Chemical Constituents and Their Bioactivities of Plants from the Genus Eupatorium (2015–Present)

Simple Summary

Based on the important findings of our research group about the chemical constituents of Eupatorium adenophorum, the present review shares an update about the research progress on the chemical constituents of Eupatorium and their biological activities in the last 10 years. For the first time, it also reviews some studies investigating the chemical constituents of the plant. Considering the multiple properties of this genus, the next step should be to strengthen the study of the action mechanism underlying the active components of this genus. Hopefully, this review can provide new insights for prompting future research on Eupatorium applications and drug development.

Abstract

The genus Eupatorium belongs to the Asteraceae (Compositae) family and has multiple properties, such as invasiveness and toxicity, and is used in folk medicine. The last review on the chemical constituents of this genus and their biological activities was published in 2015. The present review provides an overview of 192 natural products discovered from 2015 to the present. These products include 63 sesquiterpenoids, 53 benzofuran derivatives, 39 thymol derivatives, 15 fatty acids, 7 diterpenoids, 5 monoterpenoids, 4 acetophenones, and 6 other compounds. We also characterized their respective chemical structures and cytotoxic, antifungal, insecticidal, antibacterial, anti-inflammatory, and antinociceptive activities.

1. Introduction

Plant-derived natural products have always been a paramount source of novel drugs and pesticides [1,2,3,4,5,6,7,8]. For example, the plant-derived drugs paclitaxel (Taxol) and artemisinin are widely used in antitumor and antimalarial treatment, respectively, and continue to occupy a crucial position among other drugs used for these medical conditions [9,10,11,12,13,14]. Meanwhile, active plant-derived natural products can also serve as substrates for structural modifications for new drug discovery. For example, the anticancer drugs topotecan and irinotecan are the derivatives of camptothecin, which is isolated and identified from the plant Camptotheca acuminata [15,16].

Eupatorium is a large genus belonging to the Asteraceae family that contains approximately 1200 species. This genus is widely distributed in global countries, such as America, Europe, Africa, and Asia [17]. The chemical constituents of Eupatorium have been investigated for more than 100 years, starting from the study of the volatile oil constituents of E. triplinerve [18]. Until now, more than 300 compounds have been reported to be present in Eupatorium, of which some have exhibited certain anticancer, antibacterial, and anti-inflammatory effects [19,20]. Among them, flavonoids and terpenes are the two main chemical constituents of Eupatorium. However, the latest reviews discussing the phytochemical investigations and the biological activities of this genus were published almost 10 years ago [20]. Recent major progress in the study of the chemical constituents of E. adenophorum was made by our group. We discovered two classes of sesquiterpenoids with novel structures, which were continuously selected as hot molecules by Natural Product Reports (NPRs) [21,22]. Considering that E. adenophorum has a potent affinity toward the other plants of the genus, we believe that the discovery of novel structural and active chemical components in the genus Eupatorium deserves further investigation. Consequently, to attract more research attention toward this genus, we summarized the research progress of natural products of this genus discovered since 2015, including their sources, structure types, and biological activities. Here, we reviewed a total of 192 compounds (Figure 1), including their chemical structures and biological activities. In the framework of this review presentation, we want to classify those natural products based on the plant species that produce them, rather than their structural types. We hope this review provides insights into the in-depth study, development, and utilization of this genus.

2. Progress on Chemical Components and Their Biological Activities of the Genus Eupatorium

2.1. Chemical Components of E. adenophorum and Their Biological Activities

E. adenophorum Spreng. (E. adenophorum) is synonymous with Ageratina adenophora (Spreng.) R. M. King & H. Rob., a perennial and herbaceous invasive plant that is ubiquitous worldwide [23]. Although it is invasive, it has been traditionally used as a medicine for treating wounds, inflammation, fever, diabetes, dysentery, and other ailments. Phytochemical investigations have revealed that this is a sesquiterpenoid-rich plant (Figure 2). In total, 30 new compounds were reported (

Table 1. Chemical constituents (1–30) from the plant E. adenophorum.

No.	Plant Source	Compound Name	Structure Classification	Extraction Method	Type of Bioactivity Evaluation	Ref.
1	E. adenophorum	Eupatorid A	Sesquiterpenoid	Petroleum ether at room temperature	Anti-inflammatory, antibacterial, and cytotoxic	[23]
2	E. adenophorum	Eupatorester A	Sesquiterpenoid	Petroleum ether at room temperature	Anti-inflammatory, antibacterial, and cytotoxic	[23]
3	E. adenophorum	Eupatorester B	Sesquiterpenoid	Petroleum ether at room temperature	Anti-inflammatory, antibacterial, and cytotoxic	[23]
4	E. adenophorum	Eupatorester C	Sesquiterpenoid	Petroleum ether at room temperature	Anti-inflammatory, antibacterial, and cytotoxic	[23]
5	E. adenophorum	Adenophorone	Sesquiterpenoid	Reflux with ethyl acetate	Neuroprotective	[24]
6	E. adenophorum	Eupatorione A	Sesquiterpenoid	Petroleum ether at room temperature	Anti-inflammatory	[25]
7	E. adenophorum	Dihyroeupatorid A	Sesquiterpenoid	Petroleum ether at room temperature	Anti-inflammatory and cytotoxic	[26]
8	E. adenophorum	(5S, 6S, 7R, 9R, 10S)-7-Hydroxyageraphorone	Sesquiterpenoid	Petroleum ether at room temperature	Anti-inflammatory and cytotoxic	[26]
9	E. adenophorum	Adenophorone	Sesquiterpenoid	Methanol at room temperature	α-glycosidase and AChE inhibitory	[27]
10	E. adenophorum	Eupatorinone A	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic and antidiabetic	[28]
11	E. adenophorum	Eupatorinone B	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic and antidiabetic	[28]
12	E. adenophorum	Eupatorinone C	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic and antidiabetic	[28]
13	E. adenophorum	Ageratinone A	Sesquiterpenoid	Petroleum ether at room temperature	Cytotoxic	[29]
14	E. adenophorum	Ageratinone B	Sesquiterpenoid	Petroleum ether at room temperature	Cytotoxic	[29]
15	E. adenophorum	Ageratinone C	Sesquiterpenoid	Petroleum ether at room temperature	Cytotoxic	[29]
16	E. adenophorum	Eupatorinol	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[30]
17	E. adenophorum	1,6-Dihydroxy-1-isopropyl-4,7-dimethyl-3,4- dihydronaphthalen-2(1H)-one	Sesquiterpenoid	95% ethanol at room temperature	Antibacterial	[31]
18	E. adenophorum	2α-Methoxyl-3β-methyl-6-(acetyl-O-methyl)-2,3-dihydrobenzofuran	Thymol	95% ethanol at room temperature	Antibacterial	[31]
19	E. adenophorum	7-Formyl-9-isobutyryloxy-8-hydroxythymol	Thymol	95% ethanol at room temperature	Antibacterial and cytotoxic	[32]
20	E. adenophorum	7,9-Di-isobutyryloxy-8,10-dehydrothymol	Thymol	95% ethanol at room temperature	Antibacterial and cytotoxic	[32]
21	E. adenophorum	2a-Methoxyl-3b-methyl-6-methylol-2,3-dihydrobenzofuran	Thymol	95% ethanol at room temperature	Antibacterial and cytotoxic	[32]
22	E. adenophorum	7,9-Diisobutyryloxy-8-ethoxythymol	Thymol	95% ethanol at room temperature	Antibacterial and cytotoxic	[33]
23	E. adenophorum	7-Acetoxy-8-methoxy-9-isobutyryloxythymol	Thymol	95% ethanol at room temperature	Antibacterial and cytotoxic	[33]
24	E. adenophorum	7-Hydroxy-dehydrotremetone	Benzofuran	Methanol at room temperature	Antipathogenic fungi	[34]
25	E. adenophorum	7,10,11-Trihydroxy-dehydrotremetone	Benzofuran	Methanol at room temperature	Antipathogenic fungi	[34]
26	E. adenophorum	10-oxo-7-Hydroxy-nordehydrotremetone	Benzofuran	Methanol at room temperature	Antipathogenic fungi	[34]
27	E. adenophorum	5-β-Glucosyl-7-demethoxy-encecalin	Chromene	Methanol at room temperature	Antipathogenic fungi	[34]
28	E. adenophorum	8-Hydroxy-8-β-glucosyl-2-carene	Monoterpenoid	Methanol at room temperature	Antipathogenic fungi	[34]
29	E. adenophorum	Gossypetin-5-O-(6″-(E)-caffeoyl)-β-D-glucoside	Flavonoid	Reflux with 70% ethanol	Cytotoxic and antiradical	[35]
30	E. adenophorum	Herbacetin-5-O-(6″-(E)-caffeoyl)-β-D-glucoside	Flavonoid	Reflux with 70% ethanol	Cytotoxic and antiradical	[35]

), namely 17 sesquiterpenoids, 6 thymol derivatives, 3 benzofuran derivatives, 2 flavonoid glycosides, 1 monoterpenoid glucoside, and 1 chromene derivative [23,24,25,26,27,28,29,30,31,32,33,34,35].

Compounds 1–7 represent two classes of sesquiterpenoids with a novel carbon skeleton. Eupatorid A (1) and its esterified derivatives, eupatoresters A–C (2–4) [23] and dihyroeupatorid A (7) [26], have a 5/5 bicyclic carbon skeleton. Adenophorone (5) [28] and eupatorione A (6) [25] possess a 5/5/6 tricyclic carbon skeleton. Conspicuously, NPRs had continuously selected compounds 1 and 6 as hot molecules [21,22], because their structures were novel. Unfortunately, the aforementioned seven compounds exhibited no significant activities in the anti-inflammatory, in vitro tumor growth inhibitory, and antibacterial assays, except 5, which displayed potent neuroprotective activity in H₂O₂-treated human neuroblastoma cells (SH-SY5Y) and pheochromocytoma cells (PC12) [24]. Compounds 8–17 are typical cadinene-type sesquiterpenoids. However, none of them exhibited significant activities in bacteriostatic, α-glycosidase, and acetylcholine esterase (AChE) inhibitory tests [26,27,28,29,30,31]. Compounds 18–23 are thymol derivatives. Compound 18 displayed in vitro bacteriostatic activity against Gram-positive bacteria such as Staphylococcus aureus, Bacillus cereus, and B. subtilis, with minimum inhibitory concentrations ranging from 25 to 50 μg/mL [31,32,33]. Compound 19 exhibited a strong activity against five microorganisms, S. aureus, B. cereus, B. thuringiensis, Escherichia coli, and Salmonella enterica, with MIC values ranging from 3.9 to 15.6 μg/mL. Additionally, compound 19 showed strong cytotoxicity against human breast cancer cells (MCF-7), human cervical carcinoma cells (HeLa), and human large-cell lung cancer cells (NCI-H460) and its half-maximal inhibitory concentration (IC50) values were 7.45, 9.45, and 8.32 μM, respectively [32]. Compounds 24–26 are benzofuran derivatives. Among them, compound 24 at 50 μg/disk exhibited broad-spectrum antifungal activity against the growth of Colletotrichum gloeosporioides, C. musae, Rhizoctonia solani, and Fusarium oxysporum f. sp. Niveum, with inhibitory zones having diameters ranging from 13.90 to 17.28 mm [34]. Compounds 27 and 28 are a chromene derivative and a monoterpenoid glucoside, respectively [34]. Compounds 29 and 30 are two highly oxygenated flavonoid glycosides exhibiting potent 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, with IC50 values of 12.0 and 22.9 μM, respectively [35].

2.2. Chemical Components of E. chinense and Their Biological Activities

E. chinense is used as Chinese medicine in the Tujia and Miao minorities of China. The leaves of this plant are also termed “Liu-Yue-Xue” and are used as a folk medicine for cold prevention and treatment. Its roots are widely used as a traditional Chinese medicinal material “Tu-Niu-Xi” and it has a long history of medicinal applications, because of its various pharmacological activities, such as heat-clearing, anticancer, anti-inflammatory, and antiviral activities. It is especially used as a well-known drug for the treatment of diphtheria in Guangdong Province, China [36,37]. Consequently, chemical investigations on E. chinense have predominantly focused on its roots to discover active components. In summary, 57 chemical constituents (31–87) were found in different parts of E. chinense (

Table 2. Chemical constituents (31–87) from the plant E. chinense.

No.	Plant Source	Compound Name	Structure Classification	Extraction Method	Type of Bioactivity Evaluation	Ref.
31	E. chinense	(+)-Dieupachinin A	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
32	E. chinense	(−)-Dieupachinin A	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
33	E. chinense	(+)-Dieupachinin B	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
34	E. chinense	(−)-Dieupachinin B	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
35	E. chinense	(+)-Dieupachinin C	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
36	E. chinense	(−)-Dieupachinin C	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
37	E. chinense	(+)-Dieupachinin D	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
38	E. chinense	(−)-Dieupachinin D	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
39	E. chinense	(+)-Dieupachinin E	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
40	E. chinense	(−)-Dieupachinin E	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
41	E. chinense	Dieupachinin F	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
42	E. chinense	(+)-Dieupachinin G	Benzofuran	95% ethanol at room temperature	Cytotoxic	[37]
43	E. chinense	(−)-Dieupachinin G	Benzofuran	95% ethanol at room temperature	Cytotoxic	[37]
44	E. chinense	(+)-Dieupachinin H	Benzofuran	95% ethanol at room temperature	Cytotoxic	[37]
45	E. chinense	(−)-Dieupachinin H	Benzofuran	95% ethanol at room temperature	Cytotoxic	[37]
46	E. chinense	(+)-Dieupachinin I	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
47	E. chinense	(−)-Dieupachinin I	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
48	E. chinense	(+)-Dieupachinin J	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
49	E. chinense	(−)-Dieupachinin J	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
50	E. chinense	(+)-Dieupachinin K	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
51	E. chinense	(−)-Dieupachinin K	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
52	E. chinense	(+)-Dieupachinin L	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
53	E. chinense	(−)-Dieupachinin L	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
54	E. chinense	(+)-Dieupachinin M	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
55	E. chinense	(−)-Dieupachinin M	Benzofuran	95% ethanol at room temperature	Anti-inflammatory	[38]
56	E. chinense	Trieupachinin A	Benzofuran	Reflux with 70% ethanol	Antiviral	[36]
57	E. chinense	8R-hydroxy-9-methyl-butyryloxythymol	Thymol	95% ethanol at room temperature	Cytotoxic and anti-inflammatory	[39]
58	E. chinense	10-isobutyryloxy-8, 9-didehydrothymyl-isobutyrate	Thymol	95% ethanol at room temperature	Cytotoxic and anti-inflammatory	[39]
59	E. chinense	(8R, 9S)-1, 8-dimethyl-8, 9-dihydro benzofuran-8, 9-diol	Thymol	95% ethanol at room temperature	Cytotoxic and anti-inflammatory	[39]
60	E. chinense	8R-hydroxy-9-isobutyryloxythymol	Thymol	95% ethanol at room temperature	Cytotoxic	[40]
61	E. chinense	(Z)-8(9)-ene-9-isobutyryloxythymol	Thymol	95% ethanol at room temperature	Cytotoxic	[40]
62	E. chinense	Eupachinsin E	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[37]
63	E. chinense	Eupachinsin F	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[37]
64	E. chinense	14-Deacetylguaiaglehnin A	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[37]
65	E. chinense	Eupatorinolide A	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
66	E. chinense	Eupatorinolide B	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
67	E. chinense	Eupatorinolide C	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
68	E. chinense	Eupatorinolide D	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
69	E. chinense	Eupatorinolide E	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
70	E. chinense	Eupatorinolide F	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
71	E. chinense	Eupatorinic acid A	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
72	E. chinense	Eupatorinic acid B	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
73	E. chinense	Eupatorinic acid C	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
74	E. chinense	Eupatorinic acid D	Sesquiterpenoid	95% ethanol at room temperature	None	[41]
75	E. chinense	Eupaguaiane A	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[42]
76	E. chinense	Eupaguaiane B	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[42]
77	E. chinense	Eupachinsin A	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
78	E. chinense	Eupachinisin A 2-acetate	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
79	E. chinense	Eupachinsin B	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
80	E. chinense	3-Epi-eupachinisin B	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
81	E. chinense	15-Hydroxyeupachinisin B	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
82	E. chinense	Eupachinsin C	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
83	E. chinense	4′-Hydroxyeupachinisin C 15-acetate	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
84	E. chinense	Eupachinsin D	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
85	E. chinense	15-Hydroxyeupachinisin D	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
86	E. chinense	3-Epi-eupachinisin D	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[43]
87	E. chinense	Eupaditerpenoid A	Diterpenoid	95% ethanol at room temperature	Cytotoxic	[42]

), namely 26 benzofuran oligomers, 25 sesquiterpenoids, 5 thymol derivatives, and 1 diterpenoid [36,37,38,39,40,41,42,43]. Of note, its roots are chiefly composed of benzofuran oligomers and thymol derivatives, whereas sesquiterpenoids are dominant in the aboveground parts (Figure 3). Compounds 31–56 are benzofuran dimers and trimers and are isolated from the roots. Of them, compounds 31–45, 50 and 51, as well as 54–56 displayed inconspicuous activities in in vitro antiviral, anti-inflammatory, and cytotoxic assays [40,41,42]. Compounds 46–49, 52, and 53 exhibited promising inhibitory effects on NO production, with IC50 values of 6.42, 6.29, and 16.03 μM, respectively [38]. Compounds 57–61 are thymol derivatives and are isolated from the roots [39,40]. Compound 59 exhibited moderate inhibitory effects on NO production, with the inhibition rate reaching 23.08% at 50 μM [39]. Compound 60 displayed marked cytotoxic activities against human nasopharyngeal carcinoma cells (CNE 2), human cervical cancer cells (Caski), and human gastric cancer cells (HGC-27), with IC50 values of 4.2, 11.9, and 7.3 μM, respectively [40]. Compounds 62–86 are sesquiterpenoids, namely 10 germacrane-type and 2 guaiane-type, and are isolated from the aerial parts of the plant [37,41,42,43]. Compounds 62 and 63 exhibited moderate cytotoxic activities against human breast cancer cells (MDA-MB-231) and human hepatocellular carcinoma cells (HepG2), with IC50 values ranging from 3.1 to 9.3 μM [37]. Compounds 79–81 exhibited cytotoxicity against MDA-MB-231 and HepG2, with IC50 values of 0.8–7.6 μM [43]. Compound 87 is an acyclic diterpenoid. Usually, a diterpenoid is rarely found in the genus Eupatorium [42].

2.3. Chemical Components of E. fortunei and Their Biological Activities

E. fortunei Turcz. is a perennial herb that primarily grows in the subtropical and warm temperate regions of China. Being a common aromatic and medicinal species with over 2000 years of utilization, it is widely cultivated in most eastern provinces of China. This herb has the function of removing dampness and summer heat from the body. From a modern scientific perspective, some medical symptoms relieved using this herb are partially related to inflammation. The National Health Commission of China has also incorporated this plant into the list of herbal species that can be used as additives to functional foods [44,45,46,47,48,49]. In total, 53 compounds (88–140) are isolated from the aerial parts of E. fortunei (

Table 3. Chemical constituents (88–140) from the plant E. fortunei.

No.	Plant Source	Compound Name	Structure Classification	Extraction Method	Type of Bioactivity Evaluation	Ref.
88	E. fortunei	9-O-Angeloxy-10-hydroxy-8-methoxythymol	Thymol	Methanol at room temperature	None	[44]
89	E. fortunei	9-Angeloyloxy-8,9-dehydrothymol	Thymol	Refluxed with 95% ethanol	Cytotoxic	[45]
90	E. fortunei	9-(3-Methyl-2-butenoyloxy)-8,10-dehydrothymol	Thymol	Refluxed with 95% ethanol	Cytotoxic	[45]
91	E. fortunei	7-Isobutyryloxythymol	Thymol	Refluxed with 95% ethanol	Cytotoxic	[45]
92	E. fortunei	7-Isobutyryloxy-8,9-dehydrothymol	Thymol	Refluxed with 95% ethanol	Cytotoxic	[45]
93	E. fortunei	2-Acetyl-7-tigloyloxy-isothymol	Isothymol	Refluxed with 95% ethanol	Cytotoxic	[45]
94	E. fortunei	8, 9-dehydrothymol-3-O-β-glucoside	Thymol	95% ethanol at room temperature	Cytotoxic	[46]
95	E. fortunei	3-methylbut-2-enoate	Thymol	95% ethanol at room temperature	Cytotoxic	[46]
96	E. fortunei	2-(2-hydroxy-4-methylphenyl)-2-methyl-3-(5-methylbenzofuran-3-yl)propanoic acid	Thymol	Methanol at room temperature	None	[47]
97	E. fortunei	9-acetoxyl-3-isobutyroylthymol	Thymol	Methanol at room temperature	a-Glucosidase and acetylcholinesterase inhibitory	[47]
98	E. fortunei	7,8,9-trihydroxythymol	Thymol	95% ethanol at room temperature	Antibacterial	[48]
99	E. fortunei	8,10-didehydro-7,9-dihydroxythymol	Thymol	95% ethanol at room temperature	Antibacterial	[48]
100	E. fortunei	(−)-Eupafortunin A	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
101	E. fortunei	(+)-Eupafortunin A	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
102	E. fortunei	(+)-Eupafortunin B	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
103	E. fortunei	(−)-eupafortunin B	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
104	E. fortunei	Eupafortunin C	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
105	E. fortunei	Eupafortunin D	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
106	E. fortunei	Eupafortunin E	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
107	E. fortunei	(+)-Eupafortunin F	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
108	E. fortunei	(−)-Eupafortunin F	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
109	E. fortunei	Eupafortunin G	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
110	E. fortunei	Eupafortunin H	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
111	E. fortunei	Eupafortunin I	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
112	E. fortunei	Eupafortunin J	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
113	E. fortunei	(+)-Eupafortunin K	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
114	E. fortunei	(−)-Eupafortunin K	Thymol	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
115	E. fortunei	Eupafortunin L	Acetophenone	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
116	E. fortunei	Eupafortunin M	Acetophenone	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
117	E. fortunei	Eupafortunin N	Acetophenone	95% ethanol at room temperature	Antiradical and anti-inflammatory	[49]
118	E. fortunei	Eupatofortunone	Acetophenone	Methanol at room temperature	Cytotoxic	[50]
119	E. fortunei	Eupatodibenzofuran A	Benzofuran	Methanol at room temperature	Cytotoxic	[50]
120	E. fortunei	Eupatodibenzofuran B	Benzofuran	Methanol at room temperature	Cytotoxic	[50]
121	E. fortunei	6-acetyl-8-methoxy-2,2-dimethylchroman-4-one	Chromanone	Methanol at room temperature	Cytotoxic	[50]
122	E. fortunei	Eupatodithiecine	Dithiecine	Methanol at room temperature	Cytotoxic	[50]
123	E. fortunei	(+)-Eupafortin A	Monoterpenoid	95% ethanol at room temperature	Anti-inflammatory	[51]
124	E. fortunei	(−)-Eupafortin A	Monoterpenoid	95% ethanol at room temperature	Anti-inflammatory	[51]
125	E. fortunei	(+)-Eupafortin B	Monoterpenoid	95% ethanol at room temperature	Anti-inflammatory	[51]
126	E. fortunei	(−)-Eupafortin B	Monoterpenoid	95% ethanol at room temperature	Anti-inflammatory	[51]
127	E. fortunei	Eupatorid A	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
128	E. fortunei	Eupatorid A	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
129	E. fortunei	Eupatorid B	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
130	E. fortunei	Eupatorid B	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
131	E. fortunei	Eupatorid C	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
132	E. fortunei	Eupatorid C	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
133	E. fortunei	Eupatorid D	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
134	E. fortunei	Eupatorid D	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
135	E. fortunei	Eupatorid E	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
136	E. fortunei	Eupatorid E	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
137	E. fortunei	Eupatorid F	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
138	E. fortunei	Eupatorid F	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
139	E. fortunei	Eupatorid G	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]
140	E. fortunei	Eupatorid G	Fatty acid	95% ethanol at room temperature	Anti-inflammatory	[52]

), namely 27 thymol derivatives (88–114), 4 acetophenones (115–118), 2 benzofuran derivatives (119–120), 1 chromanone (121), 1 dithiecine (122), 4 monoterpenoids (123–126), and 14 fatty acid derivatives (127–140) (Figure 4) [44,45,46,47,48,49,50,51,52]. Compounds 89 and 90 exhibited cytotoxicity against MCF-7, HeLa, human lung cancer cells (A549), and HepG-2, with IC50 values of 6.24–11.96 μM [45]. Compound 105 displayed moderate activity, with an IC50 value of 24.27 μM [49]. Compound 119 showed potent cytotoxicity against A549 and MCF-7, with IC50 values of 5.95 and 5.32 µM, respectively [50]. Compounds 123–126 showed promising inhibitory effects on NO production, with the inhibition rate reaching 68.9%, 67.4%, 62.6%, and 65.1%, respectively, at 10 µM [51].

2.4. Chemical Components of E. heterophyllum and Their Biological Activities

E. heterophyllum DC. is a species endemic to China and is widely distributed in the grasslands and forest areas of the Hengduan Mountains and surrounding areas, at an altitude of 1700–3000 m. In Chinese folk medicine, the stems and whole plants of this species have been used to treat various injuries and trauma [53]. However, phytochemical studies are very limited in this plant. The research on the chemical compositions of this plant species has only begun recently and the research is relatively concentrated. Therefore, this is also the first review reporting the chemical compositions of this plant (

Table 4. Chemical constituents (141–179) from the plant E. heterophyllum.

No.	Plant Source	Compound Name	Structure Classification	Extraction Method	Type of Bioactivity Evaluation	Ref.
141	E. heterophyllum	Eupaheterin A	Benzofuran	Methanol at room temperature	None	[53]
142	E. heterophyllum	Eupaheterin B	Benzofuran	Methanol at room temperature	None	[53]
143	E. heterophyllum	Eupaheterin C	Benzofuran	Methanol at room temperature	None	[53]
144	E. heterophyllum	Eupaheterin D	Benzofuran	Methanol at room temperature	None	[53]
145	E. heterophyllum	Eupaheterin E	Benzofuran	Methanol at room temperature	None	[53]
146	E. heterophyllum	Eupaheterin F	Benzofuran	Methanol at room temperature	None	[53]
147	E. heterophyllum	Eupaheterin G	Benzofuran	Methanol at room temperature	None	[53]
148	E. heterophyllum	Eupaheterin H	Benzofuran	Methanol at room temperature	None	[53]
149	E. heterophyllum	Eupaheterin I	Benzofuran	Methanol at room temperature	None	[53]
150	E. heterophyllum	Eupaheterin J	Benzofuran	Methanol at room temperature	None	[53]
151	E. heterophyllum	4-Acetyl-3β,5-dihydroxy-2α-(propen-2-yl)-2,3-dihydrobenzofuran	Benzofuran	Methanol at room temperature	None	[54]
152	E. heterophyllum	4-Acetyl-3β-angeloyloxy-5-hydroxy-2α-(propen-2-yl)- 2,3-dihydrobenzofuran	Benzofuran	Methanol at room temperature	None	[54]
153	E. heterophyllum	6-Acetyl-3β,5-dihydroxy-2α-(propen-2-yl)-2,3-dihydrobenzofuran	Benzofuran	Methanol at room temperature	None	[54]
154	E. heterophyllum	5-Acetyl-6-hydroxy-3α-methoxyl-2α-(propen-2-yl)-2,3- dihydrobenzofuran	Benzofuran	Methanol at room temperature	None	[54]
155	E. heterophyllum	5-Acetyl-3α-angeloyloxy-6-hydroxy-2α-(2-methyloxiran-2-yl)-2,3-dihydrobenzofuran	Benzofuran	Methanol at room temperature	None	[54]
156	E. heterophyllum	5-Acetyl-3α-angeloyloxy-6-hydroxy-2α-(2-methyloxiran-2-yl)-2,3-dihydrobenzofuran	Benzofuran	Methanol at room temperature	None	[54]
157	E. heterophyllum	3,9β-Epoxy-9α-isobutanoyloxymentha-13,5-trien-8α-ol	Benzofuran	Methanol at room temperature	None	[54]
158	E. heterophyllum	Dieupaheterin A	Benzofuran	Methanol at room temperature	None	[53]
159	E. heterophyllum	Dieupaheterin B	Benzofuran	Methanol at room temperature	None	[53]
160	E. heterophyllum	Dieupaheterin C	Benzofuran	Methanol at room temperature	None	[53]
161	E. heterophyllum	Dieupaheterin D	Benzofuran	Methanol at room temperature	None	[53]
162	E. heterophyllum	Dieupaheterin E	Benzofuran	Methanol at room temperature	None	[55]
163	E. heterophyllum	Dieupaheterin F	Benzofuran	Methanol at room temperature	None	[55]
164	E. heterophyllum	Trieupaheterin A	Benzofuran	Methanol at room temperature	None	[53]
165	E. heterophyllum	2-(Hydroxyacetyl)-3-methoxy-5-(propyn-1-yl)thiophene	Thiophene	Methanol at room temperature	None	[54]
166	E. heterophyllum	2-Acetyl-3-hydroxy-5-(propyn-1-yl)thiophene-3-O-(6-O-malonyl)-β-glucoside	Thiophene	Methanol at room temperature	None	[54]
167	E. heterophyllum	(3R,6R,7R,8R)-(4Z)-3α-acetoxy-8β-(3-furoyloxy)germacra-1(10),4,11(13)-trien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
168	E. heterophyllum	(4Z)-3α-acetoxy-8β-(4′,5′ -dihydroxytigloyloxy)-1β-hydroperoxygermacra-4,10(14),11(13)-trien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
169	E. heterophyllum	5′-deoxy-(4Z)-3α-acetoxy-8β-(4′,5′ -dihydroxytigloyloxy)-1β-hydroperoxygermacra-4,10(14),11(13)-trien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
170	E. heterophyllum	(4Z)-3β-acetoxy-1β,10α-epoxy-8β-(4′,5-epoxy-4′-hydroxytigloyloxy)germacra-4,11(13)-dien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
171	E. heterophyllum	8β-(2′-methylbutanoyloxy)germacra-1(10),4,11(13)-trien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
172	E. heterophyllum	1β-hydroperoxy-2α-hydroxy-8β-(5′-hydroxyangeloyloxy)germacra-4,10(14),11(13)-trien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
173	E. heterophyllum	8β-(4′-acetoxytigloyloxy)-1β-hydroperoxy-3β-hydroxygermacra-4,10(14),11(13)-trien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
174	E. heterophyllum	1β-hydroxy-8β-(5′-hydroxyangeloyloxy)eudesma-4(15),11(13)-dien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
175	E. heterophyllum	1β,2α-dihydroxy-8β-(5′-hydroxyangeloyloxy)eudesma-4(15),11(13)-dien- (12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
176	E. heterophyllum		Sesquiterpenoid	Methanol at room temperature	None	[56]
177	E. heterophyllum	8β-(4′,5′-dihydroxytigloyloxy)-3α-hydroperoxyguaia-4,10(14),11(13)-trien-(12,6α)-olide	Sesquiterpenoid	Methanol at room temperature	None	[56]
178	E. heterophyllum		Sesquiterpenoid	Methanol at room temperature	None	[56]
179	E. heterophyllum	8β-(5′-hydroxyangeloyloxy)-1-oxo-2-norelema-3,11(13)-dien-(12,6α)-olid	Sesquiterpenoid	Methanol at room temperature	None	[56]

Compounds 141–150 and 158–164 were not named in the original article, but were named by the author for ease of reading.

). Compounds 141–179 are isolated and characterized from the roots and leaves of E. heterophyllum (Figure 5) [53,54,55,56]. Compounds 141–166 are benzofuran and thiophene derivatives isolated from the roots of E. heterophyllum [53,54,55]. Compounds 167–179 are sesquiterpenoids and are isolated from the leaves of this plant [56]. Unfortunately, none of the aforementioned compounds have been evaluated for any activity. Therefore, in terms of chemical structures, the discovered compounds have a large polarity. In fact, excavation of the medium to lower polarity compounds of this plant may be continued and discoveries may happen.

2.5. Chemical Components of E. lindleyanum and Their Biological Activities

E. lindleyanum, referred to as “Ye-Ma-Zhui” by the local Chinese population, is used for tracheitis and cough treatment and has a bitter, acerbic taste. Compounds 180–183 are sesquiterpenoids isolated from E. lindleyanum (

Table 5. Chemical constituents from the plants E. lindleyanum (180–183), E. macrocephalum (184–186), and E. obtusissmum (187–192).

No.	Plant Source	Compound Name	Structure Classification	Extraction Method	Type of Bioactivity Evaluation	Ref.
180	E. lindleyanum	Eupalinolide L	Sesquiterpenoid	Boiling water	Anti-inflammatory	[57]
181	E. lindleyanum	Eupalinolide M	Sesquiterpenoid	Boiling water	Anti-inflammatory	[57]
182	E. lindleyanum	Eupalinolide N	Sesquiterpenoid	Refluxed with 90% ethanol	Anti-inflammatory	[58]
183	E. lindleyanum	Eupalinolide O	Sesquiterpenoid	95% ethanol at room temperature	Cytotoxic	[59]
184	E. macrocephalum	Macrocephalide A	Sesquiterpenoid	Methanol at room temperature	Cytotoxic	[60]
185	E. macrocephalum	Macrocephalide B	Sesquiterpenoid	Methanol at room temperature	Cytotoxic	[60]
186	E. macrocephalum	Macrocephalide C	Sesquiterpenoid	Methanol at room temperature	Cytotoxic	[60]
187	E. obtusissmum	Uasdlabdane A	Diterpenoid	95% ethanol at room temperature	Cytotoxic	[61]
188	E. obtusissmum	Uasdlabdane B	Diterpenoid	95% ethanol at room temperature	Cytotoxic	[61]
189	E. obtusissmum	Uasdlabdane C	Diterpenoid	95% ethanol at room temperature	Cytotoxic	[61]
190	E. obtusissmum	Uasdlabdane D	Diterpenoid	95% ethanol at room temperature	Cytotoxic	[61]
191	E. obtusissmum	Uasdlabdane E	Diterpenoid	95% ethanol at room temperature	Cytotoxic	[61]
192	E. obtusissmum	Uasdlabdane F	Diterpenoid	95% ethanol at room temperature	Cytotoxic	[61]

and Figure 6) [57,58,59]. Compounds 180 and 181 displayed excellent anti-inflammatory activities by lowering tumor necrosis factor-α and interleukin 6 levels in lipopolysaccharide-stimulated murine macrophage RAW 264.7 cells (p < 0.001) [57]. Compound 182 can dramatically attenuate NO secretion at 7.5 μM [58].

2.6. Chemical Components of E. macrocephalum and Their Biological Activities

E. macrocephalum Less. is a perennial herb widely distributed in the New World, from Mexico to Argentina. It is described as an invader of grasslands, wetlands, and roadsides in several provinces of South Africa. However, it is used in Paraguayan folk medicine as an anti-inflammatory and sedative agent and for the treatment of cardiac diseases [60]. Compounds 184–186 are three undescribed germacranolide sesquiterpenoids isolated from the aerial parts of E. macrocephalum (Table 5 and Figure 6). Of them, compounds 184 and 185 displayed moderate-to-potent cytotoxicity against nine human cancer cell lines, namely human glioma cells (U251), human melanoma cells (UACC-62), MCF-7, human multiple-drug resistant breast cancer cells (NCI/ADR-RES), renal clear cell adenocarcinoma cells (786–0), non-small cell lung cancer cells (NCI–H460), human ovarian cancer cells (OVCAR-3), human colon cancer cells (HT-29), and human erythroleukemia cells (K562), with IC50 values of 0.576–6.37 μM [60].

2.7. Chemical Components of E. obtusissmum and Their Biological Activities

E. obtusissmum P. DC. is an uncommon and narrowly distributed species in Eupatorium. This is an endemic plant from the island of Hispaniola [61]. Therefore, only one report is available on the chemical composition of E. obtusissmum. Compounds 187–192 are six ent-labdane diterpenoids and are isolated from the aerial parts of the plant (Table 5 and Figure 6). No compound displayed conspicuous cytotoxicity against A549, human breast carcinoma cells (HBL-100), HeLa, human lung tumor cells (SW1573), human breast cancer cells (T-47D), and human colorectal cancer cells (WiDr) [61].

3. Conclusions

This review discusses the recent discoveries of new compounds isolated and identified from seven plant species belonging to Eupatorium, since 2015; then, they were categorized according to the plant species. Notably, results of phytochemical investigations on E. heterophyllum and E. obtusissmum have recently been reported. Consequently, this is the first review of these two plant species. Although several compounds have shown anticancer, antibacterial, and anti-inflammatory effects, more compounds exhibited no significant activities and even some new compounds displayed no activity in bioactivity assays. However, if activity assays are continued in vivo or in vitro for these new compounds, we believe that more positive results may be obtained. By providing an essential reference and fresh insights, we hope this review of the recent research progress on the chemical constituents of Eupatorium can support and inspire researchers engaged in studies on natural products and their biological properties.