesized examples with antimicrobial activity.


Introduction
According to the Center for Disease Control and Prevention, almost half of all antibiotics prescribed in outpatient clinics are unnecessary [1,2], where the overuse of antibiotics is one of the causes of increasing bacterial resistance [3]. Additionally, the unregulated availability of antibiotics in a community frequently leads to ill-advised self-medication. For example, in certain countries of Africa and Asia, the use of non-prescription antimicrobials is quite frequent, which leads to unnecessary and inadequate consumption, dose, and treatment periods [3]. These behaviors prompt microorganism adaptation rather than treating infections [4], pointing towards an alarming increase of infections triggered by resistant strains. Therefore, treatments tend to be more expensive and with lower efficiency. Infections caused by strains with no response to antibiotics, such as vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureaus (MRSA) are becoming more frequent and fatal [1]. Consequently, research for new antimicrobial agents to fight these pathogens remains a challenge [1]. Frequently, the marked antibiotics interfere with bacterial biosynthesis, which is easily mutated, leading to a loss of activity and development of new resistant strains [5]. Therefore, it is important to develop new antimicrobial agents using different strategies to minimize mutations or other mechanisms of resistance [5].
This review reunites the natural and synthetic chiral derivatives of xanthones (CDXs) with relevant antimicrobial activities. The described configuration of the stereogenic centers, the specific rotation, the enantiomeric ratio, and the enantioselectivity are presented in accordance to the source of the work.

Natural Chiral Derivatives of Xanthones
Natural products usually are complex structures with multiple stereogenic centers and a wide spectrum of biological activities [26,37,38]. The bulk of the plant extracts with pharmacological activity was established due to their traditional health care use in tribes and indigenous population [9,[39][40][41]. Natural xanthone derivatives offer a wide range of biological activities with established pharmacological purposes [42]. One of the most studied xanthones found in nature is α-mangostin, isolated from tropical fruits of Garcinia mangostana. These fruits have been used for many decades in folk medicine to treat diarrhea, skin infections, and chronic wounds in Southeast Asia [10,43]. Several studies have been reported about its anticancer and antimicrobial activities, among others [10,14,16,27,[43][44][45][46]. The xanthone α-mangostin is not chiral, but many chiral derivatives were isolated and presented interesting antimicrobial activity along with other similar structures.
In order to verify the structure-activity relationship (SAR) of natural CDXs with common chemical groups, such as furan, pyran, hydroxy side chains, and others, the CDXs and antimicrobial activity were reunited in different topics.
This review reunites the natural and synthetic chiral derivatives of xanthones (CDXs) with relevant antimicrobial activities. The described configuration of the stereogenic centers, the specific rotation, the enantiomeric ratio, and the enantioselectivity are presented in accordance to the source of the work.

Natural Chiral Derivatives of Xanthones
Natural products usually are complex structures with multiple stereogenic centers and a wide spectrum of biological activities [26,37,38]. The bulk of the plant extracts with pharmacological activity was established due to their traditional health care use in tribes and indigenous population [9,[39][40][41]. Natural xanthone derivatives offer a wide range of biological activities with established pharmacological purposes [42]. One of the most studied xanthones found in nature is α-mangostin, isolated from tropical fruits of Garcinia mangostana. These fruits have been used for many decades in folk medicine to treat diarrhea, skin infections, and chronic wounds in Southeast Asia [10,43]. Several studies have been reported about its anticancer and antimicrobial activities, among others [10,14,16,27,[43][44][45][46]. The xanthone α-mangostin is not chiral, but many chiral derivatives were isolated and presented interesting antimicrobial activity along with other similar structures.
In order to verify the structure-activity relationship (SAR) of natural CDXs with common chemical groups, such as furan, pyran, hydroxy side chains, and others, the CDXs and antimicrobial activity were reunited in different topics.
Calozeyloxanthone (8N) revealed an interesting activity against many strains of MRSA and MSSA [55], and tovophyllin-B (7N) and artoindonesianin-C (10N) presented activity against mycobacterial strain [46,56] (Table 2). Regarding the structural similarity, these compounds (7N, 8N, and 10N), unlike the others of this group, contain two cycle units that contribute toward increasing the lipophilicity, which is a determinant factor to improve antimicrobial activity [46].
Calozeyloxanthone (8N) revealed an interesting activity against many strains of MRSA and MSSA [55], and tovophyllin-B (7N) and artoindonesianin-C (10N) presented activity against mycobacterial strain [46,56] (Table 2). Regarding the structural similarity, these compounds (7N, 8N, and 10N), unlike the others of this group, contain two cycle units that contribute toward increasing the lipophilicity, which is a determinant factor to improve antimicrobial activity [46].
Calozeyloxanthone (8N) revealed an interesting activity against many strains of MRSA and MSSA [55], and tovophyllin-B (7N) and artoindonesianin-C (10N) presented activity against mycobacterial strain [46,56] (Table 2). Regarding the structural similarity, these compounds (7N, 8N, and 10N), unlike the others of this group, contain two cycle units that contribute toward increasing the lipophilicity, which is a determinant factor to improve antimicrobial activity [46].
Calozeyloxanthone (8N) revealed an interesting activity against many strains of MRSA and MSSA [55], and tovophyllin-B (7N) and artoindonesianin-C (10N) presented activity against mycobacterial strain [46,56] (Table 2). Regarding the structural similarity, these compounds (7N, 8N, and 10N), unlike the others of this group, contain two cycle units that contribute toward increasing the lipophilicity, which is a determinant factor to improve antimicrobial activity [46].

Natural CDXs with Hydroxy Side Chains
Oxygenated and prenylated xanthones have been investigated as new drugs due to their pharmacological properties [58], such as antimalarial [59] and antimicrobial activities [60], among others. Besides these xanthones, only a few structures are found in nature containing hydroxy group in the lateral chains, and some of them displayed interesting antimicrobial activities (Table 3).

Natural CDXs with Hydroxy Side Chains
Oxygenated and prenylated xanthones have been investigated as new drugs due to their pharmacological properties [58], such as antimalarial [59] and antimicrobial activities [60], among others. Besides these xanthones, only a few structures are found in nature containing hydroxy group in the lateral chains, and some of them displayed interesting antimicrobial activities (Table 3). Fuscaxanthone I (12N) was isolated from G. fusca and presented anti-H. pylori activity [61]. Caledol (13N) and dicaledol (14N) were isolated from C. caledonicum, and both presented antifungal activity against A. fumigates [62]. Antimycobacterial activity was exhibited by mangostenol (15N), isolated from G. Mangostana, which was evaluated against M. tuberculosis [45,46].

Natural Caged Xanthones
Another important type of CDXs are the caged xanthones, where one of the aromatic rings of the xanthone scaffold lost the aromaticity to form a bicyclic ring resulting in multiple stereogenic centers.

Natural Caged Xanthones
Another important type of CDXs are the caged xanthones, where one of the aromatic rings of the xanthone scaffold lost the aromaticity to form a bicyclic ring resulting in multiple stereogenic centers.

Natural Caged Xanthones
Another important type of CDXs are the caged xanthones, where one of the aromatic rings of the xanthone scaffold lost the aromaticity to form a bicyclic ring resulting in multiple stereogenic centers.

Natural Caged Xanthones
Another important type of CDXs are the caged xanthones, where one of the aromatic rings of the xanthone scaffold lost the aromaticity to form a bicyclic ring resulting in multiple stereogenic centers.

Natural Caged Xanthones
Another important type of CDXs are the caged xanthones, where one of the aromatic rings of the xanthone scaffold lost the aromaticity to form a bicyclic ring resulting in multiple stereogenic centers.
A few caged xanthones with antimicrobial activity were reported (Table 4).  concentrations [69][70][71][72][73][74]. A few caged xanthones with antimicrobial activity were reported (Table 4).    The antimicrobial studies were determined using the disc diffusion method, where the inhibitory growth zones inhibition caused by the tested compounds is expressed in millimeters.
Rukachaisirikul et al. [65,75] described the scortechinone structures (16-31N) and Reutrakul et al. [17,64] reported the prenylated caged xanthones (32-36N). The specific rotations were measured and the configuration of the stereogenic centers were defined for all of the scortechinones structures (16-31N) [65,66,75,76] (Table 4). According to the antimicrobial assays, scortechinones B (17N) and C (18N) stand out due to their promising antibacterial activity against MRSA [75]. It is important to highlight that some compounds are epimers of each other, as for example scortechinone L (27N) and scortechinone A (16N) in carbon C-15, being the activity of L (27N) higher than the activity of A (16N), with MIC values of >64 and 128 µg/mL, respectively [65]. This result emphasizes the relevance of the stereochemistry in the development of new antimicrobial agents.
Additionally, Sukpondma et al. [66] found out that the crude methanol extract from the fruits of Garcinia hanburyi was significantly active against MRSA. This discovery led to exploring the antimicrobial activity of the compounds 37-41N present in this extract. These compounds embody a pyran group, which leads to an increase of their activity. Reutrakul et al. [17,64] also reported the antimicrobial properties of some caged xanthones with pyran group (42-44N) ( Table 5). Rukachaisirikul et al. [65,75] described the scortechinone structures (16-31N) and Reutrakul et al. [17,64] reported the prenylated caged xanthones (32-36N). The specific rotations were measured and the configuration of the stereogenic centers were defined for all of the scortechinones structures (16-31N) [65,66,75,76] (Table 4). According to the antimicrobial assays, scortechinones B (17N) and C (18N) stand out due to their promising antibacterial activity against MRSA [75]. It is important to highlight that some compounds are epimers of each other, as for example scortechinone L (27N) and scortechinone A (16N) in carbon C-15, being the activity of L (27N) higher than the activity of A (16N), with MIC values of >64 and 128 µg/mL, respectively [65]. This result emphasizes the relevance of the stereochemistry in the development of new antimicrobial agents.
Additionally, Sukpondma et al. [66] found out that the crude methanol extract from the fruits of Garcinia hanburyi was significantly active against MRSA. This discovery led to exploring the antimicrobial activity of the compounds 37-41N present in this extract. These compounds embody a pyran group, which leads to an increase of their activity. Reutrakul et al. [17,64] also reported the antimicrobial properties of some caged xanthones with pyran group (42-44N) ( Table 5). Rukachaisirikul et al. [65,75] described the scortechinone structures (16-31N) and Reutrakul et al. [17,64] reported the prenylated caged xanthones (32-36N). The specific rotations were measured and the configuration of the stereogenic centers were defined for all of the scortechinones structures (16-31N) [65,66,75,76] (Table 4). According to the antimicrobial assays, scortechinones B (17N) and C (18N) stand out due to their promising antibacterial activity against MRSA [75]. It is important to highlight that some compounds are epimers of each other, as for example scortechinone L (27N) and scortechinone A (16N) in carbon C-15, being the activity of L (27N) higher than the activity of A (16N), with MIC values of >64 and 128 µg/mL, respectively [65]. This result emphasizes the relevance of the stereochemistry in the development of new antimicrobial agents.
Additionally, Sukpondma et al. [66] found out that the crude methanol extract from the fruits of Garcinia hanburyi was significantly active against MRSA. This discovery led to exploring the antimicrobial activity of the compounds 37-41N present in this extract. These compounds embody a pyran group, which leads to an increase of their activity. Reutrakul et al. [17,64] also reported the antimicrobial properties of some caged xanthones with pyran group (42-44N) ( Table 5).  [65,66,75,76] (Table 4). According to the antimicrobial assays, scortechinones B (17N) and C (18N) stand out due to their promising antibacterial activity against MRSA [75]. It is important to highlight that some compounds are epimers of each other, as for example scortechinone L (27N) and scortechinone A (16N) in carbon C-15, being the activity of L (27N) higher than the activity of A (16N), with MIC values of >64 and 128 µg/mL, respectively [65]. This result emphasizes the relevance of the stereochemistry in the development of new antimicrobial agents. According to Table 4, prenylated caged xanthones (32-36N) showed little or no activity against MRSA and MSSA strains [17,64].
Additionally, Sukpondma et al. [66] found out that the crude methanol extract from the fruits of Garcinia hanburyi was significantly active against MRSA. This discovery led to exploring the antimicrobial activity of the compounds 37-41N present in this extract. These compounds embody a pyran group, which leads to an increase of their activity. Reutrakul et al. [17,64] also reported the antimicrobial properties of some caged xanthones with pyran group (42-44N) ( Table 5). Table 5. Antimicrobial activity of natural caged xanthones with pyran group. (16-31N) [65,66,75,76] (Table 4). According to the antimicrobial assays, scortechinones B (17N) and C (18N) stand out due to their promising antibacterial activity against MRSA [75]. It is important to highlight that some compounds are epimers of each other, as for example scortechinone L (27N) and scortechinone A (16N) in carbon C-15, being the activity of L (27N) higher than the activity of A (16N), with MIC values of >64 and 128 µg/mL, respectively [65]. This result emphasizes the relevance of the stereochemistry in the development of new antimicrobial agents. According to Table 4, prenylated caged xanthones (32-36N) showed little or no activity against MRSA and MSSA strains [17,64].
Additionally, Sukpondma et al. [66] found out that the crude methanol extract from the fruits of Garcinia hanburyi was significantly active against MRSA. This discovery led to exploring the antimicrobial activity of the compounds 37-41N present in this extract. These compounds embody a pyran group, which leads to an increase of their activity. Reutrakul et al. [17,64] also reported the antimicrobial properties of some caged xanthones with pyran group (42-44N) ( Table 5). Table 5. Antimicrobial activity of natural caged xanthones with pyran group.

39N
Morellin and the configuration of the stereogenic centers were defined for all of the scortechinones structures (16-31N) [65,66,75,76] (Table 4). According to the antimicrobial assays, scortechinones B (17N) and C (18N) stand out due to their promising antibacterial activity against MRSA [75]. It is important to highlight that some compounds are epimers of each other, as for example scortechinone L (27N) and scortechinone A (16N) in carbon C-15, being the activity of L (27N) higher than the activity of A (16N), with MIC values of >64 and 128 µg/mL, respectively [65]. This result emphasizes the relevance of the stereochemistry in the development of new antimicrobial agents. According to Table 4, prenylated caged xanthones (32-36N) showed little or no activity against MRSA and MSSA strains [17,64].
Additionally, Sukpondma et al. [66] found out that the crude methanol extract from the fruits of Garcinia hanburyi was significantly active against MRSA. This discovery led to exploring the antimicrobial activity of the compounds 37-41N present in this extract. These compounds embody a pyran group, which leads to an increase of their activity. Reutrakul et al. [17,64] also reported the antimicrobial properties of some caged xanthones with pyran group (42-44N) ( Table 5). Table 5. Antimicrobial activity of natural caged xanthones with pyran group. Comparing the structures and activities from compounds 37N to 44N (Table 5), the moreollic acid (40N) and morellic acid (41N) presented higher activity than the others [64,66]. This suggested that antimicrobial activity comes from the simultaneous presence of a carboxylic group in the prenylated chain in C-8 (according to xanthone scaffold, Figure 1) and another prenyl chain (C-1) [66]. The same conclusion was found by Chaiyakunvat et al. [64] who reported that morelic acid (41N) and gambogic acid (44N) revealed the greatest activities. Only a few examples measured the specific rotations. Comparing the structures and activities from compounds 37N to 44N (Table 5), the moreollic acid (40N) and morellic acid (41N) presented higher activity than the others [64,66]. This suggested that antimicrobial activity comes from the simultaneous presence of a carboxylic group in the prenylated chain in C-8 (according to xanthone scaffold, Figure 1) and another prenyl chain (C-1) [66]. The same conclusion was found by Chaiyakunvat et al. [64] who reported that morelic acid (41N) and gambogic acid (44N) revealed the greatest activities. Only a few examples measured the specific rotations. Comparing the structures and activities from compounds 37N to 44N (Table 5), the moreollic acid (40N) and morellic acid (41N) presented higher activity than the others [64,66]. This suggested that antimicrobial activity comes from the simultaneous presence of a carboxylic group in the prenylated chain in C-8 (according to xanthone scaffold, Figure 1) and another prenyl chain (C-1) [66]. The same conclusion was found by Chaiyakunvat et al. [64] who reported that morelic acid (41N) and gambogic acid (44N) revealed the greatest activities. Only a few examples measured the specific Comparing the structures and activities from compounds 37N to 44N (Table 5), the moreollic acid (40N) and morellic acid (41N) presented higher activity than the others [64,66]. This suggested that antimicrobial activity comes from the simultaneous presence of a carboxylic group in the prenylated chain in C-8 (according to xanthone scaffold, Figure 1) and another prenyl chain (C-1) [66]. The same conclusion was found by Chaiyakunvat et al. [64] who reported that morelic acid (41N) Comparing the structures and activities from compounds 37N to 44N (Table 5), the moreollic acid (40N) and morellic acid (41N) presented higher activity than the others [64,66]. This suggested that antimicrobial activity comes from the simultaneous presence of a carboxylic group in the prenylated chain in C-8 (according to xanthone scaffold, Figure 1) and another prenyl chain (C-1) [66]. The same conclusion was found by Chaiyakunvat et al. [64] who reported that morelic acid (41N) The antimicrobial studies were determined using the disc diffusion method, where the inhibitory growth zones' inhibition caused by the tested compounds is expressed in millimeters.
Comparing the structures and activities from compounds 37N to 44N (Table 5), the moreollic acid (40N) and morellic acid (41N) presented higher activity than the others [64,66]. This suggested that antimicrobial activity comes from the simultaneous presence of a carboxylic group in the prenylated chain in C-8 (according to xanthone scaffold, Figure 1) and another prenyl chain (C-1) [66]. The same conclusion was found by Chaiyakunvat et al. [64] who reported that morelic acid (41N) and gambogic acid (44N) revealed the greatest activities. Only a few examples measured the specific rotations.
The stereochemistry of the natural caged xanthones is represented in all the structures but their absolute configuration was only described and determined by Ren et al. [71,77] for structures 41 and 44N, gambogic and morellic acid, respectively.

Other Natural CDXs
Antimicrobial activity of natural CDXs such as kielcorins or structures with glycoside and peptide groups, were also reported. In this subsection, natural CDXs with diverse chemical nature are presented ( Table 6). Table 6. Antimicrobial activity of other natural CDXs.

No.
Name/Structure Antimicrobial Activity (MIC or Zone of Growth)

Kielcorin
Molecules 2019, 24, x FOR PEER REVIEW 10 of 28 Table 6. Antimicrobial activity of other natural CDXs. Coqueiro et al. [78] explored the benefits of Kielmeyera variabilis, a tree used in folk medicine to treat several tropical diseases, which is known to harbor active compounds against MRSA, such as kielcorin (45N). Another example is mangiferin (46N), which comprises a glycoside structure and its pharmacological and biological benefits have been studied for many years [7,79]. In USA, mangiferin can be found in Vimang ® , an antioxidant commercialized aqueous extract of M. indica and G.  Table 6. Antimicrobial activity of other natural CDXs. Coqueiro et al. [78] explored the benefits of Kielmeyera variabilis, a tree used in folk medicine to treat several tropical diseases, which is known to harbor active compounds against MRSA, such as kielcorin (45N). Another example is mangiferin (46N), which comprises a glycoside structure and its pharmacological and biological benefits have been studied for many years [7,79]. In USA, mangiferin can be found in Vimang ® , an antioxidant commercialized aqueous extract of M. indica and G. mangostana commonly known to improve human health [7,80]. In addition, mangiferin has been  Table 6. Antimicrobial activity of other natural CDXs. Coqueiro et al. [78] explored the benefits of Kielmeyera variabilis, a tree used in folk medicine to treat several tropical diseases, which is known to harbor active compounds against MRSA, such as kielcorin (45N). Another example is mangiferin (46N), which comprises a glycoside structure and its pharmacological and biological benefits have been studied for many years [7,79]. In USA, mangiferin can be found in Vimang ® , an antioxidant commercialized aqueous extract of M. indica and G. mangostana commonly known to improve human health [7,80]. In addition, mangiferin has been tested as an antiviral treatment [81,82].  Table 6. Antimicrobial activity of other natural CDXs. Coqueiro et al. [78] explored the benefits of Kielmeyera variabilis, a tree used in folk medicine to treat several tropical diseases, which is known to harbor active compounds against MRSA, such as kielcorin (45N). Another example is mangiferin (46N), which comprises a glycoside structure and its pharmacological and biological benefits have been studied for many years [7,79]. In USA, mangiferin can be found in Vimang ® , an antioxidant commercialized aqueous extract of M. indica and G. mangostana commonly known to improve human health [7,80]. In addition, mangiferin has been tested as an antiviral treatment [81,82].  Table 6. Antimicrobial activity of other natural CDXs. Coqueiro et al. [78] explored the benefits of Kielmeyera variabilis, a tree used in folk medicine to treat several tropical diseases, which is known to harbor active compounds against MRSA, such as kielcorin (45N). Another example is mangiferin (46N), which comprises a glycoside structure and its pharmacological and biological benefits have been studied for many years [7,79]. In USA, mangiferin can be found in Vimang ® , an antioxidant commercialized aqueous extract of M. indica and G. mangostana commonly known to improve human health [7,80]. In addition, mangiferin has been Coqueiro et al. [78] explored the benefits of Kielmeyera variabilis, a tree used in folk medicine to treat several tropical diseases, which is known to harbor active compounds against MRSA, such as kielcorin (45N). Another example is mangiferin (46N), which comprises a glycoside structure and its pharmacological and biological benefits have been studied for many years [7,79]. In USA, mangiferin can be found in Vimang ® , an antioxidant commercialized aqueous extract of M. indica and G. mangostana commonly known to improve human health [7,80]. In addition, mangiferin has been tested as an antiviral treatment [81,82].
Recent studies concern pharmacological properties of mangiferin, such as antipyretic [80] and antimicrobial [79] properties, leading Sigh et al. [79] to explore other derivatives ( Table 6). The promising results led the group to develop mangiferin analogues with antimicrobial activity [79,80], which are described in Section 3.2 (Mangiferin Analogues).
In another study, Siler et al. [83] analyzed extracts of Centaurium species with antibacterial agents for food preservation. According to this report, mangiferin (46N) was considered a good hit structure in antimicrobial drug development [83].
Moon et al.'s studies [84] in Streptomyces strains resulted in the discovery of a new secondary metabolite, buanmycin (47N), a pentacyclic xanthone with one stereogenic center determined as (S)-enantiomer. The antimicrobial potential of these marine strains was explored against S. aureus, B. subtilis, and K. rhizophila (Table 6).
Microluside A (48N) is a glycosylated disubstituted xanthone. It was isolated by Eltamany et al. [85] from the broth culture of Micrococcus sp. EG45, a species presented in the Red Sea sponge: Spheciospongia vagabunda (Table 6).
Wang et al. [86] isolated the first dimer xanthone derivative from the bark of G. mangostana, garmoxanthone (49N), which announced the strong activity against two strains of MRSA (Table 6).

Synthetic CDXs
Synthetic derivatives are especially important structures, not only for performing SAR studies, but also to develop new compounds, to increase the chemical diversity, and to increase the biological activities. The majority of synthetic CDXs are inspired in natural xanthone derivatives, to take advantage of their already reported biological properties, and to attempt to improve their biological response [7,31,87].
Despite the fact that natural compounds possess pharmacological applications, their structures are limited to their production, and sometimes, comprise high levels of complexity, making them difficult to extract and purify, and even harder to synthesize. SAR studies are meant to determine the important moieties of natural compounds in order to improve their pharmacological/biological properties with smaller and simple molecules [88][89][90].
The synthesis of small molecules is, normally, an easier procedure being less time-consuming than the processes of extraction, purification, and identification, as well as being economically viable. Additionally, synthesis on a gram scale can be easier to achieve than isolation from natural sources [36,89,90]. Besides, the enantioselectivity in biological assays can be explored because both enantiomers can be obtained via enantioselective synthesis or racemic approach, with further separation of the enantiomers [29,89,91,92].
Throughout this section, the synthetic CDXs, as well as their antimicrobial activity, were compiled according to their structures.

Muchimangins Analogues
Muchimangins are benzophenone-xanthone hybrid polyketides isolated from the roots of Securidaca longepedunculata, and are used in traditional Congolese medicine [93]. Among these structures, muchimangin B has been known to induce an apoptotic-like cell death in human pancreatic cancer cells [94]. Kodama et al. [93] synthesized five new muchimangins analogues to develop new antimicrobial agents ( Table 7). The compounds presented inhibitory activity against S. aureus and B. Subtilis [93].  Table 7. Antimicrobial activity of muchimangins analogues. According to the results displayed in Table 7, the enantioselectivity of antimicrobial activity was explored for compounds 1-3S, being the racemate and both enantiomers evaluated against S. aureus and B. subtilis. Enantioselectivity was evident in compound 3S, with the dextro enantiomer being more active against S. aureus than the levo enantiomer and the racemate. Compounds 4S and 5S were assayed as racemates which haven't displayed any activity against these strains [93].
The SAR studies suggested that the presence of a hydroxy group at C-6 was important for the growth inhibitory activity against both strains, S. aureus and B. subtilis. Besides that, these results exposed the importance of enantioselectivity studies for the development of antimicrobial agents [93].

Mangiferin Analogues
Singh et al. [79], inspired by the large range of pharmacological activities of mangiferin (45N), synthesized new mangiferin analogues (6-11S) and screened their antimicrobial activity (Table 8) [79].  Table 7. Antimicrobial activity of muchimangins analogues. According to the results displayed in Table 7, the enantioselectivity of antimicrobial activity was explored for compounds 1-3S, being the racemate and both enantiomers evaluated against S. aureus and B. subtilis. Enantioselectivity was evident in compound 3S, with the dextro enantiomer being more active against S. aureus than the levo enantiomer and the racemate. Compounds 4S and 5S were assayed as racemates which haven't displayed any activity against these strains [93].
The SAR studies suggested that the presence of a hydroxy group at C-6 was important for the growth inhibitory activity against both strains, S. aureus and B. subtilis. Besides that, these results exposed the importance of enantioselectivity studies for the development of antimicrobial agents [93].

Mangiferin Analogues
Singh et al. [79], inspired by the large range of pharmacological activities of mangiferin (45N), synthesized new mangiferin analogues (6-11S) and screened their antimicrobial activity (Table 8) [79].  Table 7. Antimicrobial activity of muchimangins analogues. According to the results displayed in Table 7, the enantioselectivity of antimicrobial activity was explored for compounds 1-3S, being the racemate and both enantiomers evaluated against S. aureus and B. subtilis. Enantioselectivity was evident in compound 3S, with the dextro enantiomer being more active against S. aureus than the levo enantiomer and the racemate. Compounds 4S and 5S were assayed as racemates which haven't displayed any activity against these strains [93].
The SAR studies suggested that the presence of a hydroxy group at C-6 was important for the growth inhibitory activity against both strains, S. aureus and B. subtilis. Besides that, these results exposed the importance of enantioselectivity studies for the development of antimicrobial agents [93].

Mangiferin Analogues
Singh et al. [79], inspired by the large range of pharmacological activities of mangiferin (45N), synthesized new mangiferin analogues (6-11S) and screened their antimicrobial activity (Table 8) [79].  Table 7. Antimicrobial activity of muchimangins analogues. According to the results displayed in Table 7, the enantioselectivity of antimicrobial activity was explored for compounds 1-3S, being the racemate and both enantiomers evaluated against S. aureus and B. subtilis. Enantioselectivity was evident in compound 3S, with the dextro enantiomer being more active against S. aureus than the levo enantiomer and the racemate. Compounds 4S and 5S were assayed as racemates which haven't displayed any activity against these strains [93].
The SAR studies suggested that the presence of a hydroxy group at C-6 was important for the growth inhibitory activity against both strains, S. aureus and B. subtilis. Besides that, these results exposed the importance of enantioselectivity studies for the development of antimicrobial agents [93].

Mangiferin Analogues
Singh et al. [79], inspired by the large range of pharmacological activities of mangiferin (45N), synthesized new mangiferin analogues (6-11S) and screened their antimicrobial activity (Table 8) [79].  Table 7. Antimicrobial activity of muchimangins analogues. According to the results displayed in Table 7, the enantioselectivity of antimicrobial activity was explored for compounds 1-3S, being the racemate and both enantiomers evaluated against S. aureus and B. subtilis. Enantioselectivity was evident in compound 3S, with the dextro enantiomer being more active against S. aureus than the levo enantiomer and the racemate. Compounds 4S and 5S were assayed as racemates which haven't displayed any activity against these strains [93].
The SAR studies suggested that the presence of a hydroxy group at C-6 was important for the growth inhibitory activity against both strains, S. aureus and B. subtilis. Besides that, these results exposed the importance of enantioselectivity studies for the development of antimicrobial agents [93].
According to the results displayed in Table 7, the enantioselectivity of antimicrobial activity was explored for compounds 1-3S, being the racemate and both enantiomers evaluated against S. aureus and B. subtilis. Enantioselectivity was evident in compound 3S, with the dextro enantiomer being more active against S. aureus than the levo enantiomer and the racemate. Compounds 4S and 5S were assayed as racemates which haven't displayed any activity against these strains [93].
The SAR studies suggested that the presence of a hydroxy group at C-6 was important for the growth inhibitory activity against both strains, S. aureus and B. subtilis. Besides that, these results exposed the importance of enantioselectivity studies for the development of antimicrobial agents [93].

Mangiferin Analogues
Singh et al. [79], inspired by the large range of pharmacological activities of mangiferin (45N), synthesized new mangiferin analogues (6-11S) and screened their antimicrobial activity (Table 8) [79].   According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids ( Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives.   According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids ( Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives.   According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids ( Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives.   According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids (Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives.   According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids (Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives.   According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids (Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives.   According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids (Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives. The antimicrobial studies were determined using a disc diffusion method, where the inhibitory growth zones inhibition caused by the tested compounds in 15% concentration is expressed in millimeters (mm); * compounds at 15% concentration (with microbial activity) and at 30%.
According to antimicrobial results, mangiferin (45N) and analogues revealed powerful activity in the growth inhibition of S. virchow and significant antibacterial activity against B. pumilus and B. cereus. On the other hand, all tested compounds revealed poor growth inhibition of P. aeruginosa and low antifungal activity [79].

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids (Table 9). Table 9. Antimicrobial activity of amino acid xanthone derivatives.

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids ( Table 9).

Amino Acid Xanthone Derivatives
Inspired by natural xanthone properties, and by Dahiya and collaborators [95] work of iodoquinazolinones and nitroimidazoles conjugated with amino acids which presented strong antimicrobial activity, led Chen et al. [96] to synthesize xanthone derivatives with conjugated L-amino acids ( Table 9).  According to Table 9, the compounds with the best antimicrobial activity were the ones that were conjugated with L-phenylalanine (16S and 26S), L-tyrosine (17S and 27S), and L-tryptophan (18S and 28S), followed by compounds conjugated with L-cysteine (19S and 29S), L-methionine (20S and 30S), and L-proline (21S and 31S). These compounds contain amino acids with high aromaticity and hydrophobicity, which makes them stable amphiphilic structures. The antimicrobial effect comes from the penetration of the amino acid hydrophobic chains in the bacterial membranes where the cationic moiety of the amino acids interacts with the membrane phospholipids disturbing the bacterial membrane. This is a strategy to develop new antimicrobial agents [96]. Due to the membrane's essential properties, its disruption would lead to death without mutations resulting in loss of recognition by the antibiotics, leading to ineffective treatments [5].

α-Mangostin Analogues
Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al. [99] developed small molecules with CAMPs essential moieties (32-38S) ( Table 10). The adopted strategy was to use the α-mangostin, a xanthone core with isoprenyl groups, and conjugate the lipophilic side chains with basic amino acids. The aims of the work were According to Table 9, the compounds with the best antimicrobial activity were the ones that were conjugated with L-phenylalanine (16S and 26S), L-tyrosine (17S and 27S), and L-tryptophan (18S and 28S), followed by compounds conjugated with L-cysteine (19S and 29S), L-methionine (20S and 30S), and L-proline (21S and 31S). These compounds contain amino acids with high aromaticity and hydrophobicity, which makes them stable amphiphilic structures. The antimicrobial effect comes from the penetration of the amino acid hydrophobic chains in the bacterial membranes where the cationic moiety of the amino acids interacts with the membrane phospholipids disturbing the bacterial membrane. This is a strategy to develop new antimicrobial agents [96]. Due to the membrane's essential properties, its disruption would lead to death without mutations resulting in loss of recognition by the antibiotics, leading to ineffective treatments [5].

α-Mangostin Analogues
Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al. [99] developed small molecules with CAMPs essential moieties (32-38S) ( Table 10). The adopted strategy was to use the α-mangostin, a xanthone core with isoprenyl groups, and conjugate the lipophilic side chains with basic amino acids. The aims of the work were According to Table 9, the compounds with the best antimicrobial activity were the ones that were conjugated with L-phenylalanine (16S and 26S), L-tyrosine (17S and 27S), and L-tryptophan (18S and 28S), followed by compounds conjugated with L-cysteine (19S and 29S), L-methionine (20S and 30S), and L-proline (21S and 31S). These compounds contain amino acids with high aromaticity and hydrophobicity, which makes them stable amphiphilic structures. The antimicrobial effect comes from the penetration of the amino acid hydrophobic chains in the bacterial membranes where the cationic moiety of the amino acids interacts with the membrane phospholipids disturbing the bacterial membrane. This is a strategy to develop new antimicrobial agents [96]. Due to the membrane's essential properties, its disruption would lead to death without mutations resulting in loss of recognition by the antibiotics, leading to ineffective treatments [5].

α-Mangostin Analogues
Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al. [99] developed small molecules with CAMPs essential moieties (32-38S) ( Table 10). The adopted strategy was to use the α-mangostin, a xanthone core with isoprenyl According to Table 9, the compounds with the best antimicrobial activity were the ones that were conjugated with L-phenylalanine (16S and 26S), L-tyrosine (17S and 27S), and L-tryptophan (18S and 28S), followed by compounds conjugated with L-cysteine (19S and 29S), L-methionine (20S and 30S), and L-proline (21S and 31S). These compounds contain amino acids with high aromaticity and hydrophobicity, which makes them stable amphiphilic structures. The antimicrobial effect comes from the penetration of the amino acid hydrophobic chains in the bacterial membranes where the cationic moiety of the amino acids interacts with the membrane phospholipids disturbing the bacterial membrane. This is a strategy to develop new antimicrobial agents [96]. Due to the membrane's essential properties, its disruption would lead to death without mutations resulting in loss of recognition by the antibiotics, leading to ineffective treatments [5].

α-Mangostin Analogues
Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al. [99] developed small molecules with CAMPs essential moieties (32-38S) ( Table 10). The adopted strategy was to use the α-mangostin, a xanthone core with isoprenyl S. aureus (20 mm-25 µg/mL); B. substilis (18 mm-25 µg/mL); E. coli (20 mm-25 µg.mL); K. pneumonia (18 mm-25 µg.mL) The antimicrobial activity was performed in agar well diffusion method, in triplicate, being the results expressed as the mean of the diameter of the inhibition zone in millimeter.
According to Table 9, the compounds with the best antimicrobial activity were the ones that were conjugated with L-phenylalanine (16S and 26S), L-tyrosine (17S and 27S), and L-tryptophan (18S and 28S), followed by compounds conjugated with L-cysteine (19S and 29S), L-methionine (20S and 30S), and L-proline (21S and 31S). These compounds contain amino acids with high aromaticity and hydrophobicity, which makes them stable amphiphilic structures. The antimicrobial effect comes from the penetration of the amino acid hydrophobic chains in the bacterial membranes where the cationic moiety of the amino acids interacts with the membrane phospholipids disturbing the bacterial membrane. This is a strategy to develop new antimicrobial agents [96]. Due to the membrane's essential properties, its disruption would lead to death without mutations resulting in loss of recognition by the antibiotics, leading to ineffective treatments [5].

α-Mangostin Analogues
Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al. [99] developed small molecules with CAMPs essential moieties (32-38S) ( Table 10). The adopted strategy was to use the α-mangostin, a xanthone core with isoprenyl groups, and conjugate the lipophilic side chains with basic amino acids. The aims of the work were to confirm the penetration of the lipophilic chains to enhance the membrane permeability and to examine the role of the cationic moieties by conjugating with basic amino acids (Table 10) [99].
The same strategy was used to develop new anti-tuberculosis agents (39-44S), which led them to assay a few of the previous compounds (33S, 34S, and 36S) as antimycobacterial agents (Table 10) [97]. membrane's essential properties, its disruption would lead to death without mutations resulting in loss of recognition by the antibiotics, leading to ineffective treatments [5].

α-Mangostin Analogues
Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al. [99] developed small molecules with CAMPs essential moieties (32-38S) ( Table 10). The adopted strategy was to use the α-mangostin, a xanthone core with isoprenyl groups, and conjugate the lipophilic side chains with basic amino acids. The aims of the work were to confirm the penetration of the lipophilic chains to enhance the membrane permeability and to examine the role of the cationic moieties by conjugating with basic amino acids (Table 10) [99].
The same strategy was used to develop new anti-tuberculosis agents (39-44S), which led them to assay a few of the previous compounds (33S, 34S, and 36S) as antimycobacterial agents (Table 10) [97]. and 30S), and L-proline (21S and 31S). These compounds contain amino acids with high aromaticity and hydrophobicity, which makes them stable amphiphilic structures. The antimicrobial effect comes from the penetration of the amino acid hydrophobic chains in the bacterial membranes where the cationic moiety of the amino acids interacts with the membrane phospholipids disturbing the bacterial membrane. This is a strategy to develop new antimicrobial agents [96]. Due to the membrane's essential properties, its disruption would lead to death without mutations resulting in loss of recognition by the antibiotics, leading to ineffective treatments [5].

α-Mangostin Analogues
Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al. [99] developed small molecules with CAMPs essential moieties (32-38S) ( Table 10). The adopted strategy was to use the α-mangostin, a xanthone core with isoprenyl groups, and conjugate the lipophilic side chains with basic amino acids. The aims of the work were to confirm the penetration of the lipophilic chains to enhance the membrane permeability and to examine the role of the cationic moieties by conjugating with basic amino acids (Table 10) [99].
The same strategy was used to develop new anti-tuberculosis agents (39-44S), which led them to assay a few of the previous compounds (33S, 34S, and 36S) as antimycobacterial agents (Table 10) [97]. Table 10. Antimicrobial activity of α-mangostin analogues.
According to the results, the small size might facilitate the penetration of the external bacterial membrane, where the lipophilic chains in the form of isoprenyl enhance the penetration of the bulky xanthone into the cytoplasmic membrane, and the cationic moiety to form an amphiphilic structure to interact with microbe's membrane, where the more dispersed the positive charge is, the more disruption and selectivity occurs [99].
Nevertheless, in mycobacterial assays, the compounds 42S and 43S revealed potent antimycobacterial activity, which leads to a new class of antimycobacterial agents with hitherto unprecedented modes of action [97].

No.
Structure Antimicrobial Activity (MIC or Inhibitory Growth Zones *)

64S
amine moiety led to a decrease of activity. This suggested that the activity of the compounds was not only determined by the hydrophilic character but also by the structure and spherical conformation determined by the side chains [110]. Neither configuration of the stereogenic centers nor specific rotations were reported.

Derivatives of Caged Xanthones
In order to carry on the studies of caged xanthones, Chaiyakunvat et al. [64] synthesized some compounds (64-75S) inspired by the natural structures with antimicrobial activity previously reported (Table 12). First, they synthesized compound 75S that corresponds to the methylated morellic acid (36N) (with MIC of 25 µg/mL against MRSA strains). Then, they synthesized morrelic acid derivatives (64-75S) comprising amino acid moieties, Table 12.

65S
According to Table 11, the SAR analysis showed that the presence of two hydroxy groups in the amine moiety led to a decrease of activity. This suggested that the activity of the compounds was not only determined by the hydrophilic character but also by the structure and spherical conformation determined by the side chains [110]. Neither configuration of the stereogenic centers nor specific rotations were reported.

Derivatives of Caged Xanthones
In order to carry on the studies of caged xanthones, Chaiyakunvat et al. [64] synthesized some compounds (64-75S) inspired by the natural structures with antimicrobial activity previously reported (Table 12). First, they synthesized compound 75S that corresponds to the methylated morellic acid (36N) (with MIC of 25 µg/mL against MRSA strains). Then, they synthesized morrelic acid derivatives (64-75S) comprising amino acid moieties, Table 12.

66S
According to Table 11, the SAR analysis showed that the presence of two hydroxy groups in the amine moiety led to a decrease of activity. This suggested that the activity of the compounds was not only determined by the hydrophilic character but also by the structure and spherical conformation determined by the side chains [110]. Neither configuration of the stereogenic centers nor specific rotations were reported.

Derivatives of Caged Xanthones
In order to carry on the studies of caged xanthones, Chaiyakunvat et al. [64] synthesized some compounds (64-75S) inspired by the natural structures with antimicrobial activity previously reported (Table 12). First, they synthesized compound 75S that corresponds to the methylated morellic acid (36N) (with MIC of 25 µg/mL against MRSA strains). Then, they synthesized morrelic acid derivatives (64-75S) comprising amino acid moieties, Table 12.

67S
According to Table 11, the SAR analysis showed that the presence of two hydroxy groups in the amine moiety led to a decrease of activity. This suggested that the activity of the compounds was not only determined by the hydrophilic character but also by the structure and spherical conformation determined by the side chains [110]. Neither configuration of the stereogenic centers nor specific rotations were reported.

Derivatives of Caged Xanthones
In order to carry on the studies of caged xanthones, Chaiyakunvat et al. [64] synthesized some compounds (64-75S) inspired by the natural structures with antimicrobial activity previously reported (Table 12). First, they synthesized compound 75S that corresponds to the methylated morellic acid (36N) (with MIC of 25 µg/mL against MRSA strains). Then, they synthesized morrelic acid derivatives (64-75S) comprising amino acid moieties, Table 12.
According to Table 11, the SAR analysis showed that the presence of two hydroxy groups in the amine moiety led to a decrease of activity. This suggested that the activity of the compounds was not only determined by the hydrophilic character but also by the structure and spherical conformation determined by the side chains [110]. Neither configuration of the stereogenic centers nor specific rotations were reported.

Derivatives of Caged Xanthones
In order to carry on the studies of caged xanthones, Chaiyakunvat et al. [64] synthesized some compounds (64-75S) inspired by the natural structures with antimicrobial activity previously reported (Table 12). First, they synthesized compound 75S that corresponds to the methylated morellic acid (36N) (with MIC of 25 µg/mL against MRSA strains). Then, they synthesized morrelic acid derivatives (64-75S) comprising amino acid moieties, Table 12.  As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.
As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] (Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13). As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] (Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13). As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] ( Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13). As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] ( Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13). As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] (Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13). As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] (Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13). As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] (Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13). As reported in Table 12, the morellic acid derivatives with more inhibition bacterial growth were the ones with amino acids containing hydrophobic side chain (64S, 65S, 69S, 71S, and 72S) [64]. This state is in agreement with the previous report where the antimicrobial activity was higher in the structures with the hydrophobic and/or aromatic amino acids [64,99]. The configuration of stereogenic centers are presented but specific rotations and absolute configuration were not reported.

Xanthone Derivatives of C-2-Substituted
Szkaradek et al. [18,111] developed interesting studies about antimycobacterial activity using xanthones. They started by the development of new 2-xanthone derivatives with structural moieties with well-known antimycotic properties such as the allyl (76S) and morpholine (77S) groups [18] (Table 13). Then, synthesized xanthone derivatives C2-substituted to generate new anti-tuberculosis agents (78-88S) [111] (Table 13).  Szkaradek et al. [18,111] considered that the activity increased with the enlarged size of the lateral chain, due to the mycobacterial membrane containing lipids, which makes the hydrophobic side chains easier to penetrate. According to Table 13, compound 86S possessed the most promising activity [111]. In this work, the stereochemistry was also ignored.

Conclusions and Future Perspectives
Among many of natural CDXs, a few compounds where highlighted due to their interesting antimicrobial activity. Mangostanin (1N), toxyloxanthone C (2N), formoxanthone-C (5N), scortechinone B (17N), and scortechinone I (24N) displayed strong activity against fungus and Grampositive bacteria, with formoxanthone-C (5N) also being active against Gram-negative bacteria. Geronthoxanthones G and A (3 and 4N) also presented interesting activities and should be explored along with SAR studies in order to synthesize new analogues.
The synthetic CDXs were inspired by natural scaffolds with potential antimicrobial activity. The most promising strategy among the synthesized CDXs analogues was the development of membrane-targeting potent antibacterial agents in which the lipophilic side chains contain cationic amino acid residues that can penetrate the microbial membranes in order to disrupt them.
Regarding the stereochemistry and enantioselectivity, the configuration of the stereogenic centers are often ignored and only a few examples described the antimicrobial activity for both enantiomers and/or racemate. Differences in the activity among enantiomers or epimers were observed. One example concerns the naturally occurring epimers of scortechinone A (16N) and L (27N), with 27N being more active. Another interesting example concerning the different activities of racemic or pure enantiomeric forms are the synthesized muchimangins 1S and 3S.
It was found that the use of L-amino acids in the majority of the synthesized analogues amplified the interaction with the antimicrobial membrane for a major effect. These examples emphasize the importance of chirality in the development of new antibiotics. Szkaradek et al. [18,111] considered that the activity increased with the enlarged size of the lateral chain, due to the mycobacterial membrane containing lipids, which makes the hydrophobic side chains easier to penetrate. According to Table 13, compound 86S possessed the most promising activity [111]. In this work, the stereochemistry was also ignored.

Conclusions and Future Perspectives
Among many of natural CDXs, a few compounds where highlighted due to their interesting antimicrobial activity. Mangostanin (1N), toxyloxanthone C (2N), formoxanthone-C (5N), scortechinone B (17N), and scortechinone I (24N) displayed strong activity against fungus and Grampositive bacteria, with formoxanthone-C (5N) also being active against Gram-negative bacteria. Geronthoxanthones G and A (3 and 4N) also presented interesting activities and should be explored along with SAR studies in order to synthesize new analogues.
The synthetic CDXs were inspired by natural scaffolds with potential antimicrobial activity. The most promising strategy among the synthesized CDXs analogues was the development of membrane-targeting potent antibacterial agents in which the lipophilic side chains contain cationic amino acid residues that can penetrate the microbial membranes in order to disrupt them.
Regarding the stereochemistry and enantioselectivity, the configuration of the stereogenic centers are often ignored and only a few examples described the antimicrobial activity for both enantiomers and/or racemate. Differences in the activity among enantiomers or epimers were observed. One example concerns the naturally occurring epimers of scortechinone A (16N) and L (27N), with 27N being more active. Another interesting example concerning the different activities of racemic or pure enantiomeric forms are the synthesized muchimangins 1S and 3S.
It was found that the use of L-amino acids in the majority of the synthesized analogues amplified the interaction with the antimicrobial membrane for a major effect. These examples emphasize the importance of chirality in the development of new antibiotics. Szkaradek et al. [18,111] considered that the activity increased with the enlarged size of the lateral chain, due to the mycobacterial membrane containing lipids, which makes the hydrophobic side chains easier to penetrate. According to Table 13, compound 86S possessed the most promising activity [111]. In this work, the stereochemistry was also ignored.

Conclusions and Future Perspectives
Among many of natural CDXs, a few compounds where highlighted due to their interesting antimicrobial activity. Mangostanin (1N), toxyloxanthone C (2N), formoxanthone-C (5N), scortechinone B (17N), and scortechinone I (24N) displayed strong activity against fungus and Grampositive bacteria, with formoxanthone-C (5N) also being active against Gram-negative bacteria. Geronthoxanthones G and A (3 and 4N) also presented interesting activities and should be explored along with SAR studies in order to synthesize new analogues.
The synthetic CDXs were inspired by natural scaffolds with potential antimicrobial activity. The most promising strategy among the synthesized CDXs analogues was the development of membrane-targeting potent antibacterial agents in which the lipophilic side chains contain cationic amino acid residues that can penetrate the microbial membranes in order to disrupt them.
Regarding the stereochemistry and enantioselectivity, the configuration of the stereogenic centers are often ignored and only a few examples described the antimicrobial activity for both enantiomers and/or racemate. Differences in the activity among enantiomers or epimers were observed. One example concerns the naturally occurring epimers of scortechinone A (16N) and L (27N), with 27N being more active. Another interesting example concerning the different activities of racemic or pure enantiomeric forms are the synthesized muchimangins 1S and 3S.
It was found that the use of L-amino acids in the majority of the synthesized analogues amplified the interaction with the antimicrobial membrane for a major effect. These examples emphasize the importance of chirality in the development of new antibiotics. Szkaradek et al. [18,111] considered that the activity increased with the enlarged size of the lateral chain, due to the mycobacterial membrane containing lipids, which makes the hydrophobic side chains easier to penetrate. According to Table 13, compound 86S possessed the most promising activity [111]. In this work, the stereochemistry was also ignored.

Conclusions and Future Perspectives
Among many of natural CDXs, a few compounds where highlighted due to their interesting antimicrobial activity. Mangostanin (1N), toxyloxanthone C (2N), formoxanthone-C (5N), scortechinone B (17N), and scortechinone I (24N) displayed strong activity against fungus and Grampositive bacteria, with formoxanthone-C (5N) also being active against Gram-negative bacteria. Geronthoxanthones G and A (3 and 4N) also presented interesting activities and should be explored along with SAR studies in order to synthesize new analogues.
The synthetic CDXs were inspired by natural scaffolds with potential antimicrobial activity. The most promising strategy among the synthesized CDXs analogues was the development of membrane-targeting potent antibacterial agents in which the lipophilic side chains contain cationic amino acid residues that can penetrate the microbial membranes in order to disrupt them.
Regarding the stereochemistry and enantioselectivity, the configuration of the stereogenic centers are often ignored and only a few examples described the antimicrobial activity for both enantiomers and/or racemate. Differences in the activity among enantiomers or epimers were observed. One example concerns the naturally occurring epimers of scortechinone A (16N) and L (27N), with 27N being more active. Another interesting example concerning the different activities of racemic or pure enantiomeric forms are the synthesized muchimangins 1S and 3S.
It was found that the use of L-amino acids in the majority of the synthesized analogues amplified the interaction with the antimicrobial membrane for a major effect. These examples emphasize the importance of chirality in the development of new antibiotics. Szkaradek et al. [18,111] considered that the activity increased with the enlarged size of the lateral chain, due to the mycobacterial membrane containing lipids, which makes the hydrophobic side chains easier to penetrate. According to Table 13, compound 86S possessed the most promising activity [111]. In this work, the stereochemistry was also ignored.

Conclusions and Future Perspectives
Among many of natural CDXs, a few compounds where highlighted due to their interesting antimicrobial activity. Mangostanin (1N), toxyloxanthone C (2N), formoxanthone-C (5N), scortechinone B (17N), and scortechinone I (24N) displayed strong activity against fungus and Grampositive bacteria, with formoxanthone-C (5N) also being active against Gram-negative bacteria. Geronthoxanthones G and A (3 and 4N) also presented interesting activities and should be explored along with SAR studies in order to synthesize new analogues.
The synthetic CDXs were inspired by natural scaffolds with potential antimicrobial activity. The most promising strategy among the synthesized CDXs analogues was the development of membrane-targeting potent antibacterial agents in which the lipophilic side chains contain cationic amino acid residues that can penetrate the microbial membranes in order to disrupt them.
Regarding the stereochemistry and enantioselectivity, the configuration of the stereogenic centers are often ignored and only a few examples described the antimicrobial activity for both enantiomers and/or racemate. Differences in the activity among enantiomers or epimers were observed. One example concerns the naturally occurring epimers of scortechinone A (16N) and L (27N), with 27N being more active. Another interesting example concerning the different activities of racemic or pure enantiomeric forms are the synthesized muchimangins 1S and 3S.
It was found that the use of L-amino acids in the majority of the synthesized analogues amplified the interaction with the antimicrobial membrane for a major effect. These examples emphasize the M. tuberculosis H 37 Rv (>2.5% with 59% inhibition) MIC: Minimum inhibitory concentration; a The antimicrobial studies were determined using a disc diffusion method, where the inhibitory growth zones showed inhibition at 1% concentration against representative strains of microorganisms C. albicans, C. glabrata, C. krusei, C. lusitaniae, C. neoformans, A. fumigatus, T. mentagrophytes, S. aureus, E. faecalis, E. coli, K. pneumonia, and P. aeruginosa; only the strains with activity were expressed; * Stereogenic center.
Szkaradek et al. [18,111] considered that the activity increased with the enlarged size of the lateral chain, due to the mycobacterial membrane containing lipids, which makes the hydrophobic side chains easier to penetrate. According to Table 13, compound 86S possessed the most promising activity [111]. In this work, the stereochemistry was also ignored.

Conclusions and Future Perspectives
Among many of natural CDXs, a few compounds where highlighted due to their interesting antimicrobial activity.
The synthetic CDXs were inspired by natural scaffolds with potential antimicrobial activity. The most promising strategy among the synthesized CDXs analogues was the development of membrane-targeting potent antibacterial agents in which the lipophilic side chains contain cationic amino acid residues that can penetrate the microbial membranes in order to disrupt them.
Regarding the stereochemistry and enantioselectivity, the configuration of the stereogenic centers are often ignored and only a few examples described the antimicrobial activity for both enantiomers and/or racemate. Differences in the activity among enantiomers or epimers were observed. One example concerns the naturally occurring epimers of scortechinone A (16N) and L (27N), with 27N being more active. Another interesting example concerning the different activities of racemic or pure enantiomeric forms are the synthesized muchimangins 1S and 3S.
It was found that the use of L-amino acids in the majority of the synthesized analogues amplified the interaction with the antimicrobial membrane for a major effect. These examples emphasize the importance of chirality in the development of new antibiotics.
Author Contributions: J.A. collected the primary data and contributed in writing of the manuscript. M.E.T., C.F., and M.P. supervised the development of the manuscript, and assisted in data interpretation, manuscript evaluation, and editing. Funding: