Research Progress on Sesquiterpene Compounds from Artabotrys Plants of Annonaceae

Artabotrys, a pivotal genus within the Annonaceae family, is renowned for its extensive biological significance and medicinal potential. The genus’s sesquiterpene compounds have attracted considerable interest from the scientific community due to their structural complexity and diverse biological activities. These compounds exhibit a range of biological activities, including antimalarial, antibacterial, anti-inflammatory analgesic, and anti-tumor properties, positioning them as promising candidates for medical applications. This review aims to summarize the current knowledge on the variety, species, and structural characteristics of sesquiterpene compounds isolated from Artabotrys plants. Furthermore, it delves into their pharmacological activities and underlying mechanisms, offering a comprehensive foundation for future research.

Artabotrys, belonging to the Annonaceae family, comprises about 110 species of plants around the world, predominantly distributed in tropical and subtropical regions such as Southeast Asia, Indonesia, and Malaysia.The plants of this genus are climbing shrubs.The leaves of these plants are usually compound, the flowers are small and clustered on the raceme, and the fruits are drupe-shaped.There are many traditional uses of this genus, such as the treatment of cholera, malaria, and other diseases [21].The plants of this genus have a wide range of biological significance and medicinal value.An examination of data from the Plants of the World Online database facilitated a detailed summary of Artabotrys species and their distribution (Table 1).

No. Species Distribution
The genus Artabotrys, within the Annonaceae family, is distinguished by its wealth of chemical components [22].To date, research has identified a diverse array of compounds from these plants, including alkaloids [23,24], volatile oils [25,26], cyclohexenes [27,28], phenylpropanoids [29], flavonoids [30], quinones [31], and sesquiterpenes [32].Among these, sesquiterpenes stand out as one of the principal active components, heralded for their significant medical value and importance in research.So far, there have been many research articles on the plants of Artabotrys; however, the majority have focused on individual compounds or relatively extensive research overviews.Comprehensive reviews specifically addressing the sesquiterpene compounds derived from the plants of the genus are notably scarce.Therefore, this paper aims to fill this gap by reviewing the current research progress of sesquiterpene compounds derived from the plants of Artabotrys in Annonaceae.It meticulously summarizes the variety, species, and structural characteristics of sesquiterpene compounds identified within these plants and explores their pharmacological activities and underlying mechanisms, offering a comprehensive foundation for future research.
Sesquiterpenes represent a distinguished class of natural organic compounds, notable for their widespread natural sources.These compounds are predominantly derived from a range of plants [55,56], especially those known for their aromatic properties, as well as from fungi [57][58][59], and marine organisms [60,61].Sesquiterpenes have a variety of biological activities, encompassing antimalarial [62], antioxidant [63], anti-inflammatory [64,65], antibacterial [66,67], and anti-tumor effects [68,69].Therefore, sesquiterpenes have displayed significant therapeutic potential in the pharmaceutical sector, while their unique properties also make them invaluable to the perfume industry.
Extensive research into the sesquiterpenes extracted from Artabotrys plants reveals a remarkable diversity within this genus.To date, investigations have identified over 80 distinct sesquiterpene types isolated from Artabotrys, underscoring the genus's rich contribution to the pool of naturally occurring sesquiterpenes.A detailed breakdown of these sesquiterpenes reveals a wide array of structural types, including 19 bisabolanetype, 15 eudesmane-type, 8 norbisabolane-type, 6 guaiane-type, 4 aromadendrane-type, aristolane-type, and cadinane-type, 3 eremophilane-type, 2 isodaucane-type and acoranetype, 1 germacrane-type, alongside a multitude of other sesquiterpene variants.
These findings further attest to the extraordinary potential of the plant as a 'natural drug bank', such as for the development of innovative anti-tumor and anti-inflammatory drugs.Each sesquiterpene identified offers unique insights into potential pharmacological applications and holds the promise of playing a pivotal role in devising novel therapeutic strategies.

Bisabolane-Type Sesquiterpenes
Bisabolane-type sesquiterpenes, a subclass of monocyclic sesquiterpenes, are characterized by their six-membered carbon rings and side chains.These compounds boast a plethora of natural sources, including marine invertebrates, terrestrial plants, and microorganisms.Notably, bisabolane-type sesquiterpenes exhibit a wide range of biological activities, such as anti-inflammatory and antibacterial [70,71].To date, more than 350 kinds of bisabolane-type sesquiterpenes have been isolated from various plant families, including Compositae and Zingiberaceae [72].In the context of the Artabotrys genus, several bisabolanetype sesquiterpenes have also been successfully extracted (Table 2).Among the isolated compounds, compounds 1 and 2 were extracted from the roots of Artabotrys uncinatus in 1979; their structures were elucidated by spectroscopic methods [73,74].Compounds 3 and 4 were also derived from A. uncinatus [75].Subsequently, researchers isolated 13 bisabolane-type sesquiterpenes (5-17 in Table 2) from the roots of A. hexapetalus in 2017 [76].Moreover, 25 monomeric compounds, including two bisabolanetype sesquiterpenes chlospicate E (18) and arbisabol-9-en-7,11-diol (19) [77], were isolated from Artabotrys pilosus by a combination of chromatographic separation methods and spec-tral identification techniques.The structural details of the related compounds are shown in Figure 1.

Norbisabolane-Type Sesquiterpenes
Norbisabolane-type sesquiterpenes, another subset of monocyclic sesquiterpenes, known for their spiroketal structures, have primarily been isolated from Phyllanthus spp.within the Euphorbiaceae [78].From the extracts of Artabotrys plants, several norbisabolanetype sesquiterpenes (Table 3) were successfully purified by a series of chromatographic techniques, and the structures were elucidated via comprehensive analysis of nuclear magnetic resonance (NMR), mass spectrometry (MS) and other technical means.Among them, compound 20 was isolated from A. hexapetalus [76], while compounds 21-27 were isolated from the branches and leaves of A. hongkongensis in 2017 [79].The detailed structures of the compounds are shown in Figure 2. type sesquiterpenes (Table 3) were successfully purified by a series of chromatographi techniques, and the structures were elucidated via comprehensive analysis of nuclea magnetic resonance (NMR), mass spectrometry (MS) and other technical means.Among them, compound 20 was isolated from A. hexapetalus [76], while compounds 21-27 were isolated from the branches and leaves of A. hongkongensis in 2017 [79].The detailed struc tures of the compounds are shown in Figure 2.

Eudesmane-Type Sesquiterpenes
Eudesmane-type sesquiterpenes, classified as bicyclic sesquiterpenes, are notable fo their widespread distribution in nature.Eudesmane-type sesquiterpenes are character ized by a core structure comprising two six-membered rings and four substituents with a total of 15 carbon atoms, leading to a considerable structural diversity primarily attributed to variations in the substituents' positioning and the double bonds within the rings.Stud ies have shown that these compounds displayed anti-inflammatory [80], anti-fungal [81] anti-cancer [82], anti-diabetic nephropathy [83], and the ability to inhibit the proliferation of leukemia cell lines [84].

Eudesmane-Type Sesquiterpenes
Eudesmane-type sesquiterpenes, classified as bicyclic sesquiterpenes, are notable for their widespread distribution in nature.Eudesmane-type sesquiterpenes are characterized by a core structure comprising two six-membered rings and four substituents with a total of 15 carbon atoms, leading to a considerable structural diversity primarily attributed to variations in the substituents' positioning and the double bonds within the rings.Studies have shown that these compounds displayed anti-inflammatory [80], anti-fungal [81], anticancer [82], anti-diabetic nephropathy [83], and the ability to inhibit the proliferation of leukemia cell lines [84].

Guaiane-Type Sesquiterpenes
Guaiane-type sesquiterpenes, a subclass of bicyclic sesquiterpenes, are distinguished by their unique structural framework, which features a seven-membered ring fused with a five-membered lactone ring, augmented by two methyl groups and one isopropyl group.These compounds are prevalent across more than 30 families of plants, demonstrating a

Guaiane-Type Sesquiterpenes
Guaiane-type sesquiterpenes, a subclass of bicyclic sesquiterpenes, are distinguished by their unique structural framework, which features a seven-membered ring fused with a five-membered lactone ring, augmented by two methyl groups and one isopropyl group.These compounds are prevalent across more than 30 families of plants, demonstrating a broad spectrum of biological activities, including anti-tumor, anti-inflammatory, antibacterial, and antioxidant [87,88].The genus Artabotrys plants, known for its rich chemical diversity, also harbors guaiane-type sesquiterpenes.Compounds 43-48 represent guaianetype sesquiterpenes isolated from various Artabotrys species (Table 5).Guaiane pogostol O-methyl ether (46) from Artabotrys stenopetalus in 1997 marked the beginning of the identification of such compounds within the genus [89].Compounds 43 and 44 are two sesquiterpenes isolated from the 90% ethanol extract of the branches and leaves of A. hainanensis, both identified as guaiane-type sesquiterpenes [86].Compound 45, a colorless oily substance isolated from A. pilosus [77], was confirmed as guaianediol through NMR data analysis and comparison with existing literature [90].Additionally, alismol (47) and alismoxide (48) were derived from the stem [91] and flower of A. hainanensis [86], respectively, with the latter previously identified in Alisma orientalis [92].The structures of these guaiane-type sesquiterpenes are depicted in Figure 4. broad spectrum of biological activities, including anti-tumor, anti-inflammatory, antibac terial, and antioxidant [87,88].The genus Artabotrys plants, known for its rich chemica diversity, also harbors guaiane-type sesquiterpenes.Compounds 43-48 represent guai ane-type sesquiterpenes isolated from various Artabotrys species (Table 5).Guaiane po gostol O-methyl ether (46) from Artabotrys stenopetalus in 1997 marked the beginning o the identification of such compounds within the genus [89].Compounds 43 and 44 ar two sesquiterpenes isolated from the 90% ethanol extract of the branches and leaves of A hainanensis, both identified as guaiane-type sesquiterpenes [86].Compound 45, a colorles oily substance isolated from A. pilosus [77], was confirmed as guaianediol through NMR data analysis and comparison with existing literature [90].Additionally, alismol (47) and alismoxide (48) were derived from the stem [91] and flower of A. hainanensis [86], respec tively, with the latter previously identified in Alisma orientalis [92].The structures of thes guaiane-type sesquiterpenes are depicted in Figure 4.

Eremophilane-Type Sesquiterpenes
Eremophilane-type sesquiterpenes, derived from the biosynthetic precursor farnesy diphosphate (FPP), represent a distinct group within the bicyclic sesquiterpene com pound family.These compounds are characterized by their unique irregular bicycli structures, with structural variations primarily arising from various oxidations on the bi cyclic skeleton and the isopropyl side chain [93].Related studies have shown that thes compounds displayed anti-inflammatory effects and can inhibit the NO produced by lip opolysaccharide (LPS)-induced RAW 264.7 macrophages [94].In studying the chemica constituents of the Artabotrys genus, researchers have successfully isolated several ere mophilane-type sesquiterpenes (Table 6).Among them, compounds 49 and 50 are two er emophilane-type sesquiterpenes obtained from the branches and leaves of A. hongkongen sis in the same research process [79], while compound 51 was obtained from the branche and leaves of A. hainanensis in another study one year later [86].The chemical structure of these three eremophilane-type sesquiterpenes with serial numbers 49-51 are shown in Figure 5.

Eremophilane-Type Sesquiterpenes
Eremophilane-type sesquiterpenes, derived from the biosynthetic precursor farnesyl diphosphate (FPP), represent a distinct group within the bicyclic sesquiterpene compound family.These compounds are characterized by their unique irregular bicyclic structures, with structural variations primarily arising from various oxidations on the bicyclic skeleton and the isopropyl side chain [93].Related studies have shown that these compounds displayed anti-inflammatory effects and can inhibit the NO produced by lipopolysaccharide (LPS)-induced RAW 264.7 macrophages [94].In studying the chemical constituents of the Artabotrys genus, researchers have successfully isolated several eremophilane-type sesquiterpenes (Table 6).Among them, compounds 49 and 50 are two eremophilane-type sesquiterpenes obtained from the branches and leaves of A. hongkongensis in the same research process [79], while compound 51 was obtained from the branches and leaves of A. hainanensis in another study one year later [86].The chemical structures of these three eremophilane-type sesquiterpenes with serial numbers 49-51 are shown in Figure 5.

Isodaucane-Type Sesquiterpenes
Isodaucane-type sesquiterpenes, which belong to bicyclic sesquiterpenes, are distin guished by their distinctive structural configuration, featuring a five-membered ring cou pled with a seven-membered ring.Despite their relatively scarce occurrence in natur compared with other common types of sesquiterpenes, dedicated research efforts hav led to the successful isolation of two isodaucane-type sesquiterpenes from the Artabotry genus (Table 7).Compounds 52 and 53 were isolated from the branches and leaves of A hongkongensis and the stem bark of A. stenopetalus, respectively [79,89].The structures o the two compounds are shown in Figure 6.

Acorane-Type Sesquiterpenes
Acorane-type sesquiterpenes are distinguished by their spiro [4.5] decane skeleton featuring an isopropyl unit at C-1 and a dimethyl substitution at C-4 and C-8 [95].Thi unique natural product category falls within the bicyclic sesquiterpene compound, known for its wide range of pharmacological activities, such as antiviral activity [96] and anti inflammatory activity [97,98].Despite their notable bioactivity, acorane-type sesquiter penes are exceedingly rare in both plants and microorganisms.In a significant discovery two acorane-type sesquiterpenes were successfully isolated from the genus of Artabotry (Table 8).Compounds 54 and 55 were isolated from the roots of A. hexapetalus in 2017 alongside 13 bisabolane-type sesquiterpenes (5-17 in Table 2) [76].The structures of th two compounds are shown in Figure 7.

Isodaucane-Type Sesquiterpenes
Isodaucane-type sesquiterpenes, which belong to bicyclic sesquiterpenes, are distinguished by their distinctive structural configuration, featuring a five-membered ring coupled with a seven-membered ring.Despite their relatively scarce occurrence in nature compared with other common types of sesquiterpenes, dedicated research efforts have led to the successful isolation of two isodaucane-type sesquiterpenes from the Artabotrys genus (Table 7).Compounds 52 and 53 were isolated from the branches and leaves of A. hongkongensis and the stem bark of A. stenopetalus, respectively [79,89].The structures of the two compounds are shown in Figure 6.

Isodaucane-Type Sesquiterpenes
Isodaucane-type sesquiterpenes, which belong to bicyclic sesquiterpenes, are distin guished by their distinctive structural configuration, featuring a five-membered ring cou pled with a seven-membered ring.Despite their relatively scarce occurrence in natur compared with other common types of sesquiterpenes, dedicated research efforts hav led to the successful isolation of two isodaucane-type sesquiterpenes from the Artabotry genus (Table 7).Compounds 52 and 53 were isolated from the branches and leaves of A hongkongensis and the stem bark of A. stenopetalus, respectively [79,89].The structures o the two compounds are shown in Figure 6.

Acorane-Type Sesquiterpenes
Acorane-type sesquiterpenes are distinguished by their spiro [4.5] decane skeleton featuring an isopropyl unit at C-1 and a dimethyl substitution at C-4 and C-8 [95].Thi unique natural product category falls within the bicyclic sesquiterpene compound, known for its wide range of pharmacological activities, such as antiviral activity [96] and anti inflammatory activity [97,98].Despite their notable bioactivity, acorane-type sesquiter penes are exceedingly rare in both plants and microorganisms.In a significant discovery two acorane-type sesquiterpenes were successfully isolated from the genus of Artabotry (Table 8).Compounds 54 and 55 were isolated from the roots of A. hexapetalus in 2017 alongside 13 bisabolane-type sesquiterpenes (5-17 in Table 2) [76].The structures of th two compounds are shown in Figure 7.

Acorane-Type Sesquiterpenes
Acorane-type sesquiterpenes are distinguished by their spiro [4.5] decane skeleton, featuring an isopropyl unit at C-1 and a dimethyl substitution at C-4 and C-8 [95].This unique natural product category falls within the bicyclic sesquiterpene compound, known for its wide range of pharmacological activities, such as antiviral activity [96] and antiinflammatory activity [97,98].Despite their notable bioactivity, acorane-type sesquiterpenes are exceedingly rare in both plants and microorganisms.In a significant discovery, two acorane-type sesquiterpenes were successfully isolated from the genus of Artabotrys (Table 8).Compounds 54 and 55 were isolated from the roots of A. hexapetalus in 2017 alongside 13 bisabolane-type sesquiterpenes (5-17 in Table 2) [76].The structures of the two compounds are shown in Figure 7.

Cadinane-Type Sesquiterpenes
Cadinane-type sesquiterpenes, a class of bicyclic sesquiterpenes, are synthesized through the catalytic action of sesquiterpene synthase (STS) on FPP [99].These com pounds have complex stereochemistry and a wide range of pharmacological activities such as hypoglycemic [100], antifungal [101], and anti-inflammatory [102].To date, a con siderable diversity of cadinane-type sesquiterpenes with diverse structures and biologica activities have been isolated and identified from a variety of plants and microorganisms Furthermore, with the continuous advancement of modern biotechnology, the biosyn thetic pathways of representative cadinene-type sesquiterpenes have been substantially elucidated [103].The following compounds are cadinene-type sesquiterpenes obtained from the genus of Artabotrys (Table 9).Notably, 10β, 15-hydroxy-α-cadinol (56) was iso lated from both A. pilosus [77]and A. hainanensis [86].Additionally, amorph-4-en-10α-o (57) was isolated from the branches and leaves of A. hainanensis [86].Compounds 58 and 59, further enriching the variety of cadinene-type sesquiterpenes, were derived from the branches and leaves of A. pilosus [77].The detailed structures of these compounds are de picted in Figure 8.

Cadinane-Type Sesquiterpenes
Cadinane-type sesquiterpenes, a class of bicyclic sesquiterpenes, are synthesized through the catalytic action of sesquiterpene synthase (STS) on FPP [99].These compounds have complex stereochemistry and a wide range of pharmacological activities, such as hypoglycemic [100], antifungal [101], and anti-inflammatory [102].To date, a considerable diversity of cadinane-type sesquiterpenes with diverse structures and biological activities have been isolated and identified from a variety of plants and microorganisms.Furthermore, with the continuous advancement of modern biotechnology, the biosynthetic pathways of representative cadinene-type sesquiterpenes have been substantially elucidated [103].The following compounds are cadinene-type sesquiterpenes obtained from the genus of Artabotrys (Table 9).Notably, 10β, 15-hydroxy-α-cadinol (56) was isolated from both A. pilosus [77] and A. hainanensis [86].Additionally, amorph-4-en-10α-ol (57) was isolated from the branches and leaves of A. hainanensis [86].Compounds 58 and 59, further enriching the variety of cadinene-type sesquiterpenes, were derived from the branches and leaves of A. pilosus [77].The detailed structures of these compounds are depicted in Figure 8.

Cadinane-Type Sesquiterpenes
Cadinane-type sesquiterpenes, a class of bicyclic sesquiterpenes, are synthesized through the catalytic action of sesquiterpene synthase (STS) on FPP [99].These com pounds have complex stereochemistry and a wide range of pharmacological activities such as hypoglycemic [100], antifungal [101], and anti-inflammatory [102].To date, a con siderable diversity of cadinane-type sesquiterpenes with diverse structures and biologica activities have been isolated and identified from a variety of plants and microorganisms Furthermore, with the continuous advancement of modern biotechnology, the biosyn thetic pathways of representative cadinene-type sesquiterpenes have been substantially elucidated [103].The following compounds are cadinene-type sesquiterpenes obtained from the genus of Artabotrys (Table 9).Notably, 10β, 15-hydroxy-α-cadinol (56) was iso lated from both A. pilosus [77]and A. hainanensis [86].Additionally, amorph-4-en-10α-o (57) was isolated from the branches and leaves of A. hainanensis [86].Compounds 58 and 59, further enriching the variety of cadinene-type sesquiterpenes, were derived from the branches and leaves of A. pilosus [77].The detailed structures of these compounds are de picted in Figure 8.

Aristolane-Type Sesquiterpenes
Aristolane-type sesquiterpenes are naturally occurring sesquiterpenes, primarily obtained from Nardostachys, Axinyssa, and Russula [104].Aristolane-type sesquiterpenes usually contain a gem-dimethyl cyclopropane structure [105], which belongs to the tricyclic sesquiterpenes.These compounds play a pivotal role in regulating serotonin transporter (SERT) to enhance or inhibit SERT [106], which offers therapeutic potential for the treatment of neuropsychiatric and digestive diseases.Advances in research and technology have enabled the isolation of several aristolane-type sesquiterpenes from Artabotrys plants (Table 10).10-hydroxyaristolan-9-one (60), initially isolated from the stems of A. uncinatus in 2007, has also been found in the branches and leaves of A. hongkongensis in another study a few years later [79,107], alongside compounds 61-63 [79].The structures of aristolane-type sesquiterpenes involved are shown in Figure 9. (SERT) to enhance or inhibit SERT [106], which offers therapeutic potential for the treat ment of neuropsychiatric and digestive diseases.Advances in research and technology have enabled the isolation of several aristolane-type sesquiterpenes from Artabotrys plant (Table 10).10-hydroxyaristolan-9-one (60), initially isolated from the stems of A. uncinatu in 2007, has also been found in the branches and leaves of A. hongkongensis in anothe study a few years later [79,107], alongside compounds 61-63 [79].The structures of aris tolane-type sesquiterpenes involved are shown in Figure 9.

Aromadendrane-Type Sesquiterpenes
Aromadendrane-type sesquiterpenes, akin to the aristolane-type sesquiterpene mentioned earlier, belong to the tricyclic sesquiterpenes family, noted for their anti-in flammatory [108].Studies have found that certain aromadendrane-type sesquiterpene compounds can interact with benzoquinone to form heterodimers, offering cytoprotectiv effects on glutamate-induced neurological deficits [109].The following three compound (64)(65) are classified as aromadendrane-type sesquiterpenes obtained from Artabotrys (Ta ble 11).Compound 64 was obtained from branches and leaves of A. hainanensis [86].Th remaining compound (-)-ent-4β-hydroxy-10α-methoxyaromadendrane(65) was obtained from the stem of A. uncinatus by numerous efforts of researchers in 2007 [107].Com pounds 66 and 67 are two sesquiterpenes obtained from the flowers of A. hexapetalus [110] Figure 10 shows the detailed structures of the five aromadendrane-type sesquiterpenes.

Other Types of Sesquiterpenes
Beyond the previously mentioned sesquiterpenes, many other types of sesquiter penes have also been obtained from the plants of Artabotrys, as detailed in Table 12.
Notably, β-caryophyllene oxide (68), caryophyllene-type sesquiterpenes with a unique polycyclic structure, were isolated from the stem bark of A. stenopetalus [89].Com pounds 74 and 76 in Table 12 also belong to this class of sesquiterpenes.Compounds 69 and 70, derived by reducing some carbon atoms in cadinane-type sesquiterpenes, repre sent a class of bicyclic sesquiterpene.4-hydroxy-4,7-dimethyl-1-tetralone (69), reduced by 3 carbons, and oxyphyllone D (70), reduced by 1 carbon, have been isolated from the branches and leaves of A. pilosus [77] and A. hainanensis [86], respectively.Additionally 1β-hydroxy-4(15),5E,10(14)-germacratriene ( 71), a germacrane-type sesquiterpene, was isolated from the branches and leaves of A. hainanensis [86] and belongs to monocyclic sesquiterpenes.artahongkongol A (72), a unique trinoreudesmane sesquiterpene derived from the corresponding eudesmane-type sesquiterpenes by removing a propyl group was obtained from the stems and leaves of A. hongkongensis [85].(4R,5R,7R)-1(10)-spiro vetiven-11-ol-2-one (81), a rare natural spirovetivane-type sesquiterpene, was first isolated from the flower of A. hainanensis [86].Compounds 82, 83, and 84 are three bisabolene-type sesquiterpenes isolated from the roots of A. hexapetalus, with compounds 83 and 84 iden tified as a pair of enantiomers [32].The remaining compounds listed in Table 12, not de scribed in detail here, represent unique sesquiterpenes with special structural types rare in nature isolated from Artabotrys plants.The specific structures of the related compounds are illustrated as follows (Figure 11).spirovetivane-type sesquiterpene, was first isolated from the flower of A. hainanensis [86].Compounds 82, 83, and 84 are three bisabolene-type sesquiterpenes isolated from the roots of A. hexapetalus, with compounds 83 and 84 identified as a pair of enantiomers [32].The remaining compounds listed in Table 12, not described in detail here, represent unique sesquiterpenes with special structural types rare in nature isolated from Artabotrys plants.The specific structures of the related compounds are illustrated as follows (Figure 11).

Pharmacological Activities
Sesquiterpenes, with their distinct carbon skeletons and roles in diverse biochemica processes, play a pivotal role in drug discovery and development.Their unique structures enable a wide array of biological and pharmacological actions, making them invaluable in modern medicinal research.In particular, sesquiterpenes from the plants of the genus Artabotrys have shown significant activity across numerous pharmacological studies.The following are some key pharmacological activities attributed to sesquiterpenes isolated from Artabotrys plants.

Antimalarial Activity
Malaria is one of the oldest diseases in humans.It is a disease caused by parasites [111] mainly transmitted to humans through mosquito bites [112].Malaria is an infectious disease caused by malaria parasites [113][114][115].Predominantly prevalent in tropical and subtropical regions, especially in Africa, South Asia, Southeast Asia, and Central America [116], malaria accounts for more than 200 million cases worldwide each year [117].The development of effective antimalarial drugs can reduce the spread and infection of ma laria and accelerate the early recovery of patients [118].Therefore, it is of great significance to find more effective antimalarial drugs.In the process of studying antimalarial drugs researchers have found that some sesquiterpenes and some other natural components de

Pharmacological Activities
Sesquiterpenes, with their distinct carbon skeletons and roles in diverse biochemical processes, play a pivotal role in drug discovery and development.Their unique structures enable a wide array of biological and pharmacological actions, making them invaluable in modern medicinal research.In particular, sesquiterpenes from the plants of the genus Artabotrys have shown significant activity across numerous pharmacological studies.The following are some key pharmacological activities attributed to sesquiterpenes isolated from Artabotrys plants.

Antimalarial Activity
Malaria is one of the oldest diseases in humans.It is a disease caused by parasites [111] mainly transmitted to humans through mosquito bites [112].Malaria is an infectious disease caused by malaria parasites [113][114][115].Predominantly prevalent in tropical and subtropical regions, especially in Africa, South Asia, Southeast Asia, and Central America [116], malaria accounts for more than 200 million cases worldwide each year [117].The development of effective antimalarial drugs can reduce the spread and infection of malaria and accelerate the early recovery of patients [118].Therefore, it is of great significance to find more effective antimalarial drugs.In the process of studying antimalarial drugs, researchers have found that some sesquiterpenes and some other natural components derived from Artabotrys plants have shown antimalarial activity.Notably, yingzhaosu A (1) is the first antimalarial drug with a clear structure containing an endoperoxide structure in history [119].This discovery has spurred further research and the synthesis of new antimalarial drugs, although the exact mechanism of yingzhaosu A's antimalarial action remains partially understood.Current research suggests that yingzhaosu A's mechanism of action may involve two primary processes.Firstly, in the presence of oxygen and iron (II), yingzhaosu A will undergo a degradation reaction due to the induction of iron (II), forming unsaturated ketones and cyclohexyl radicals, respectively.The active substances produced in this process may be the reason for its antimalarial effect [120].
Secondly, a recent study found that when yingzhaosu A plays a role in the body, it is attacked by heme, which destroys its peroxide structure, produces tertiary oxygen-centered radicals, and rearranges to remove the side chain.Therefore, the yingzhaosu A is split into two parts.Heme is an important marker of malaria parasites.Based on the above findings, a heme-activatable probe has been successfully developed, which will play an important role in the field of antimalarial [121].

Antibacterial and Antifungal Activity
Bacterial infections significantly impact global health, causing widespread morbidity and mortality, and placing a significant burden on health care systems [125,126].At present, many bacteria are resistant to antibiotics, which has become an extremely important public health problem [127][128][129].However, due to the increase in global antimicrobial resistance, the efficacy of some treatments for bacterial infections is reduced or even ineffective.Therefore, it is particularly important to find new therapeutic drugs and design new treatment strategies in the field of antibacterial [130,131].
Among the promising candidates, sesquiterpenes derived from Artabotrys plants have demonstrated antibacterial effects through different mechanisms, showing potential against a variety of bacterial and fungal pathogens.Notably, isodaucane-type sesquiterpene artabotrol (53), isolated from the stem bark of A. stenopetalus, a plant belonging to the genus Artabotrys, exhibits a specific inhibitory effect on Cryptococcus neoformans [132].
Dihydroactinidiolide (78) also has significant anti-tumor activity against four human tumor cell lines, epithelial cell carcinoma (Hela), human prostate cancer (PC-3), breast cancer (MCF-7), and hepatocellular carcinoma (HePG-2) [137].Additionally, βcaryophyllene oxide (68) has been studied for its antitumor mechanism.It is well known that phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase 1 (S6K1) and mitogen-activated protein kinase (MAPK) signaling cascades play an important role in many physiological processes of tumor cells, including cell proliferation, survival, angiogenesis, and metastasis of tumor cells.Through Western blot analysis, MTT assay, and other research methods, it was found that β-caryophyllene oxide (68) not only inhibited the constitutive activation of PI3K/AKT/mTOR/S6K1 signaling cascade in human prostate cancer PC-3 and breast cancer MCF-7 cells; it also causes the activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK in tumor cells, and down-regulates various gene products related to cell proliferation, anti-apoptosis, and metastasis.In addition, in different tumor cells, β-caryophyllene oxide (68) can simultaneously target PI3K/AKT/mTOR/S6K1 and MAPK signaling pathways, inhibit the proliferation of related tumor cells and induce the apoptosis of tumor cells by activating caspase-3 and releasing cytochrome c.These results suggest that β-caryophyllene oxide ( 68) is a potential candidate drug for the prevention and treatment of cancer [138][139][140].

Anti-Inflammatory and Analgesic Activity
Inflammation is a complex immune response, which is the body's defense mechanism against injury and infection [141,142].The five main symptoms of inflammation are pain, fever, redness, swelling, and loss of function.Inflammation can be divided into acute and chronic inflammation [143].If inflammation is left unchecked, it may lead to autoimmune diseases, neurodegenerative diseases, etc. [144].At present, there are many effective anti-inflammatory drugs, which are also the most common clinical treatment drugs.However, the commonly used anti-inflammatory drugs will have some side effects during the treatment [145,146].Therefore, in addition to using traditional non-steroidal anti-inflammatory drugs to treat inflammation, some compounds isolated from natural sources are also considered new options for treating inflammatory diseases [147][148][149][150].Among these, some natural sesquiterpenes obtained from the Artabotrys genus have demonstrated promising anti-inflammatory and analgesic activities.For instance, caryolane-1,9β-diol (76), which was found in A.uncinatus in 2007, exhibits significant anti-inflammatory activity in a dose-dependent manner [107,151].Similarly, spathulenol (64), isolated from the twigs and leaves of A. hainanensis and previously found in other species such as Psidium guineense Sw. has shown notable inhibitory effect on the related pathological symptoms of the Cg-induced paw edema and pleurisy model in mice established in the experiment [152].
Additionally, alismol (47) also has anti-inflammatory effects, reducing the levels of NO and prostaglandin E2 in cells and inhibiting the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) stimulated by lipopolysaccharide in the body.It also inhibits the messenger RNA (mRNA) and protein expression of pro-inflammatory cytokines including interleukin and tumor necrosis factor α (TNF-α) [153].

Antiviral Activity
The ongoing threat of viral infections, such as influenza virus [154], coronavirus disease 2019 (COVID-19) virus [155], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus [156], underscores the importance of effective antiviral therapies in preventing disease spread, mitigating viral damage, and facilitating patient recovery.Antiviral drugs not only help control outbreaks and improve treatment outcomes but also minimize the risk of viral mutations and drug resistance.In this context, sesquiterpenes, a class of compounds derived from natural products, hold significant promise for antiviral drug development.Their potential for inhibiting viral activity, supporting drug development, and boosting immunity offers valuable insights for future antiviral strategies.
Research indicates that sesquiterpene compounds 3, 11, 12, 17, 54, and 55 have inhibitory effects on Coxsackievirus B3 and influenza A virus.Specifically, compounds 3, 54, and 55 have moderate antiviral activity against Coxsackievirus B3, with IC 50 values ranging from 6.41 to 33.33 µM.Meanwhile, compounds 12 and 17 showed weak inhibitory activity against the influenza A virus with IC 50 values ranging from 19.24 to 33.33 µM [76].Furthermore, guaianediol (45) obtained from A. pilosus in 2016 displayed anti-human immunodeficiency virus type 1 (anti-HIV-1) virus activity.In previous related studies, a variety of research methods have been used to explore its anti-HIV-1 activity, such as human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) assay, syncytium assay, and other research methods.In addition to its significant anti-HIV-1 activity in syncytium assay, the results suggest that Guaianediol may inhibit HIV-1 RT, though its exact IC 50 value requires further investigation [157].

Antioxidant Activity
Studies have shown that some sesquiterpene compounds have significant antioxidant activity [158,159].These compounds can exhibit antioxidant properties in vivo through a variety of mechanisms, including scavenging free radicals, increasing antioxidant enzyme activity, and regulating oxidation-reduction balance.Among these, spathulenol (64) not only exhibits an anti-inflammatory effect but also demonstrates a significant antioxidant effect, with its IC 50 value ranging from 26.13 to 85.60 µM [152].Furthermore, studies on the dichloromethane extract of dihydroactinidiolide (78) have revealed its free radical scavenging activity, underscoring the antioxidant potential of sesquiterpenes [137].

Discussion on Structure-Activity Relationships
In general, compounds with the same skeleton structure are often possessed of similar biological activities and pharmacological effects.Through comparison and analysis of some compounds with the same skeleton structure, as well as known activities, the possible structure-activity relationship of some sesquiterpene compounds with the same skeleton structure is discussed.
Compounds 56, 58, and 59 are cadinane-type sesquiterpenes, with the same skeleton structure.They are all possessed of anti-tumor activities, but the inhibitory effect on the same tumor cells is different.The difference in the structure of compounds 56 and 58 structure is only the difference in the hydrogen atom configuration at the C-1 position.The hydrogen atom at the C-1 position of compound 56 is the R configuration, and the hydrogen atom at the C-1 position of 58 is the S configuration.It is speculated that it may be the main factor affecting the pharmacological activity of the two.When the hydrogen atom at the C-1 position of the two is the R configuration, this may have a better inhibitory effect on the tumor cells of A-549, MCF-7, and SW480.

Conclusions
Artabotrys, a prominent genus within the Annonaceae family, is renowned for its vast global presence and rich chemical diversity, including flavonoids, alkaloids, and terpenoids.Many of the chemical components have shown good pharmacological activity and have high research value.
This paper presents a comprehensive review of the sesquiterpene compounds identified in plants and their pharmacological activities, aiming to provide a solid scientific foundation for further exploring and utilizing this genus.It also seeks to deepen the understanding of sesquiterpene compounds' pharmacological actions and mechanisms.An extensive review of research literature has cataloged approximately 85 sesquiterpene compounds and their sources from Artabotrys plants, categorizing them according to their structural characteristics.In addition to the common types of sesquiterpenes, such as bisabolane-type sesquiterpenes and eudesmane-type sesquiterpenes, which are rich in plant and microbial sources, this genus also harbors sesquiterpenes with special structures that are relatively rare.Pharmacological research reveals that these compounds exhibit a broad spectrum of activities, including antimalarial, anti-inflammatory, antiviral, and antitumor effects, underscoring their significant medicinal potential and positioning them as potential leads for drug development.
Despite the promising pharmacological activity, the mechanism behind the activities of sesquiterpenes from Artabotrys plants remains insufficiently explored, posing challenges to their clinical application of the related sesquiterpenes.Furthermore, many sesquiterpene components in the genus of Artabotrys remain undiscovered, suggesting vast opportunities for future research.It is anticipated that ongoing studies will uncover new sesquiterpene compounds and elucidate their mechanisms of action, enhancing the therapeutic value of Artabotrys sesquiterpenes.

Figure 11 .
Figure 11.The structures of other types of sesquiterpenes from Artabotrys.

Figure 11 .
Figure 11.The structures of other types of sesquiterpenes from Artabotrys.