Sage Journals: Discover world-class research

Abstract

Background

In traditional medicine of Southeast Asian countries, Baeckea frutescens L. (family Myrtaceae) has a long history of use. Numerous research projects have shown that this plant contains metabolites with remarkable medicinal value. No review document, to date, has given an insight into the role of B frutescens constituents in pharmacological development.

Objective

The current review briefly offers crucial information on the phytochemistry, biosynthesis, synthesis, and pharmacology of B frutescens.

Methods

B frutescens is the most meaningful keyword to search for literature data. It was used either on its own or in combination with other keywords. References have been gathered from various resources such as Google Scholar, SciFinder, and PubMed. More than 50 electronic references were collected from the 1960s.

Results

Approximately 130 metabolites have been isolated and structurally determined from this medicinal plant. They included phloroglucinols, phloroglucinol-based meroterpenoids, sesquiterpenoids, triterpenoids, flavonoids, chromones, 5-membered ring compounds, and others. B frutescens fresh tissues were thought to be a rich resource of essential oils. Tasmanone is a precursor in the biosynthesis of various B frutescens compounds, while phloroglucinol derivatives can be seen as initial compounds in the synthetic procedures of various B frutescens molecules. B frutescens plant extracts and compounds isolated from them possess a variety of pharmacological properties, such as cytotoxic, antimicrobial, anti-inflammatory, antioxidant, antirheumatoid, skin protective, and mosquito larvicidal activities.

Conclusion

More experimental reports on phytochemistry and pharmacology are required. In vivo pharmacological studies on the mechanisms of action of the active compounds are urgently required since most of the results obtained so far have been from in vitro assays.

Keywords

phytochemistry biosynthesis synthesis pharmacology

Introduction

Baeckea frutescens L. is a member of the family Myrtaceae and is indigenous to Australia, New Guinea, and eastern Southeast Asia.¹ It is a shrub with arched branches, linear leaves, and 7-13 stamens on each of its white flowers. B frutescens, also known as “Jungrahab,” is an Indonesian folk medicine.² Its aerial parts are employed to treat influenza, malaria, fever, headache, dysentery, and abdominal pain.² The leaves of this plant are recommended as a remedy for headache, rheumatism, and fever.³ The leaf decoction was used in Malaysia for diuretic and emmenagogue features.⁴ In China, the leaves have been applied as a refreshing herbal tea to cure fever and sunstroke, and the dried leaves could be a febrifuge.⁴ The roots of this plant, known as “Pu Lao Zhong,” have good effects in treating rheumatism and snake bites.^5,6 B frutescens is used as a daily health tea with the well-known name of “Gang Song Cha.”⁷

By chromatographic procedures and liquid chromatography-mass spectrometry (LC-MS) analysis, diverse classes of phytochemicals have been detected. Along with other classes, phloroglucinols, flavonoids, and chromones are likely to be the main types of B frutescens secondary metabolites.^5–14 B frutescens essential oils are dominated by terpenoids.^15,16 The plant extracts, fractions, and their isolates are now potential agents for drug development since they possess pivotal pharmacological properties, such as cytotoxic, antimicrobial, and anti-inflammatory activities.^13,17,18 As an example, frutescone O, at 0.2-0.8 µM, suppressed lipopolysaccharide (LPS)-stimulated RAW264.7 cells by blocking TLR4-mediated mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) signaling pathways and inhibiting MyD88 and iNOS expressions.¹⁹

Although there are plenty of experimental reports, no review article has been recorded until now. For the first time, we review several important aspects of this plant, including phytochemical separations, essential oil identifications, biosynthetic and synthetic pathways, and, especially, the applications of chemical constituents in biomedical examinations.

Phytochemistry

In this section, the outcomes of phytochemical investigations of B frutescens are based on the use of column chromatography (CC) to isolate purified compounds and LC-MS analysis to detect compounds in plant extracts. A list of isolates is summarized in Table 1 and Figures 1 to 3, including phloroglucinols 1-14,^{3,13,14,20,21} phloroglucinol-based meroterpenoids 15-61,^{17,20,22–26} sesquiterpenoids 62-65,^3,27 triterpenoids 66-68,^3,12 flavonoids 69-102,^{5–13,21,24,28–32} chromones 103-121,^{9,12,28,30,33,34} 5-membered ring compounds 122-126,^2,21 mono-phenol 127,¹² and phytosterol 128.¹² In addition, the names of these isolates have been ordered in an alphabetic arrangement.

Figure 1.

Phloroglucinols, phloroglucinol-based meroterpenoids, sesquiterpenes, and triterpenoids from Baeckea frutescens.

Figure 2.

Flavonoids from Baeckea frutescens.

Figure 3.

Chromones, 5-membered ring compounds, and others from Baeckea frutescens.

Table 1.

Chemical Constituents of Baeckea frutescens.

No.	Compounds	Plant part used	Methods	References
Phloroglucinols
1	Baekeol (BF-3)	Leaf	CC	^13,20
2	Baeckenone A	Leaf	CC	¹³
3	Baeckenone B	Leaf	CC	¹³
4	Baeckenone C	Leaf	CC	¹³
5	Baeckenone D	Leaf	CC	¹⁴
6	Baeckenone E	Leaf	CC	¹⁴
7	Baeckenone F	Leaf	CC	¹⁴
8	Baeckenone G	Leaf	CC	³
9	Baeckenone H	Leaf	CC	³
10	Baeckenone I	Leaf	CC	³
11	Baeckenone J	Leaf	CC	³
12	Baeckenone K	Leaf	CC	³
13	BF-1^a	Leaf	CC	²⁰
14	(8aR)-8,8a-Dihydro-8a- hydroxy-7-methoxy-3,3,6, 8,8-pentamethyl- 1,2-benzodioxin-5(3H)-one	Leaf and aerial part	CC	^14,21
Phloroglucinol-based meroterpenoids
15	Baefrutone A	Aerial part	CC	²³
16	Baefrutone B	Aerial part	CC	²³
17	Baefrutone C	Aerial part	CC	²³
18	Baefrutone D	Aerial part	CC	²³
19	Baefrutone E	Aerial part	CC	²³
20	Baefrutone F	Aerial part	CC	²³
21	Baeckfrutone A	Twig and leaf	CC	²⁵
22	(±)-Baeckfrutone B	Twig and leaf	CC	²⁵
23	(±)-Baeckfrutone C	Twig and leaf	CC	²⁵
24	Baeckfrutone D	Twig and leaf	CC	²⁵
25	Baeckfrutone E	Twig and leaf	CC	²⁵
26	Baeckfrutone F	Twig and leaf	CC	²⁵
27	Baeckfrutone G	Twig and leaf	CC	²⁵
28	Baeckfrutone H	Twig and leaf	CC	²⁵
29	(±)-Baeckfrutone I	Twig and leaf	CC	²⁵
30	Baeckfrutone J	Twig and leaf	CC	²⁵
31	Baeckfrutone K	Twig and leaf	CC	²⁵
32	Baeckfrutone L	Twig and leaf	CC	²⁵
33	Baeckfrutone M	Twig and leaf	CC	²⁶
34	Baeckfrutone N	Twig and leaf	CC	²⁶
35	Baeckfrutone O	Twig and leaf	CC	²⁶
36	Baeckfrutone P	Twig and leaf	CC	²⁶
37	Baeckfrutone Q	Twig and leaf	CC	²⁶
38	Baeckfrutone R	Twig and leaf	CC	²⁶
39	Baeckfrutone S	Twig and leaf	CC	²⁶
40	BF-2^a	Leaf	CC	²⁰
41	Frutescone A	Aerial part	CC	¹⁷
42	Frutescone B	Aerial part	CC	¹⁷
43	Frutescone C	Aerial part	CC	¹⁷
44	Frutescone D	Aerial part	CC	¹⁷
45	Frutescone E	Aerial part	CC	¹⁷
46	Frutescone F	Aerial part	CC	¹⁷
47	(±)-Frutescone G	Aerial part	CC	¹⁷
48	Frutescone H	Aerial part	CC	²²
49	Frutescone I	Aerial part	CC	²²
50	Frutescone J	Aerial part	CC	²²
51	Frutescone K	Aerial part	CC	²²
52	Frutescone L	Aerial part	CC	²²
53	Frutescone M	Aerial part	CC	²²
54	(±)-Frutescone N	Aerial part	CC	²²
55	Frutescone O	Aerial part	CC	²²
56	Frutescone P	Aerial part	CC	²²
57	(±)-Frutescone Q	Aerial part	CC	²²
58	(±)-Frutescone R	Aerial part	CC	²²
59	Frutescone S	Aerial part	CC	²⁴
60	Frutescone T	Aerial part	CC	²⁴
61	Frutescone U	Aerial part	CC	²⁴
Sesquiterpenoids
62	Caryophyllene-4β,5α-epoxide	Aerial part	CC	²⁷
63	(−)-Clovane-2,9-diol	Aerial part	CC	²⁷
64	Humulene	Leaf	CC	³
65	(±)-Humulene epoxide II	Aerial part	CC	²⁷
Triterpenoids
66	Betulinic acid	Whole plant	CC	¹²
67	Oleanolic acid	Whole plant	CC	¹²
68	Ursolic acid	Leaf	CC	³
Flavonoids
Flavones
69	Baeckein A	Root and aerial part	CC LC-MS	^5,8,9
70	Baeckein B	Root and aerial part	CC LC-MS	^5,8,9
71	Baeckein C	Root and aerial part	CC LC-MS	^6,8,9
72	Baeckein D	Root and aerial part	CC LC-MS	^6,8,9
73	Baeckein E	Root and aerial part	CC LC-MS	^8,9
74	Baeckein F	Root and aerial part	CC LC-MS	^7,9
75	Baeckein G	Root and aerial part	CC LC-MS	^7,9
76	Baeckein H	Root and aerial part	CC LC-MS	^7,9
77	Baeckein I	Root and aerial part	CC LC-MS	^7,9
78	Baeckein J	Root	CC	¹⁰
79	Baeckein K	Root	CC	¹⁰
80	Baeckein L	Root	CC	¹¹
81	Baeckein M	Root	CC	¹¹
82	Betmidin	Aerial part	CC	³²
83	6,8-Di-C-methylkaempferol	Aerial part	CC	³²
84	6,8-Di-C-methylkaempferol 3-O-α-L-rhamnopyranoside	Aerial part	CC LC-MS	^9,32
85	6-C-Methylquercetin (pinoquercetin)	Aerial part and root	CC LC-MS	^8,9,28,29,32
86	6-Methylquercetin 7-O-β-D-glucopyranoside	Aerial part	CC LC-MS	^28,29
87	6-C-Methylquercetin 4′-O-β-D-glucopyranoside	Aerial part and root	CC LC-MS	^8,9,28,32
88	6-C-Methylquercetin 3-O-α-L-rhamnopyranoside	Aerial part	CC LC-MS	^9,32
89	Myricetin	Aerial part	LC-MS	^9,29
90	Myricetin 3-O-(5″-O-galloyl)-α-L-arabinofuranoside	Aerial part	CC LC-MS	^28,29
91	Myricitrin (myricetin 3-O-α-L-rhamnopyranoside)	Leaf and aerial part	CC LC-MS	^9,30,32
92	Quercetin	Aerial part	CC LC-MS	^9,32
93	Quercetin-3-O-α-L-rhamnoside	Aerial part	LC-MS	^9,29
94	Quercetin 3-O-(5″-O-galloyl)-α-L-arabinofuranoside	Aerial part	CC	²⁸
Flavanones
95	BF-4^a	Leaf	CC	³¹
96	BF-5^a	Leaf	CC	³¹
97	BF-6^a	Leaf	CC	³¹
98	2,3-Dihydro-5,7-dihydroxy-8-[1-(2-hydroxy-4-methoxy-3,3,5-trimethyl-6-oxo-1,4-cyclohexadien-1-yl)-2-methylpropyl]-6-methyl-2-phenyl-4H-1-benzopyran-4-one	Leaf and aerial part	CC	^13,21
99	5,7-Dihydroxy-6,8-dimethylflavanone	Leaf and aerial part	CC LC-MS	^13,29
100	(±)-5,7-Dihydroxy-8-isobutyryl-6-methyldihydroflavonol	Aerial part	CC	²⁴
101	5-Hydroxy-6-methyl-7-methoxyflavanone	Whole plant and aerial part	CC LC-MS	^9,12
102	5-Hydroxy-7-methoxy-8-methylflavanone	Whole plant and aerial part	CC LC-MS	^9,12
Chromones
103	2,5-Dihydroxy-7-methoxy-2-isopropylchromanone	Aerial part	CC	³⁴
104	2,5-Dihydroxy-7-methoxy-2,6-dimethylchromanone	Aerial part	CC	³⁴
105	2,5-Dihydro-7-methoxy-2,8-dimethylchromanone	Aerial part	CC	³⁴
106	2,5-Dihydro-7-methoxy-2-isopropyl-6-methylchromanone	Aerial part	CC	³⁴
107	2,5-Dihydro-7-methoxy-2-isopropyl-8-methylchromanone	Aerial part	CC	³⁴
108	7-O-(4′,6′-Digalloyl)-β-D-glucopyranosyl-5-hydroxy-2-methylchromone	Aerial part	CC	²⁸
109	5-Hydroxy-7-methoxy-2-isopropylchromone	Aerial part and whole plant	CC LC-MS	^9,12,34
110	5-Hydroxy-7-methoxy-2-isopropyl-6-methylchromone	Aerial part	CC LC-MS	^9,34
111	5-Hydroxy-7-methoxy-2-isopropyl-8-methylchromone	Aerial part	CC LC-MS	^9,34
112	5-Hydroxy-7-methoxy-2-methylchromone (eugenin)	Aerial part	CC LC-MS	^9,34
113	5-Hydroxy-7-methoxy-2,8-dimethylchromone	Aerial part	LC-MS	⁹
114	6-β-C-Glucopyranosyl-5,7-dihydroxy-2-methylchromone	Leaf	CC	^30,33
115	6-β-C-Glucopyranosyl-5,7-dihydroxy-2-isopropylchromone	Leaf	CC	^30,33
116	6-β-C-(2′-Galloylglucopyranosyl)-5,7-dihydroxy-2-methylchromone (5)	Leaf	CC	³⁰
117	6-β-C-(2′-Galloylglucopyranosyl)-5,7-dihydroxy-2-isopropylchromone	Leaf	CC	^30,33
118	8-β-C-Glucopyranosyl-5,7-dihydroxy-2-methylchromone	Leaf	CC	³⁰
119	8-β-C-Glucopyranosyl-5,7-dihydroxy-2-isopropylchromone	Leaf	CC	^30,33
120	8-β-C-(2′-Galloylglucopyranosyl)-5,7-dihydroxy-2-methylchromone	Leaf	CC	³⁰
121	8-β-C-(2′-Galloylglucopyranosyl)-5,7-dihydroxy-2-isopropylchromone	Leaf	CC	^30,33
5-membered ring compounds
122	Frutescencenone A	Leaf	CC	²
123	Frutescencenone B	Leaf	CC	²
124	Frutescencenone C	Leaf	CC	²
125	4-Hydroxy-2,2,5-trimethyl-4-cyclopentene-1,3-dione	Leaf	CC	²
126	5-(2-Hydroxy-2-methylpropylidene)-3-methoxy-2,4,4-trimethyl-2-cyclopenten-1-one	Leaf and aerial part	CC	^2,21
Mono-phenol
127	Ethyl gallate	Whole plant	CC	¹²
Phytosterol
128	β-Sitosterol	Whole plant	CC	¹²

No name.

Abbreviations: CC, column chromatography; LC-MS, liquid chromatography-mass spectrometry.

Phloroglucinols, Phloroglucinol-Based Meroterpenoids, Sesquiterpenoids, and Triterpenoids

Phloroglucinols 1-14 are the first chemical class found in this species (Table 1 and Figure 1).^{3,13,14,20,21} From the EtOH leaf extract, Fujimoto et al²⁰ isolated a new phloroglucinol BF-1 (13) and a known analog, baekeol (1). Significantly, 11 new phloroglucinols, baeckenones A-K (2-12), were successfully separated from the CHCl₃ extracts of Indonesian B frutescens.^3,13,14 (8aR)-8,8a-Dihydro-8a-hydroxy-7-methoxy-3,3,6,8,8-pentamethyl-1,2-benzodioxin-5(3H)-one (14) was first isolated as a new racemic mixture from the aerial part and then was found in the leaf.^14,21 Compound 14, containing an endoperoxide part, was an unusual metabolite. The successful isolation of this compound suggested a close chemotaxonomic relationship between Myrtaceae species since some analogs were also isolated from other Myrtaceae plants.²¹

The hybrid-type phloroglucinol-based meroterpenoids 15-61 were the second chemical class detectable in B frutescens (Table 1 and Figure 1)^{17,20,22–26}; all of these isolates were new in nature. Six new meroterpenoids with rare phloroglucinol-monoterpene/sesquiterpene backbones, named baefrutones A-F (15-20), were isolated from the 95% EtOH aerial part extract under high-performance liquid chromatography (HPLC)-Q/TOF-MS² guidance.²³ In the same manner, 19 previously undescribed compounds, baeckfrutones A-S (21-39), were observed in the twig and leaf, in which compounds 22-23 and 29 were present in enantiomeric forms.^25,26 BF-2 (40) was among the new compounds found in the EtOH leaf extract.²⁰ The 95% EtOH extract of the Chinese B frutescens aerial part contained new secondary metabolites, frutescones A-U (41-61).^17,22,24 Compounds 47, 54, and 57-58 appeared as enantiomeric forms, whereas 41 and 44 were marked with an unprecedented oxa-spiro[5.8] tetradecadiene skeleton.

Four sesquiterpenoids 62-65 have been isolated from B frutescens to date.^3,27 Chromatographic procedures aided by HPLC of the CH₂Cl₂ aerial part extract afforded a new sesquiterpene, (−)-clovane-2,9-diol (63), along with 2 known analogs caryophyllene-4β,5α-epoxide (62) and (±)-humulene epoxide II (65).²⁷ Humulene (64), a well-known sesquiterpene, was 1 of the isolates from the leaf.³ Two common triterpenoids, betulinic acid (66) and oleanolic acid (67), were detectable in the whole plant, while the other known agent ursolic acid (68) was only found in the leaf.^3,12

Flavonoids

Flavonoids are low-molecular-weight phenolic compounds that are found in a variety of higher plants.^35–37 As shown in Table 1 and Figure 2, flavonoids derived from B frutescens can be divided into flavones 69-94^{5–11,28–30,32} and flavanones 95-102.^{9,12,13,21,24,29,31}

Regarding flavones, 13 new derivatives, baeckeins A-M (69-81), were isolated from the roots and structurally determined from spectroscopic and mass spectrometric evidence.^5–8,10,11 From the EtOAc extract of the aerial part, a new flavone, 6,8-di-C-methylkaempferol (83), and 3 new glycoside derivatives, 6,8-di-C-methylkaempferol 3-O-α-L-rhamnopyranoside (84), 6-C-methylquercetin 4′-O-β-D-glucopyranoside (87), and 6-C-methylquercetin 3-O-α-L-rhamnopyranoside (88) were isolated.³² 6-C-Methylquercetin (85) is a well-known compound,^8,9,28,29,32 but its 7-O-β-D-glucopyranoside (86) was a new flavone separated from the aerial part.²⁸ Likewise, myricetin (89)^9,29 and myricitrin (91)^9,30,32 are 2 well-known plant constituents, but myricetin 3-O-(5″-O-galloyl)-α-L-arabinofuranoside (90) was isolated by CC and then identified by LC-MS from the aerial part for the first time.^28,29 In the last case, by either CC or LC-MS procedures, quercetin (92), its 3-O-α-L-rhamnoside (93), and 3-O-(5″-O-galloyl)-α-L-arabinofuranoside (94) were confirmed to be present in the aerial part.^8,28,29,32

In the search for bioactive compounds from natural resources, 3 new cytotoxic flavanones, BF-4 (95), BF-5 (96), and BF-6 (97), were separated from the EtOH leaf extract.³¹ 2,3-Dihydro-5,7-dihydroxy-8-[1-(2-hydroxy-4-methoxy-3,3,5-trimethyl-6-oxo-1,4-cyclohexadien-1-yl)-2-methylpropyl]-6-methyl-2-phenyl-4H-1-benzopyran-4-one (98) was a new derivative found in the CH₂Cl₂ extract of the aerial part.²¹ It was then isolated from the leaf.¹³ The aerial part of B frutescens has been further recorded to contain another new enantiomeric flavanone, (±)-5,7-dihydroxy-8-isobutyryl-6-methyldihydroflavonol (100).²⁴ Two known flavanones, 5-hydroxy-6-methyl-7-methoxyflavanone (101) and 5-hydroxy-7-methoxy-8-methylflavanone (102), were also identified by both CC and LC-MS techniques.^9,12

Chromones, 5-Membered Ring Compounds, and Others

Chromones, a subclass of flavonoids, are also present in B frutescens. A list of 19 metabolites (103-121) is compiled in Table 1.^{9,12,28,30,33,34} Their structures were characterized as either free or glycosylated forms (Figure 3). Besides 6 known compounds (103-107 and 112), the CH₂Cl₂ extract of the aerial part contained 3 new chromones, 5-hydroxy-7-methoxy-2-isopropylchromone (109), 5-hydroxy-7-methoxy-2-isopropyl-6-methylchromone (110), and 5-hydroxy-7-methoxy-2-isopropyl-8-methylchromone (111).³⁴ Compound 108, named 7-O-(4′,6′-digalloyl)-β-D-glucopyranosyl-5-hydroxy-2-methylchromone, was a new metabolite due to substitution of a digalloyl-glycopyranosyl unit at carbon C-7.²⁸ Glycosylated chromones 114-121 were secondary metabolites found in the leaf, in which 6-β-C-glucopyranosyl-5,7-dihydroxy-2-methylchromone (114), 6-β-C-glucopyranosyl-5,7-dihydroxy-2-isopropylchromone (115), 6-β-C-(2′-galloylglucopyranosyl)-5,7-dihydroxy-2-isopropylchromone (117), 8-β-C-glucopyranosyl-5,7-dihydroxy-2-isopropylchromone (119), and 8-β-C-(2′-galloylglucopyranosyl)-5,7-dihydroxy-2-isopropylchromone (121) were new in the literature.^30,33

Phytochemical studies on B frutescens further identified the presence of 5-membered ring compounds 122-126 (Table 1 and Figure 3).^2,21 In addition to the known compound 4-hydroxy-2,2,5-trimethyl-4-cyclopentene-1,3-dione (125), 4 derivatives, frutescencenones A-C (122-124) and 5-(2-hydroxy-2-methylpropylidene)-3-methoxy-2,4,4-trimethyl-2-cyclopenten-1-one (126), were new metabolites detected in the leaf.² Compound 126 was also found in the aerial part.²¹ Compounds 122-126 have also been isolated from the genus Baeckea for the first time. Two final compounds, 127-128, can be classified as a mono-phenol and phytosterol, respectively. They originated from the 95% EtOH extract of the whole plant.¹²

Essential Oils

Essential oils are made up of lipophilic and extremely volatile secondary plant metabolites that are physically separable from other plant parts and have a mass below a molecular weight of 300.³⁸ Hydrodistillation extraction (HE) is likely to be the best extraction approach to obtain a high yield of essential oil.^39,40 The major compounds (≥5.0%) of the essential oil of B frutescens, analyzed by gas chromatography-mass spectrometry (GC-MS), are listed in Table 2.

Table 2.

The Main Compounds in Baeckea frutescens Essential Oils.

Part of use	Collection	Main compounds	References
Leaf	Hatinh, Vietnam	α-Humulene (19.2%), α-caryophyllene (17.3%), baeckeol (13.8%), α-thujene (8.8%), linalool (5.6%), and 1,8-cineole (5.4%)	¹⁵
Leaf	Danang, Vietnam	β-Pinene (19.0%), γ-terpinene (11.7%), α-pinene (11.1%), 1,8-cineole (10.1%), α-humulene (9.9%), and (E)-caryophyllene (7.1%)	¹⁶
Leaf and stem	Hue, Vietnam	p-Cymene (22.2%), α-thujene (12.3%), 1,8-cineole (10.9%), terpinen-4-ol (7.9%), linalool (6.0%), α-humulene (5.8%), and humulene 6,7-epoxide (5.4%)	⁴¹
Leaf and stem	Hanoi, Vietnam	β-Pinene (23.3%), 1,8-cineole (8.6%), α-pinene (8.2%), α-eudesmol (6.5%), β-eudesmol and γ-terpinene (6.3%), and α-humulene (5.3%)	⁴¹
Leaf and stem	Quangbinh, Vietnam	Tasmanone (24.3%), γ-terpinene (9.4%), β-pinene (9.0%), 1,8-cineole (6.6%), and p-cymene (5.0%)	⁴¹
Leaf	Sabah, Malaysia	β-Pinene (37.3%), α-pinene (18.2%), and borneol (8.9%)	⁴
Leaf	Kepong, Malaysia	α-Pinene (20.9%), β-pinene (19.0%), γ-terpinene (17.0%), α-humulene (6.1%), and α-terpineol (5.3%)	⁴
Leaf	Selangor, Malaysia	α-Pinene (48.2%), γ-terpinene (18.7%), linalool (8.6%), and 1,8-cineole (6.0%)	⁴
Leaf	Terengganu, Malaysia	γ-Terpinene (34.1%), α-humulene (10.6%), p-cymene (9.6%), β-caryophyllene (6.3%), linalool (7.1%), and α-pinene (5.1%)	⁴
Leaf	Guangxi, China	β-Caryophyllene (28.05%), α-caryophyllene (24.02%), δ-cadinene (6.29%), eucalyptol (5.46%), and β-pinene (5.21%)	⁴²

The leaf oil, collected from Hatinh, Vietnam, was dominated by α-humulene (19.2%), α-caryophyllene (17.3%), baeckeol (13.8%), α-thujene (8.8%), linalool (5.6%), and 1,8-cineole (5.4%), whereas the sample from Danang, Vietnam, yielded β-pinene (19.0%), γ-terpinene (11.7%), α-pinene (11.1%), 1,8-cineole (10.1%), α-humulene (9.9%), and (E)-caryophyllene (7.1%).^15,16 In another report, the compounds present in the highest amount in the leaf and stem oils collected from Hue, Hanoi, and Quangbinh, Vietnam, were p-cymene (22.2%), β-pinene (23.3%), and tasmanone (24.3%), respectively.⁴¹ By means of GC-MS analysis, 2 pinene isomers were the best representatives for the leaf oils of Sabah, Kepong, and Selangor, Malaysia, but the leaf oil obtained from Terengganu, Malaysia, contained γ-terpinene (34.1%) and others.⁴ β-Caryophyllene (28.05%), α-caryophyllene (24.02%), δ-cadinene (6.29%), eucalyptol (5.46%), and β-pinene (5.21%) were characteristic compounds in the leaf oil of a Chinese sample (Table 2).

Biosynthesis and Synthesis

Biosynthesis

Information on the biosynthesis of B frutescens metabolites is now available in the literature and is focused on meroterpenoids. As shown in Figure 4, phloroglucinol-based meroterpenoids baeckfrutones A-L (21-32) could biosynthetically originate from tasmanone and its demethylated derivative by divergent hetero-Diels-Alder (HAD) reactions.²⁵ The reduction of tasmanone and its demethylated derivative and subsequent dehydration could generate intermediates A1 and A2, which could undergo HAD reactions through pathways I and II with various monoterpenes, comprising α-phellandrene, sabinene, and β-pinene, to afford compounds 21-32 by region and stereoselective [4 + 2] cycloaddition reactions.²⁵

Figure 4.

Biosynthetic pathway of baeckfrutones A-L (21-32).

Along with the isolation of frutescones A-G (41-47), Hou et al¹⁷ suggested a plausible biosynthetic pathway of these compounds based on the key precursor, tasmanone (Figure 5). The key compound, tasmanone, β-caryophyllene, and α-humulene appeared as the major constituents of B frutescens essential oil. Selective reduction and dehydration of tasmanone provided the intermediate A3. Then, this intermediate could undergo HAD reactions with either β-caryophyllene or α-humulene to achieve compounds 41-47 in regio- and stereoselective manners.

Figure 5.

Biosynthetic pathway of frutescones A-G (41-47).

Synthesis

The synthetic procedure for baeckenone B (3) has been outlined in Figure 6.⁴³ Friedel–Craft acylation of phloroglucinol gave isobutyrylphloroglucinol A in 91% yield. Trimethylated B was formed from isobutyrylphloroglucinol in 67% yield by treatment with MeI. Methylation of B generated tasmanone, which then underwent a reduction–carbonylation reaction with diisobutylaluminum hydride (DIBAL-H) to provide the Michael reaction acceptor C. The Michael addition reaction between C and D (which was also prepared from phloroglucinol through a sequence of Vilsmeier–Haack formylation, reduction with sodium cyanoborohydride, and isobutyrylation) furnished compound 3 in 83% yield.

Figure 6.

Synthetic pathway of phloroglucinol 3.

In 2003, Gray et al⁴⁴ demonstrated synthetic steps of 5-hydroxy-7-methoxy-2-isopropylchromone (109) and 5-hydroxy-7-methoxy-2-methylchromone (112) (Figure 7). The procedure started with 2,4,6-trihydroxyacetophenone. Treatment of this compound with dimethyl sulfate and anhydrous K₂CO₃ in acetone under reflux provided E in 90% yield. The resulting dimethylated compound was treated with NaOEt in EtOH, and then ethyl carboxylate esters [RCOOEt; R = (CH₃)₂CH, CH₃] afforded mixtures of condensation products in enol tautomer form F and their cyclized derivatives G. Treatment of these mixtures with HOAc and H₂SO₄ generated 5,7-dimethoxychromone derivative H, which was converted to 109 and 112 by heating with Ac₂O and hydriodic acid.

Figure 7.

Synthetic pathway of chromones 109 and 112.

Pharmacology

Cytotoxicity

BF-1 (13), BF-2 (40), and BF-6 (96) have cytotoxic effects on L-1210 cancer cells, with respective half maximal inhibitory concentration (IC₅₀) values of 50, 5, and 10 µg/mL. In particular, compounds BF-4 (94) and BF-5 (95) were very active with the same IC₅₀ value of 0.25 µg/mL.^20,31 New phloroglucinol-based meroterpenoids frutescones A-G (41-47) suppressed the proliferation of Caco-2 and A549 cancer cells with IC₅₀ values of 7.96-41.33 µM, but they failed to control HepG2 liver cancer cells (IC₅₀ > 50 µM).¹⁷ The difference in results between compounds 42 and 43, as well as between 45 and 46, may be due to the stereochemistry at carbon C-7.

Baeckenone F (7) moderately restricted the growth of A549, PSN-1, and MDA-MB-231 cancer cells with IC₅₀ values of 33.3-39.3 µM when 5-fluorouracil was used as a positive control (IC₅₀ 1.8-4.0 µM).¹⁴ Baeckenones J-K (11-12) strongly inhibited A549 and PSN-1 cancer cells, with IC₅₀ values of 11.8-19.2 µM, but baeckenone I (10) showed either weak activity (IC₅₀ = 91.7 µM/A549) or was inactive (IC₅₀ > 100 µM/PSN-1).³ This result can be explained by functional groups at carbons C-7 and C-8. Five isolated compounds (122-126) showed cytotoxicity at different levels (Table 3); frutescencenone A (122) was remarkably active against A549, PSN-1, and MDA-MB-231 cancer cells, with IC₅₀ values of 36.3, 29.3, and 38.2 µM.² Frutescencenone C (124) showed selective activity against PSN-1 cancer cells, with an IC₅₀ value of 20.1 µM, but 4-hydroxy-2,2,5-trimethyl-4-cyclopentene-1,3-dione (125) was inactive toward these 3 cancer cells (IC₅₀ > 100 µM).²

Table 3.

Pharmacological Activities of Isolated Compounds and Plant Extracts from Baeckea frutescens.

Compounds	Models	Effect	References
Cytotoxicity
5	In vitro	IC₅₀ = 60 µM/A549	¹⁴
7	In vitro	IC₅₀ = 34 µM/A549 IC₅₀ = 33.3 µM/PSN-1 IC₅₀ = 39.3 µM/MDA-MB-231	¹⁴
10	In vitro	IC₅₀ = 91.7 µM/A549	³
11	In vitro	IC₅₀ = 19.2 µM/A549 IC₅₀ = 11.8 µM/PSN-1	³
12	In vitro	IC₅₀ = 17.8 µM/A549 IC₅₀ = 15.8 µM/PSN-1	³
13	In vitro	IC₅₀ = 50 µg/mL/L-1210	²⁰
14	In vitro	IC₅₀ = 74.1 µM/A549	¹⁴
(+)-22	In vitro	IC₅₀ = 79.45 µM/DU145	²⁵
(−)-22	In vitro	IC₅₀ = 1.33 µM/DU145	²⁵
(+)-23	In vitro	IC₅₀ = 62.64 µM/HCT116 IC₅₀ = 85.79 µM/HeLa IC₅₀ = 17.65 µM/DU145 IC₅₀ = 86.68 µM/A549	²⁵
(−)-23	In vitro	IC₅₀ = 49.09 µM/HCT116 IC₅₀ = 91.22 µM/HeLa IC₅₀ = 15.85 µM/DU145 IC₅₀ = 86.62 µM/A549	²⁵
24	In vitro	IC₅₀ = 38.32 µM/HCT116 IC₅₀ = 83.85 µM/HeLa IC₅₀ = 6.46 µM/DU145 IC₅₀ = 76.47 µM/A549	²⁵
26	In vitro	IC₅₀ = 39.5 µM/HCT116 IC₅₀ = 80.72 µM/DU145 IC₅₀ = 15.61 µM/A549	²⁵
27	In vitro	IC₅₀ = 49.76 µM/HCT116 IC₅₀ = 31.87 µM/HeLa IC₅₀ = 17.40 µM/DU145 IC₅₀ = 62.64 µM/A549	²⁵
28	In vitro	IC₅₀ = 19.50 µM/HCT116 IC₅₀ = 30.44 µM/HeLa IC₅₀ = 15.14 µM/DU145 IC₅₀ = 82.75 µM/A549	²⁵
(+)-29	In vitro	IC₅₀ = 19.5 µM/HCT116 IC₅₀ = 53.71 µM/HeLa IC₅₀ = 26.11 µM/DU145 IC₅₀ = 84.13 µM/A549	²⁵
30	In vitro	IC₅₀ = 52.93 µM/HCT116 IC₅₀ = 4.04 µM/DU145 IC₅₀ = 79.45 µM/A549	²⁵
31	In vitro	IC₅₀ = 12.89 µM/HCT116 IC₅₀ = 77.06 µM/DU145 IC₅₀ = 80.11 µM/A549	²⁵
32	In vitro	IC₅₀ = 16.48 µM/HCT116 IC₅₀ = 19.81 µM/HeLa IC₅₀ = 10.0 µM/DU145 IC₅₀ = 88.81 µM/A549	²⁵
40	In vitro	IC₅₀ = 5 µg/mL/L-1210	²⁰
41	In vitro	IC₅₀ = 8.08 µM/Caco-2 IC₅₀ = 20.07 µM/A549	¹⁷
42	In vitro	IC₅₀ = 23.25 µM/Caco-2 IC₅₀ = 41.33 µM/A549	¹⁷
43	In vitro	IC₅₀ = 14.83 µM/Caco-2 IC₅₀ = 27.74 µM/A549	¹⁷
44	In vitro	IC₅₀ = 10.2 µM/Caco-2 IC₅₀ = 26.25 µM/A549	¹⁷
45	In vitro	IC₅₀ = 7.96 µM/Caco-2 IC₅₀ = 12.14 µM/A549	¹⁷
46	In vitro	IC₅₀ = 16.51 µM/Caco-2 IC₅₀ = 39.02 µM/A549	¹⁷
47	In vitro	IC₅₀ = 14.31 µM/Caco-2 IC₅₀ = 25.71 µM/A549	¹⁷
94 and 95	In vitro	IC₅₀ = 0.25 µg/mL/L-1210	³¹
96	In vitro	IC₅₀ = 10 µg/mL/L-1210	³¹
122	In vitro	IC₅₀ = 36.3 µM/A549 IC₅₀ = 29.3 µM/PSN-1 IC₅₀ = 38.2 µM/MDA-MB-231	²
123	In vitro	IC₅₀ = 83.9 µM/A549 IC₅₀ = 76.0 µM/PSN-1	²
124	In vitro	IC₅₀ = 88.0 µM/A549 IC₅₀ = 20.1 µM/PSN-1	²
126	In vitro	IC₅₀ = 80.3 µM/MDA-MB-231	²
The 50% EtOH leaf extract	In vitro	IC₅₀ = 108 µg/mL/MCF-7	⁴⁵
The 70% EtOH leaf extract	In vitro	IC₅₀ = 124 µg/mL/MCF-7	⁴⁵
The 90% EtOH leaf extract	In vitro	IC₅₀ = 84 µg/mL/MCF-7	⁴⁵
The water leaf extract	In vitro	IC₅₀ = 115 µg/mL/MCF-7	⁴⁵
The n-hexane leaf extract	In vitro	IC₅₀ = 56.24 µg/mL/A549 IC₅₀ = 26.7 µg/mL/NCI-H1299 IC₅₀ = 10 µg/mL/MCF-7 IC₅₀ = 80 µg/mL/MDA-MB-231	^45,46
The rich flavonoid fraction	In vitro	IC₅₀ = 110.8 µg/mL and apoptosis rate 27.54%/SiHa	⁴⁷
Antimicrobial activity
3	In vivo	MIC = 40 µM/Bacillus subtilis MIC = 3.125 µg/mL/Salmonella paratyphi	^13,43
15-18 and 44-46	In vivo	MIC = 25 µg/mL/S paratyphi	⁴³
41	In vivo	MIC = 6.25 µg/mL/S paratyphi	⁴³
The EtOH and water leaf extracts	In vitro	MIC < 50 µg/mL/Escherichia coli and Salmonella thypi	⁴⁸
The EtOH leaf extract (50 mg/mL)	In vitro	IZ = 11.5 mm/MRSA ST/0903-24 IZ = 8.5 mm/MRSA ST/0904-25 IZ = 11.5 mm/MRSA ST/0904-28 IZ = 8.5 mm/MRSA ST/0904-30	⁴⁹
The EtOH leaf extract (100 mg/mL)	In vitro	IZ = 14.0 mm/MRSA ST/0903-24 IZ = 12.0 mm/MRSA ST/0904-25 IZ = 14.5 mm/MRSA ST/0904-28 IZ = 12.0 mm/MRSA ST/0904-30	⁴⁹
The MeOH leaf extract (10 mg/mL)	In vitro	IZ = 13 mm/Streptococcus mutans	⁵⁰
The MeOH leaf extract (20 mg/mL)	In vitro	IZ = 14 mm/S mutans	⁵⁰
The leaf oil	In vitro	MIC = 5.11 µg/mL/Pseudopestalotiopsis camelliae MIC = 4.79 µg/mL/Colletotrichum gloeosporioides MIC = 64 µg/mL/Enterococcus faecalis MIC = 16 µg/mL/Candida albicans	^16,42
The HE and ES-UME leaf oils	In vitro	MIC = 1.25%/C albicans MIC = 0.625%/Staphylococcus aureus, E coli, and B subtilis MIC = 0.3125%/Pseudomonas aeruginosa, Fecal bacterial, and Propionibacterium acnes	⁵¹
Mosquito larvicidal activity
The leaf oil	In vitro	24-h LC₅₀ = 23 µg/mL/Aedes aegypti 24-h LC₉₀ = 40.05 µg/mL/Ae aegypti 24-h LC₅₀ = 25.73 µg/mL/Aedes albopictus 24-h LC₉₀ = 37.01 µg/mL/Ae albopictus 24-h LC₅₀ = 81.72 µg/mL/Culex quinquefasciatus 24-h LC₉₀ = 112.7 µg/mL/Cx quinquefasciatus 48-h LC₅₀ = 15.31 µg/mL/Ae aegypti 48-h LC₉₀ = 34.69 µg/mL/Ae aegypti 48-h LC₅₀ = 23.98 µg/mL/Ae albopictus 48-h LC₉₀ = 37.63 µg/mL/Ae albopictus 48-h LC₅₀ = 64.06 µg/mL/Cx quinquefasciatus 48-h LC₉₀ = 116.6 µg/mL/Cx quinquefasciatus	¹⁶
Anti-inflammatory activity
15	In vitro	IC₅₀ = 9.15 µM/NO production	²³
16	In vitro	IC₅₀ = 17.73 µM/NO production	²³
17	In vitro	IC₅₀ = 11.62 µM/NO production	²³
18	In vitro	IC₅₀ = 18.04 µM/NO production	²³
26 (50 µM)	In vitro	76.64% inhibition/NO production	²⁵
27 (50 µM)	In vitro	75.37% inhibition/NO production	²⁵
(+)-29 (50 µM)	In vitro	55.13% inhibition/NO production	²⁵
30 (50 µM)	In vitro	75.01% inhibition/NO production	²⁵
34	In vitro	IC₅₀ = 20.86 µM/NO production	²⁶
39	In vitro	IC₅₀ = 36.21 µM/NO production	²⁶
40 (0.4-1.6 µM)	In vitro	To inhibit NLRP3 inflammasome in J774A.1 macrophages via inhibiting MAPK/NF-κB signaling pathways	¹⁸
40 (50 mg/kg)	In vivo	To inhibit NLRP3 inflammasome in mice via inhibiting MAPK/NF-κB signaling pathways	¹⁸
49	In vitro	IC₅₀ = 18.75 µM/NO production	²²
52	In vitro	IC₅₀ = 30.54 µM/NO production	²²
53	In vitro	IC₅₀ = 15.17 µM/NO production	²²
54	In vitro	IC₅₀ = 1.80 µM/NO production	²²
55	In vitro	IC₅₀ = 0.36 µM/NO production	²²
55 (0.2-0.8 µM)	In vitro	To suppress LPS-stimulated RAW264.7 cells by inhibiting MAPK/NF-κB and MyD88 and iNOS expressions	¹⁹
56	In vitro	IC₅₀ = 3.7 µM/NO production	²²
57	In vitro	IC₅₀ = 2.07 µM/NO production	²²
58	In vitro	IC₅₀ = 6.50 µM/NO production	²²
59	In vitro	IC₅₀ = 0.81 µM/NO production	²⁴
74	In vitro	IC₅₀ = 54.7 µM/NO production	⁷
75	In vitro	IC₅₀ = 25.4 µM/NO production	⁷
76	In vitro	IC₅₀ = 43.8 µM/NO production	⁷
77	In vitro	IC₅₀ = 15.2 µM/NO production	⁷
85	In vitro	IC₅₀ = 5.54 µM/COX-1 IC₅₀ = 2.14 µM/COX-2	²⁸
86	In vitro	IC₅₀ = 4.53 µM/COX-1 IC₅₀ = 1.89 µM/COX-2	²⁸
87	In vitro	IC₅₀ = 4.15 µM/COX-1 IC₅₀ = 1.63 µM/COX-2	²⁸
90	In vitro	IC₅₀ = 1.95 µM/COX-1 IC₅₀ = 1.01 µM/COX-2	²⁸
94	In vitro	IC₅₀ = 5.42 µM/COX-1 IC₅₀ = 1.61 µM/COX-2	²⁸
98 (100 µg/mL)	In vitro	To show anti-inflammatory effect in MALP-2-stimulated RAW264.7 cells via inhibition of MyD88 and NF-κB	⁵²
100	In vitro	IC₅₀ = 9.73 µM/NO production	²⁴
108	In vitro	IC₅₀ = 4.17 µM/COX-1 IC₅₀ = 2.27 µM/COX-2	²⁸
Antioxidative activity
69	In vitro	IC₅₀ = 12.0 µM/DPPH radical scavenging	⁸
70	In vitro	IC₅₀ = 12.1 µM/DPPH radical scavenging	⁸
71	In vitro	IC₅₀ = 15.1 µM/DPPH radical scavenging 34.8% inhibition/H₂O₂-stimulated PC12 cells	⁸
72	In vitro	IC₅₀ = 15.0 µM/DPPH radical scavenging 36.0% inhibition/H₂O₂-stimulated PC12 cells	⁸
73	In vitro	IC₅₀ = 16.1 µM/DPPH radical scavenging 31.8% inhibition/H₂O₂-stimulated PC12 cells	⁸
78	In vitro	54.8% inhibition/H₂O₂-stimulated PC12 cells	¹⁰
79	In vitro	60.2% inhibition/H₂O₂-stimulated PC12 cells	¹⁰
83	In vitro	IC₅₀ = 120.6 µM/DPPH radical scavenging	³²
84	In vitro	IC₅₀ = 125.9 µM/DPPH radical scavenging	³²
85	In vitro	IC₅₀ = 11.8 µM/DPPH radical scavenging 43.0% inhibition/H₂O₂-stimulated PC12 cells	⁸
87	In vitro	IC₅₀ = 13.5 µM/DPPH radical scavenging 44.7% inhibition/H₂O₂-stimulated PC12 cells	^8,32
88	In vitro	IC₅₀ = 12.1 µM/DPPH radical scavenging	³²
91	In vitro	IC₅₀ = 3.39 µM/copper-induced LDL oxidation	³⁰
116	In vitro	IC₅₀ = 3.35 µM/copper-induced LDL oxidation	³⁰
117	In vitro	IC₅₀ = 3.90 µM/copper-induced LDL oxidation	³⁰
120	In vitro	IC₅₀ = 3.98 µM/copper-induced LDL oxidation	³⁰
121	In vitro	IC₅₀ = 3.91 µM/copper-induced LDL oxidation	³⁰
The EtOH leaf extract	In vitro	IC₅₀ = 41.96 µg/mL/DPPH radical scavenging	⁴⁸
The water leaf extract	In vitro	IC₅₀ = 93.3 µg/mL/DPPH radical scavenging	⁴⁸
The n-hexane leaf extract	In vitro	EC₅₀= 0.347 mg/mL/DPPH EC₅₀= 0.162 mg/mL/ferric reducing power EC₅₀= 0.047 mg/mL/metal chelating	⁴⁶
The EtOAc leaf extract	In vitro	EC₅₀= 0.084 mg/mL/DPPH EC₅₀= 0.033 mg/mL/ferric reducing power EC₅₀= 0.158 mg/mL/metal chelating	⁴⁶
The MeOH leaf extract	In vitro	EC₅₀= 0.101 mg/mL/DPPH EC₅₀= 0.041 mg/mL/ferric reducing power EC₅₀= 0.067 mg/mL/metal chelating	⁴⁶
The water leaf extract	In vitro	EC₅₀= 0.110 mg/mL/DPPH EC₅₀= 0.026 mg/mL/ferric reducing power EC₅₀= 0.039 mg/mL/metal chelating	⁴⁶
The HE leaf oil	In vitro	IC₅₀ = 15.929 µg/mL/DPPH radical scavenging	⁵¹
The ES-UME leaf oil	In vitro	IC₅₀ = 14.012 µg/mL/DPPH radical scavenging	⁵¹
The leaf oil	In vitro	EC₅₀ = 1.39 µg/mL/ferric reducing power EC₅₀ = 0.44 µg/mL/metal chelating EC₅₀ = 0.29 µg/mL/β-carotene bleaching	⁵³
Antirheumatoid arthritis
25-100 mg/kg	In vivo	To inhibit toe swelling of mice and relieve the degradation of articular cartilage matrix and inflammatory cell infiltration	⁵⁴
Skin protective activity
The EtOH leaf extract	In vitro	14% proliferation/HaCaT cells at 6.25 µg/mL 24% proliferation/HaCaT cells at 3.125 µg/mL 36% proliferation/BJ cells at 25 µg/mL 51% proliferation/BJ cells at 12.5 µg/mL	²⁹

A549, lung cancer cells; Caco-2 and HCT116, colon cancer cells; COX, cyclooxygenase; DPPH, 2,2-diphenyl-1-picrylhydrazyl; DU145, prostate cancer cells; EC₅₀, half maximal effective concentration; ES-UME, enzymatic surfactant-ultrasonic microwave extraction; HE, hydrodistillation extraction; IZ, inhibitory zone; LC₅₀, half lethal concentration; LC₉₀, 90% lethal concentration; LPS, lipopolysaccharide; L-1210, leukemia cells; LDL, low-density lipoprotein; MCF-7 and MDA-MB-231, breast cancer cells; MAPK, mitogen-activated protein kinase; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MALP-2, macrophage-activating lipopeptide-2; NO, nitric oxide; NF-κB, nuclear factor kappa B; PSN-1, pancreatic cancer cells; SiHa, cervical cancer cells.

Baeckfrutones B-L (22-32) inhibited the growth of HCT116, HeLa, DU145, and A549 cancer cells at different levels, especially (−)-22, 26, and 31, which were remarkably cytotoxic to DU145, A549, and HCT116 cells, with IC₅₀ values of 1.33, 15.61, and 12.89 µM, respectively.²⁵

Cytotoxicity of the n-hexane leaf extract against A549 and NCI-H1299 cancer cells was associated with IC₅₀ values of 56.24 and 26.7 µg/mL, respectively, but the EtOAc, MeOH, and water extracts were either weak or inactive (IC₅₀ > 100 µg/mL).⁴⁶ From Table 3, n-hexane, EtOH, and water extracts of the leaf exhibited cytotoxicity against MCF-7 cancer cells (IC₅₀ 10-124 µg/mL), but only the n-hexane extract showed activity against MDA-MB-231 (IC₅₀ 80 µg/mL).⁴⁵ The rich flavonoid fraction remarkably controlled the proliferation of SiHa cancer cells (IC₅₀ 110.8 µg/mL, 27.54% apoptosis rate).⁴⁷

Antimicrobial and Mosquito Larvicidal Activities

Baeckenone B (3) moderately controlled the bacterium Bacillus subtilis with a MIC value of 40 µM.¹³ Baefrutones A-D (15-18) and frutescones D-F (44-46) suppressed Salmonella paratyphi with the same MIC value of 25 µg/mL, as compared with that of baeckenone B (3, MIC 3.125 µg/mL), frutescone A (41, MIC 6.25 µg/mL), and the standard fluconazole (MIC 3.125 µg/mL).⁴³

The EtOH and water extracts of B frutescens leaf were active against both Escherichia coli and Salmonella thypi with MIC values of less than 50 µg/mL.⁴⁸ At 50 and 100 mg/mL, the EtOH leaf extract also suppressed methicillin-resistant Staphylococcus aureus (MRSA) with inhibitory zone (IZ) values of 8.5-14.5 mm (Table 3).⁴⁹ Similarly, at 10 and 20 mg/mL, the MeOH leaf extract was responsible for the inhibition of Streptococcus mutans with IZ values of 13 and 14 mm, respectively.⁵⁰

B frutescens leaf oil controlled the growth of Pseudopestalotiopsis camelliae, Colletotrichum gloeosporioides, Enterococcus faecalis, and Candida albicans, with MIC values of 5.11, 4.79, 64, and 16 µg/mL, respectively.^16,42 In another approach, the leaf oils extracted by HE and enzymatic surfactant-ultrasonic microwave extraction (ES-UME) exhibited the same antimicrobial activity against C albicans (MIC 1.25%), S aureus, E coli, and B subtilis (MIC 0.625%), Pseudomonas aeruginosa, and Propionibacterium acnes (MIC 0.3125%).⁵¹

Besides antimicrobial activity, B frutescens leaf oil showed 24- and 48-h LC₅₀ values of 15.31-81.72 µg/mL and LC₉₀ values of 34.69-116.6 µg/mL against Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus.¹⁶

Anti-inflammatory Activity

Compound BF2 (40), at 0.4-1.6 µM, showed in vitro NLRP3 inflammasome activation inhibition by suppressing cell proptosis and interleukin-1β (IL-1β) secretion in J774A.1 macrophages.¹⁸ In an in vivo model, this compound (50 mg/kg, gastric injection) inhibited NLRP3 inflammasome activation in mice by inhibiting the MAPK/NF-κB signaling pathway and mitochondrial damage-mediated oxidative stress.¹⁸ Frutescone O (55), at 0.2-0.8 µM, suppressed LPS-stimulated RAW264.7 cells by blocking TLR4-mediated MAPK/NF-κB signaling pathways and inhibiting MyD88 and iNOS expressions.¹⁹ At 100 µg/mL, compound 98 also showed an anti-inflammatory effect in macrophage-activating lipopeptide-2 (MALP-2)-stimulated RAW264.7 cells by inhibition of MyD88 and NF-κB (Figure 8).⁵²

Figure 8.

Anti-inflammatory mechanism of compound 98.

In an anti-inflammatory assay against nitric oxide (NO) production in LPS-stimulated RAW264.7 cells, the IC₅₀ values of baefrutones A-D, N, and S (15-18, 34, and 39), frutescones I and L-S (49 and 52-59), and 5,7-dihydroxy-8-isobutyryl-6-methyldihydroflavonol (100), ranging from 0.36 to 36.21 µM, were comparable with that of the standard N-monomethyl-L-arginine (L-NMMA) (IC₅₀ 30.92 µM), but baefrutones E-F (19-20) and frutescones H, J-K, and T-U (48, 50-51, and 60-61) did not show activity (IC₅₀ > 50 µM).^22–24,26 Furthermore, the anti-inflammatory activity of compound 55 was involved in the suppression of NF-κB p65 and the decrease of IL-6 and tumor nuclear factor-α (TNF-α).²²

The flavones baeckeins F-I (74-77) were also active against NO production with IC₅₀ values of 54.7, 25.4, 43.8, and 15.2 µM, respectively, as compared with that of the standard indomethacin (IC₅₀ 13.8 µM).⁷ This difference can be explained by the stereochemistry at carbons C-2 and C-3 and functional groups at phenyl carbon C-4. At 50 µM, compounds 26, 27, (+)-29, and 30 inhibited NO production by up to 74.64%, 75.37%, 55.13%, and 75.01%, respectively.²⁵

As shown in Table 3, flavones 85-87, 90, and 94 and chromone 108 had greater anti-inflammatory activity against cyclooxygenase (COX)-2 (IC₅₀ 1.95-5.54 µM) than COX-1 (IC₅₀ 1.01-2.27 µM).²⁸

Antioxidant Activity

Baeckeins J (78) and K (79), on the one hand, have no cytotoxicity to PC12 cells (IC₅₀ > 100 µM) but, on the other hand, at a dose of 10 µM, inhibited H₂O₂-stimulated PC12 cells by up to 54.8% and 60.2%, respectively.¹⁰ Similarly, the inhibitory rates of baeckeins C-E (71-73), 6-C-methylquercetin (85), and 6-C-methylquercetin 4′-O-β-D-glucopyranoside (87) were 31.8%-44.7%.⁸ Flavone 91 and chromones 116-117 and 120-121, containing 1 pyrogallolyl unit, inhibited copper-induced low-density lipoprotein (LDL) oxidation with IC₅₀ values of 3.35-3.91 µM, but chromones 114-115 and 118-119, which had no pyrogallolyl unit, did not show activity.³⁰

Flavones baeckeins A-E (69-73) and 6-C-methylquercetin (85), with IC₅₀ values of 11.8-16.1 µM, were also superior to the standard compound quercetin (IC₅₀ 18.2 µM) in scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals.⁸ The difference among compounds 71-73 is due to the stereochemistry at carbons C-2 and C-3.

Two new flavones 87-88 showed strong antioxidative activity to scavenge DPPH radicals, with IC₅₀ values of 12.1-13.5 µM, but their new derivatives 83-84 exerted only weak activity, with IC₅₀ values of 120.6-125.9 µM.³² Thereby, it can be concluded that the quercetin skeleton seems better than the kaempferol skeleton, and the glycosyl parts did not show a significant role in the activity.

The EtOH and water extracts of B frutescens leaf were also the subjects of a DPPH assay, producing respective IC₅₀ values of 41.96 and 93.30 µg/mL, in comparison with that of the standard gallic acid (IC₅₀ 3.81 µg/mL).⁴⁸ The n-hexane, MeOH, EtOAc, and water extracts of B frutescens leaf showed antioxidative activity in the DPPH radical scavenging, ferric reducing power, and metal chelating models (Table 3).⁴⁶ In particular, the water extract (EC₅₀ 0.039 mg/mL) was better than the standard EDTA (EC₅₀ 0.042 mg/mL) in the metal chelating assay.⁴⁶

Besides antimicrobial activity, the HE and ES-UME leaf oils generated IC₅₀ values of 15.9 and 14.0 µg/mL, respectively, in a DPPH antioxidative assay when α-tocopherol was used as a positive control (IC₅₀ 0.12 µg/mL).⁵¹ B frutescens leaf oil was also demonstrated as a potential agent in other antioxidative models, in which it possessed ferric reducing power, metal chelating, and β-carotene bleaching, with EC₅₀ values of 0.29-1.39 µg/mL.⁵³

Antirheumatoid Arthritis and Skin Protective Activities

BF-2 (40) acted as a prostaglandin E2 receptor 4 (EP4) antagonist, which has potential antirheumatoid arthritis activity. At a dose of 25-100 mg/kg, it could inhibit toe swelling of mice and relieve the degradation of articular cartilage matrix and inflammatory cell infiltration.⁵⁴

The EtOH leaf extract increased the proliferation and migration of keratinocytes and fibroblast BJ cells. In detail, HaCaT's proliferation was increased by 14% and 24% at 6.25 and 3.125 µg/mL, respectively, after 48 h treatment, and BJ's proliferation was increased by 36% and 51% at 25 and 12.5 µg/mL, respectively, after 24 h treatment.²⁹

Conclusion and Perspective

For the first time, the current review provides full information on the phytochemistry, biosynthesis, synthesis, and pharmacology of B frutescens constituents. Phytochemical studies of B frutescens tissues have led to the isolation and structural determination of 128 secondary metabolites, including 14 phloroglucinols, 47 phloroglucinol-based meroterpenoids, 4 sesquiterpenoids, 3 triterpenoids, 34 flavonoids, 19 chromones, 5 5-membered ring compounds, 1 mono-phenol, and 1 phytosterol. B frutescens is also rich in essential oils, in which monoterpenes, monoterpenoids, sesquiterpenes, and sesquiterpenoids were the main chemical classes. Generally, tasmanone acted as a precursor in biosynthesis, whereas the previous reports dealt with the use of phloroglucinol derivatives in the synthetic procedures of B frutescens molecules. Crude plant extracts, fractions, and the isolates of B frutescens possess a variety of pharmacological activities, such as cytotoxic, antimicrobial, anti-inflammatory, antioxidative, antirheumatoid, skin protective, and mosquito larvicidal activities.

However, further chemical examination is necessary. Some compounds contain stereogenic centers pending the assignment of the absolute configuration, and a good number of compounds have been described as racemic mixtures, which is not common in the biogenesis of natural products. Hence, structural elucidation studies are welcome. There is also a lack of in vitro and in vivo studies of the pharmacological mechanisms of action since most of the data obtained so far have been the result of initial screenings. Many isolated metabolites, especially the major potential compounds, have not yet received attention in pharmacological examinations. Last but not least, structure–activity relationship studies are required, as well as virtual docking calculations.

Footnotes

Authors’ Contributions

DTLH: formal analysis and revision; DXD: collection and formal analysis; and NTS: designated and wrote the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ninh The Son

Dau Xuan Duc

References

Yusuf

. Baeckea frutescens L. In: van Valkenburg

JLCH

Bunyapraphatsara

, eds. Plant resources of South-East Asia No. 12(2): medicinal and poisonous plants 2. Backhuys Publisher; 2001.

Ito

Nisa

Kodama

, et al. Two new cyclopentenones and a new furanone from Baeckea frutescens and their cytotoxicities. Fitoterapia. 2016;112:132-135. doi:10.1016/j.fitote.2016.05.017

Ito

Nisa

Rakainsa

Lallo

Morita

. New phloroglucinol derivatives from Indonesian Baeckea frutescens. Tetrahedron. 2017;73(8):1177-1181. doi:10.1016/j.tet.2017.01.016

Jantan

Ahmad

Bakar

SAA

Ahmad

Trockenbrodt

Chak

. Constituents of the essential oil of Baeckea frutescens L. from Malaysia. Flavour Fragr J. 1998;13(4):245-247. doi:10.1002/(SICI)1099-1026(1998070)13:4 < 245::AID-FFJ736 > 3.0.CO;2-J

Jia

Yang

Chen

Cao

Lai

Wang

. Baeckeins A and B, two novel 6-methylflavonoids from the roots of Baeckea frutescens. Helv Chim Acta. 2011;94(12):2283-2288. doi:10.1002/hlca.201100176

Jia

Zhou

Chen

, et al. Structure determination of baeckeins C and D from the roots of Baeckea frutescens. Magn Reson Chem. 2011;49(11):757-761. doi:10.1002/mrc.2803

Jia

Zheng

Ren

, et al. Baeckeins F–I, four novel C-methylated biflavonoids from the roots of Baeckea frutescens and their anti-inflammatory activities. Food Chem. 2014;155:31-37. doi:10.1016/j.foodchem.2014.01.022

Jia

Ren

Jia

Chen

Yang

Wang

. Baeckein E, a new bioactive C methylated biflavonoid from the roots of Baeckea frutescens. Nat Prod Res. 2013;27(22):2069-2075. doi:10.1080/14786419.2013.778852

Jia

Huangfu

Ren

, et al. Identification and quantification of flavonoids and chromes in Baeckea frutescens by using HPLC coupled with diode-array detection and quadruple time-of-flight mass spectrometry. Nat Prod Res. 2015;29(9):800-806. doi:10.1080/14786419.2014.987144

10.

Jia

, et al. Baeckeins J and K, two novel C-methylated biflavonoids from the roots of Baeckea frutescens and their cytoprotective activities. Helv Chim Acta. 2016;99(7):499-505. doi:10.1002/hlca.201600013

11.

Jia

Sun

Zhang

Wei

Jia

. Baeckeins L and M, two novel C-methylated triflavonoids from the roots of Baeckea frutescens L. Nat Prod Res. 2020;34(2):278-283. doi:10.1080/14786419.2018.1528590

12.

Chen

Liu

. Study on the chemical constituents of Baeckea frutescens. Nat Prod Res Dev. 2008;20:827-829.

13.

Nisa

Ito

Subehan Matsui

Kodama

Morita

. New acylphloroglucinol derivatives from the leaves of Baeckea frutescens. Phytochem Lett. 2016;15:42-45. doi:10.1016/j.phytol.2015.11.011

14.

Nisa

Ito

Kodama

, et al. New cytotoxic phloroglucinols, baeckenones D–F, from the leaves of Indonesian Baeckea frutescens. Fitoterapia. 2016;109:236-240. doi:10.1016/j.fitote.2016.01.013

15.

Dai

Thang

Olayiwola

Ogunwande

. Chemical composition of essential oil of Baeckea frutescens L. Int Res J Pure Appl Chem. 2015;8(1):26-32. doi:10.9734/IRJPAC/2015/17199

16.

NTG

Huong

Satyal

, et al. Mosquito larvicidal activity, antimicrobial activity, and chemical compositions of essential oils from four species of Myrtaceae from central Vietnam. Plants. 2020;9(4):544. doi:10.3390/plants9040544

17.

Hou

Guo

Zhao

Zhang

Wang

. Frutescone A-G, tasmanone-based meroterpenoids from the aerial parts of Baeckea frutescens. J Org Chem. 2017;82(3):1448-1457. doi:10.1021/acs.joc.6b02643

18.

Lin

Wang

Zhang

Hou

Yan

. Baeckein E suppressed NLRP3 inflammasome activation through inhibiting both the priming and assembly procedure: implications for gout therapy. Phytomedicine. 2021;84:153521. doi:10.1016/j.phymed.2021.153521

19.

Lin

Zhang

Fan

, et al. Frutescone O from Baeckea frutescens blocked TLR4-mediated Myd88/NF-κB and MAPK signaling pathways in LPS induced RAW264.7 macrophages. Front Pharmacol. 2021;12:643188. doi:10.3389/fphar.2021.643188

20.

Fujimoto

Usui

Makino

Sumatra

. Phloroglucinols from Baeckea frutescens. Phytochemistry. 1996;41(3):923-925. doi:10.1016/0031-9422(95)00659-1

21.

Tsui

Brown

. Unusual metabolites of Baeckea frutescens. Tetrahedron. 1996;52(29):9735-9742. doi:10.1016/0040-4020(96)00510-8

22.

Hou

Guo

Zhao

, et al. Anti-inflammatory meroterpenoids from Baeckea frutescens. J Nat Prod. 2017;80(8):2204-2214. doi:10.1021/acs.jnatprod.7b00042

23.

Hou

Wang

Han

, et al. Atropisomeric meroterpenoids with rare triketone-phloroglucinol-terpene hybrids from Baeckea frutescens. Org Biomol Chem. 2018;16:8513-8524. doi:10.1039/C8OB02433B

24.

Hou

Zhao

Chen

Wang

. New meroterpenoids and C-methylated flavonoid isolated from Baeckea frutescens. Chin J Nat Med. 2020;18(5):379-384. doi:10.1016/S1875-5364(20)30044-3

25.

Qin

Zhi

Yan

, et al. Baeckfrutones A-L, polymethylated phloroglucinol meroterpenoids from the twigs and leaves of Baeckea frutescens. Tetrahedron. 2018;74(46):6658-6666. doi:10.1016/j.tet.2018.09.050

26.

Zhi

Liu

, et al. Structurally diverse polymethylated phloroglucinol meroterpenoids from Baeckea frutescens. Nat Prod Bio. 2018;8:431-439. doi:10.1007/s13659-018-0189-3

27.

Tsui

Brown

. Sesquiterpenes from Baeckea frutescens. J Nat Prod. 1996;59(11):1084-1086. doi:10.1021/np960419w

28.

Zhou

Yan

Gao

Hou

Pham

Wang

. New flavonoids and methylchromone isolated from the aerial parts of Baeckea frutescens and their inhibitory activities against cyclooxygenases-1 and -2. Chin J Nat Med. 2018;16(8):615-620. doi:10.1016/S1875-5364(18)30099-2

29.

Kamarazaman

Ali

NAM

Abdullah

, et al. In vitro wound healing evaluation, antioxidant and chemical profiling of Baeckea frutescens leaves ethanolic extract. Arab J Chem. 2022;15(6):103871. doi:10.1016/j.arabjc.2022.103871

30.

Kamiya

Satake

. Chemical constituents of Baeckea frutescens leaves inhibit copper-induced low-density lipoprotein oxidation. Fitoterapia. 2010;81(3):185-189. doi:10.1016/j.fitote.2009.08.021

31.

Makino

Fujimoto

. Flavanones from Baeckea frutescens. Phytochemistry. 1999;50(2):273-277. doi:10.1016/S0031-9422(98)00534-2

32.

Quang

Cuong

Minh

Kiem

. New flavonoids from Baeckea frutescens and their antioxidant activity. Nat Prod Commun. 2008;3(5):755-758. doi:10.1177/1934578X080030

33.

Satake

Kamiya

Saiki

, et al. Chromone C-glycosides from Baeckea frutescens. Phytochemistry. 1999;50(2):303-306. doi:10.1016/S0031-9422(98)00513-5

34.

Tsui

Brown

. Chromones and chromanones from Baeckea frutescens. Phytochemistry. 1996;43(4):871-876. doi:10.1016/0031-9422(96)00360-3

35.

Son

. The genus Cryptocarya: a review on phytochemistry and pharmacological activities. Chem Biodiver. 2023;20(3):e20221102. doi:10.1002/cbdv.202201102

36.

Hop

Son

. Botanical description, traditional uses, phytochemistry, and pharmacology of the genus Artabotrys: a review. Chem Biodiver. 2022;19(11):e202200725. doi:10.1002/cbdv.202200725

37.

Hop

Son

. The medicinal plant Agrimonia pilosa Ledeb.: botanical description, traditional use, phytochemistry and pharmacology. Comb Chem High Throughput Screen. 2023;26(9):1660-1688. doi:10.2174/1386207325666220928163930

38.

Turek

Stintzing

. Stability of essential oils: a review. Compr Rev Food Sci Food Saf. 2013;12(1):40-53. doi:10.1111/1541-4337.12006

39.

Huong

Sam

Dai

Son

. Essential oils of two ginger plants Newmania orthostachys N.S. Lý & Škorničk. and N. serpens N.S. Lý & Škorničk.: chemical compositions and antimicrobial activity. J Essent Oil-Bear Plants. 2022;25(6):1221-1228. doi:10.1080/0972060X.2022.2158046

40.

Son

. Genus Acronychia: an extensive review on phytochemistry and pharmacological activities. Mini Rev Org Chem. 2023. doi:10.2174/1570193X20666221026162904

41.

Tam

Thuam

Bighelli

, et al. Baeckea frutescens leaf oil from Vietnam: composition and chemical variability. Flavour Fragr J. 2004;19(3):217-220. doi:10.1002/ffj.1281

42.

Jiang

Zhang

Qin

, et al. Chemical composition of a supercritical fluid (Sfe-CO₂) extract from Baeckea frutescens L. leaves and its bioactivity against two pathogenic fungi isolated from the tea plant (Camellia sinensis (L.) O. Kuntze). Plants. 2020;9(9):1119. doi:10.3390/plants9091119

43.

Hou

Zhao

, et al. Biomimetic total syntheses of baefrutones A-D, baeckenon B, and frutescones A, D–F. Org Biomol Chem. 2020;18:1135-1139. doi:10.1039/C9OB02490E

44.

Gray

Kaye

Nchinda

. Chromone studies. Part 13.1 synthesis and electron-impact mass spectrometric studies of 5-hydroxy-2-isopropyl-7-methoxychromone, a constituent of the medicinal plant Baeckea frutescens, and side-chain analogues. J Nat Prod. 2003;66(8):1144-1146. doi:10.1021/np030097d

45.

Shahruzaman

Mustafa

Ramli

Maniam

Fakurazi

Maniam

. The cytotoxic effect and glucose uptake modulation of Baeckea frutescens on breast cancer cells. BMC Complement Altern Med. 2019;19:200. doi:10.1186/s12906-019-2628-z

46.

Navanesan

Wahab

Manickam

Sim

. Evaluation of selected biological capacities of Baeckea frutescens. BMC Complement Altern Med. 2015;15:186. doi:10.1186/s12906-015-0712-6

47.

Bingbing

Hongcong

Xun

Wei

. Effects of total flavonoids from Baeckea frutescens on the migration, invasion and apoptosis of cervical cancer SiHa cells. J Int Oncol. 2021;12:206-211.

48.

Nisa

Nurhayati

Apriyana

Indrianingsih

. Investigation of total phenolic and flavonoid contents, and evaluation of antimicrobial and antioxidant activities from Baeckea frutescens extracts. IOP Conf Series: Earth and Environmental Science. 2017;101:012002. doi:10.1088/1755-1315/101/1/012002

49.

Razmavar

Abdulla

Ismail

Hassandarvish

. Antibacterial activity of leaf extracts of Baeckea frutescens against methicillin-resistant Staphylococcus aureus. BioMed Res Int. 2014:521287. doi:10.1155/2014/521287

50.

Hwang

Shim

Chung

. Anticariogenic activity of some tropical medicinal plants against Streptococcus mutans. Fitoterapia. 2004;75(6):596-598. doi:10.1016/j.fitote.2004.05.006

51.

Wan

Kou

Pang

, et al. Enzyme pretreatment combined with ultrasonic-microwave-assisted surfactant for simultaneous extraction of essential oil and flavonoids from Baeckea frutescens. Ind Crops Prod. 2021;174:114173. doi:10.1016/j.indcrop.2021.114173

52.

Wang

Hou

, et al. Suppression of Baeckea frutescens L. and its components on MyD88-dependent NF-κB pathway in MALP-2-stimulated RAW264.7 cells. J Ethnopharmacol. 2017;207(31):92-99. doi:10.1016/j.jep.2017.05.034

53.

Saad

Rahman

SNSA

Navanesan

, et al. Evaluation of antioxidant activity and phytochemical composition of Baeckea frutescens and Leptospermum javanicum essential oils. S Afr J Bot. 2021;141:474479. doi:10.1016/j.sajb.2021.06.005

54.

Lin

Wang

Zhang

Lin

Ming

. Screening of prostaglandin E2 receptor 4 antagonist from active compounds of Baeckea frutescens L. and its anti-rheumatoid arthritis effect in vivo. J China Pharm Univ. 2021;6:92-99.

Baeckea frutescens L.: A Review on Phytochemistry,Biosynthesis,Synthesis,and Pharmacology

Abstract

Background

Objective

Methods

Results

Conclusion

Keywords

Introduction

Phytochemistry

Phloroglucinols, Phloroglucinol-Based Meroterpenoids, Sesquiterpenoids, and Triterpenoids

Flavonoids

Chromones, 5-Membered Ring Compounds, and Others

Essential Oils

Biosynthesis and Synthesis

Biosynthesis

Synthesis

Pharmacology

Cytotoxicity

Antimicrobial and Mosquito Larvicidal Activities

Anti-inflammatory Activity

Antioxidant Activity

Antirheumatoid Arthritis and Skin Protective Activities

Conclusion and Perspective

Footnotes

Authors’ Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References