Emerging Biopharmaceuticals from Pimpinella Genus

Abstract

Evolved over eons to encode biological assays, plants-derived natural products are still the first dawn of drugs. Most researchers have focused on natural compounds derived from commonly used Pimpinella species, such as P. anisum, P. thellungiana, P. saxifrage, and P. brachycarpa, to investigate their antioxidant, antibacterial, and anti-inflammatory properties. Ethnopharmacological studies demonstrated that the genus Pimpinella has the homology characteristics of medicine and food and mainly in the therapy of gastrointestinal dysfunction, respiratory diseases, deworming, and diuresis. The natural product investigation of Pimpinella spp. revealed numerous natural products containing phenylpropanoids, terpenoids, flavonoids, coumarins, sterols, and organic acids. These natural products have the potential to provide future drugs against crucial diseases, such as cancer, hypertension, microbial and insectile infections, and severe inflammations. It is an upcoming field of research to probe a novel and pharmaceutically clinical value on compounds from the genus Pimpinella. In this review, we attempt to summarize the present knowledge on the traditional applications, phytochemistry, and pharmacology of more than twenty-five species of the genus Pimpinella.

1. Introduction

Secondary metabolites from nature, predominantly plant, are still elected as a first preference for drug discovery and serve as a hotpot because of their promising novel scaffolds against chronic diseases. Once the only thirst to cure diseases, elixirs and traditional medications allow for the more proficient approach to drug discovery. Plant-derived natural products were once the backbone of the pharmaceutical armamentarium, but the ready corresponding access to synthetic agents has discouraged the interest in maintaining a discovery paradigm from plants.

Recently, drug discovery from plants has sparked in many researchers and they have driven back their path toward terrestrial plants. Pimpinella is a species richness genus in the Umbelaceae family with unique morphological characteristics of monofoliate or compound leaves, three-out or one- to two-fold pinnate division. The flowers possessed characteristic umbels white or purplish-red, and ovoid and long ovoid was the most common fruit shapes [1]. The morphological characteristics of several major Pimpinella plants distributed in China are shown in Figure 1. By reviewing the literature, we discorvered about 150 species of Pimpinella were widely distributed in the area of Asia, Europe, and Africa, while only a few species were discovered in north and west of North America [2]. China, Turkey, and Iran were the three most abundant distribution centers of different species [3,4]. Approximately 39 species have been recorded in the Chinese Flora, most of which were perennial herbs, and a few were biennial or annual herbs [5]. A total of 26 species were native to Turkey and 23 species were present in Iran. Among them, P. anisum is the representative folk medicine growing in Asia, Europe, Iran, and the United States with the most research reports, the highest application value, and the widest distribution range.

According to the theoretical knowledge of TCM (traditional Chinese medicines) and the recordation of Chinese Pharmacopoeia in the 2010 edition, the Chinese herbal medicine Yanghongshan (P. thellungiana) has the effects of warming the middle and dispersing cold, invigorating the spleen and replenishing qi, nourishing the mind and transcending the mind, relieving cough and removing phlegm, and clinically used to treat Keshan disease, palpitations, shortness of breath, and cough [1]. Phytochemistry investigation revealed that the genus Pimpinella principally contained compounds of terpenoids, flavonoids, coumarins, sterols, and fatty acids [6]. Pharmacological research has revealed a variety of biopharmacological activities of the extracts and compounds from the genus Pimpinella, such as antioxidant [7], antibacterial [8], anti-inflammatory [9], antitumor [10], and hypoglycemic activity [11]. However, the in-depth research on the traditional medicinal use of extracts from Pimpinella is insufficient presently, and the research on the chemical components and pharmacological effects is only focused on several species. Hence, more theoretical support for the clinical application and toxicity of Pimpinella is necessary.

Systematic retrieval of relevant literature was consulted on the following electronic databases: the Web of Science database (http://apps.webofknowledge.com/ (accessed on 8 June 2022)), the PubMed Database (https://pubmed.ncbi.nlm.nih.gov, (accessed on 8 June 2022)), Chinese National Knowledge Infrastructure (CNKI) (http://www.cnki.net, (accessed on 8 June 2022)), Wanfang Data (http://www.wanfangdata.com.cn/, accessed on 8 June 2022), and Google Scholar, and information only written in Chinese and English were considered. The keywords included “Pimpinella”, “Hui-qin” (in Chinese), “anise”, “constituents”, “separation”, and “pharmacology”. Additional data were collected from the relevant surveys of PhD. and MSc. research in China by the CNKI database, monographs on folk medicine, and Chinese Pharmacopoeia (2020). In this review, we systematically and comprehensively consulted and summarized over 100 references on the folk-medicinal application, phytochemical constituents, and pharmacological activities of the genus Pimpinella, providing a theoretical basis for promoting the application of Pimpinella plants in medicine, food, and other fields.

2. Folk-Medicine Application

The common ethnic uses of Pimpinella around the world are summarized as shown in

Table 1. The folk-medicine applications of some Pimpinella species in several countries.

Part	Pimpinella spp.	Folk-Medicine Applications	Country/Region	Reference
Aerial parts	P. diversifolia	Cold, dyspepsia, dysentery, and diarrhea	China	[12]
	P. candollean	Chest pain, stomach pain, rheumatism, muscle and bone pain, and used as wild vegetables	China	[12]
	P. thellungiana	Anticoagulation	Chian	[12]
	P. brachycarpa	Gastrointestinal disturbances, bronchial asthma, insomnia, persistent cough, and used as vegetables	Korean	[13] [14]
	P. cappadocica	Carminative and digestive	Turkey	[16]
	P. anisum	Renal colic, gastrointestinal colic, and upper respiratory tract disease	Egypt	[21]
	P. anisum	Renal colic, gastrointestinal colic, and upper respiratory tract disease	Lebanon	[22]
	P. anisum	Used as a tea to treat constipation	Brazil	[24]
Seeds	P. brachycarpa	Gastrointestinal disturbances, bronchial asthma, insomnia, persistent cough, and used as vegetables	Korean	[14]
	P. monoica	Stomachache	India	[15]
	P. rhodantha	Sedative, expectorant, and increase lactation	Turkey	[17]
	P. peregrine	Carminative, digestive, and increase lactation	Turkey	[18]
	P. khorasanica	Carminative, digestive, and increase lactation	Turkey	[19]
	P. anisum	Epilepsy	Iran	[20]
	P. anisum	Insect repellents, stomach-cramping sedatives, diuretics, and urinary tract disinfectants	England	[23]
	P. anisum	Used as plant spice to produce spirits drinks and confectionery	Spain France	[25] [25]
Essential oil	P. anisum	Carminative, aromatic, disinfectant, and diuretic	Iran	[20]

, and it can be concluded that Pimpinella plants have the homology characteristics of medicine and food, wide varieties, and extensive traditional activities. In Asia, China was the country with the longest history and abundant resources in herbal remedy. P. diversifolia was used for the treatment of cold, indigestion, and diarrhea; P. candollean was eaten locally by Hmong as wild vegetables and used for resistance to stomach pain, bone pain, and rheumatism; P. thellungiana showed a remarkable anticoagulant effect [12]. Additionally, Koreans were keen to make P. brachycarpa delicious kimchi and were used medicinally for gastrointestinal dysfunction, asthma, and cough [13,14]. The seed of P. monoica native to India was used to fight stomachaches [15]. In the Middle East, species diversification of Pimpinella could be observed in Turkey. The recorded endemic species, P. cappadocica [16], P. rhodantha [17], P. peregrine [18], and P. khorasanica [19] were applied in the therapy of deworming, digestion, sedation, expectoration, and increasing lactation. In Iranian folk studies, P. anisum seeds treated epilepsy since ancient times [20], while residents in Egypt and Lebanon attempted to use it to treat digestive and respiratory ailments [21,22]. Notably, Pimpinella’s medicinal use is less prevalent in Europe and America, and the British and Brazilians usually used P. anisum as insect repellent, urinary disinfectant, and a deobstruent [23,24]. In Spain, France, and Italy, P. anisum was added to cooking, distilled alcoholic spirits, and confectionery industries as botanical spices [25,26].

3. Phytochemistry

Recent investigations on chemical constituents of the genus Pimpinella identified 343 compounds, principally containing phenylpropanoids, terpenoids, flavonoids, coumarins, sterols, and organic acids. More than 80% of compounds were identified after 2000 (Figure 2), among which phenylpropanoids, terpenoids, and flavonoids are the essential active components with the functions of an antioxidant, anti-inflammatory, and antitumor. Particularly, a unique and infrequent phenylpropanoid was found in the genus Pimpinella, named pseudo isoeugenol.

3.1. Phenylpropanoids

Phenylpropanoids are the main components occupying the dominant activity position in the volatile oils or extract of the Pimpinella genus, and a battery of studies have revealed anti-inflammatory, antibacterial, and antioxidant contributions [27]. Phenylpropanoids area class of natural compounds concatenated bya benzene ring and three straight-chain carbons (C₆-C₃ units) with diverse activities. According to the skeletal characteristics of the phenylpropanoids in Pimpinella, they could be divided into three groups: pseudoisoeugenol, pseudoisoeugenol derivatives, and simple phenylpropanoids. Pseudoisoeugenol, as a representative chemical marker of Pimpinella, possessed a peculiar skeleton of 1-hydroxy-2-propyl-4-methoxybenzene, which has been found exclusively in the genus Pimpinella so far [28]. Since the first pseudoisoeugenol was discovered from the P. anisum by G. T. Carter et al. [29] in 1977, scientists have successively obtained 12 pseudoisoeugenol (1–12) from the Chinese herb P. thellungiana, and llungianin A (1) and llungianin B (2), which presented significant antihypertensive activity [30,31,32,33,34,35,36,37].

Pseudoisoeugenol derivatives owned the same basic skeleton of a 1,2, 4-trisubstituted benzene ring as pseudoisoeugenol. The different was that the position of different-types substituent changed, and the phenolic hydroxyl group was combined with the acyl group to form an ester group frequently. Scientists have demonstrated the presence of 19 pseudoisoeugenol derivatives (13–31) in the genus Pimpinella, most of which were identified by GC-MS from the volatile oil [36,37,38,39,40,41,42,43,44,45].

In addition to the pseudoisoeugenol and its derivatives, the scientists have isolated 20 other types of phenylpropanoids from the genus Pimpinella. Two new phenylpropanoids (32–33) with antioxidant peculiarity were extracted by coupling with vacuum liquid chromatography and preparative thin-layer chromatography from P. aurea [45]. Additionally, eight simple phenylpropanoids (34–46) were sought during GC-MS analysis of essential oils from P. anisum, P. corymbosa, P. peregrine, P. puberula, P. anisetum, and P. flabellifolia gathered in Turkey [36,45,46,47]. Moreover, anisketone (47), methyl-O-coumarate (48), 1-(2-hydroxy-4-methoxyphenyl)-propan1-one (49), 4-methoxycinnamaldehyde (50) and dillapiole (51) were obtained from P. saxifraga and possessed antioxidant activity and DNA protection potential [46]. The phytochemical profile of P. serbica, endemic to West Balkans, was dominated by phenylpropanoids, dillapiole (35.1%) (51), and nothoapiole (9.5%) (52) [47] (Figure 3,

Table 2. Phenylpropanoids of Pimpinella plant.

No.	Name	Formula	Mol. Wt.	Species	Reference
1	2-(1′-ethoxy-2′-hydroxy)propyl-4-methoxyphenol (llungianin A)	C12H18O4	226	P. thellungiana	[30]
2	2-(1′-ethoxy-2′-hydroxy)propyl-4-methoxyphenyl-2-methyl-butyrate (llungianin B)	C17H26O5	310	P. thellungiana	[30]
3	2-(1′-methoxy-2′-hydroxy) propyl-4-methoxyphenol (llungianin E)	C11H16O4	212	P. thellungiana	[31]
4	2-(1′,2′-dihydroxy)propyl-4-methoxyphenol	C10H14O4	198	P. thellungiana	[32]
5	4-methoxy-2-propenyl-phenyl-(3′-methyl) butanoate	C15H20O3	248	P. thellungiana	[33]
6	2-(1′,2′-epoxy)propyl-4-methoxypheryl-(2″-methyl)-butyrate (llungianin G)	C15H20O4	264	P. thellungiana P. saxifraga	[34] [46]
7	4-methoxy-2-(3-methyloxiranyl) phenyl-2-methylbutenate	C15H18O4	262	P. diversifolia P. aurea P. peregrina	[35] [45]
8	4-methoxy-2-(3-methyloxiranyl)phenyl isobutyrate	C14H18O4	250	P. diversifolia P. peregrina	[35] [36]
9	4-methoxy-1-propenyl-phenyl-(2′-methyl) butanoate	C15H20O3	248	P. anisum	[29]
10	4-methoxy-2-(1-propenyl)-phenylisobutyrate	C14H18O3	234	P. peregrina	[36]
11	4-methoxy-2-(3-methyloxiranyl)-phenylangelate	C15H18O4	262	P. peregrina	[36]
12	pseudoisoeugenol	C10H12O2	164	P. saxifraga	[37]
13	2-methoxy-4-(3-methyloxiranyl) phenyl 2-methyl butanoate	C15H20O4	264	P. saxifraga	[37]
14	2-methoxy-4-(3-methyloxiranyl) phenyl2-methyl butenate	C15H18O4	262	P. saxifraga	[38]
15	4-methoxy-2-fromylphenyl-(2′-methyl) butanoate	C13H16O4	236	P. anisum	[29]
16	1-angelyloxy-2-(3-methyloxiranyl)-4-isobutyryloxybenzene	C18H22O5	318	P. diversifolia	[39]
17	l-isobuty-ryloxy-2-(3-methyloxiranyl)-4-angelyloxybenzene	C18H22O5	318	P. diversifolia	[39]
18	1,4-diangelyoxy-2-(3-methyloxiranyl)benzene	C19H22O5	330	P. diversifolia	[39]
19	4-propenyl-phenyl-2-methyl butanoate (llungianin F)	C15H20O2	232	P. thellungiana	[33]
20	4-(2-methyl-2-butenoyl)oxy)-2-(3-methyloxiran-2-yl)-phenyl2-methyl-2,3-epoxybutanoate	C19H22O6	346	P. villosa	[40]
21	4-(2-methyl-2-butenoyloxy)-2-(3-methyloxiran-2-yl)-phenyl 2-methyl-2-butenoate	C15H18O5	278	P. villosa	[40]
22	2-methoxy-4-prop-1-enylphenyl isobutyrate	C14H18O3	234	P. junoniae P. aurea	[44] [45]
23	pseudoisoeugenyltiglate	C15H18O3	246	P. junoniae	[44]
24	4-(1-propenyl)-phenyl tiglate	C14H16O2	216	P. aurea	[45]
25	4-(1-propenyl)-phenylisobutyrate	C13H16O2	204	P. corymbosa	[36]
26	4-(3-methyloxiranyl)-phenyl-2-methylbutyrate	C14H18O3	234	P. aurea	[45]
27	4-(3-Methyloxiranyl)-phenyltiglate	C14H16O3	232	P. aurea	[45]
28	epoxypseudoisoeugenyl-2-methyl butyrate	C14H18O4	250	P. corymbosa P. peregrina P. puberula	[36]
29	5-(1′-ethoxy-2′-hydroxy)propyl-3-methoxyphenol	C12H18O4	226	P. thellungiana	[41]
30	5-methoxy-2-methyl benzofuran (llungianin H)	C10H10O2	162	P. thellungiana P. junoniae P. peregrina	[42] [44] [36]
31	2-methyl-2-hydroxy-5-methoxy berzo (d) hydrofuran-3-one	C10H10O4	194	P. thellungiana	[43]
32	erythro-1′-(4-methoxyphenyl)-propan-1′,2′-diol	C10H14O3	182	P. aurea	[45]
33	erythro-1′-[4-(sec-butyl)-phenyl]-propan-1′,2′-diol	C13H20O2	208	P. aurea	[45]
34	eugenol	C10H12O2	164	P. puberula	[36]
35	elemicine	C12H16O3	208	P. puberula	[36]
36	p-cymene	C10H14	134	P. anisetum P. aurea P. corymbosa	[48] [45]
37	α,p-dimethylstyrene	C10H12	132	P. aurea	[45]
38	1-(4-hydroxyphenyl)-1,2-ethanediol	C8H10O3	154	P. candolleana	[49]
39	methyl chavicol	C10H12O	148	P. anisetum P. anisum	[48] [50]
40	cis-anethole	C10H12O	148	P. anisetum P. flabellifolia P. saxifrage P. anisum	[48] [46] [50]
41	4-propenylphenol	C9H10O	134	P. thellungiana	[41]
42	trans-anethole	C10H12O	148	P. anisetum P. flabellifolia P. aurea P. corymbosa P. peregrine P. anisum	[48] [36] [50]
43	methyl isoeugenol	C11H14O2	178	P. flabellifolia	[48]
44	p-cymen-8-ol	C10H14O	150	P. junoniae P. aurea	[44] [45]
45	methyl eugenol	C11H14O2	178	P. corymbosa P. puberula	[36]
46	carvacrol	C11H14O2	178	P. aurea P. corymbosa P. puberula	[36]
47	p-anisaldehyde	C10H12O2	164	P. saxifrage P. anisum	[46] [50]
48	methyl-O-coumarate	C10H10O3	178	P. saxifraga	[46]
49	1-(2-hydroxy-4-methoxyphenyl)propan1-one	C10H12O3	180	P. saxifraga	[46]
50	4-methoxycinnamaldehyde	C10H12O3	180	P. saxifraga	[46]
51	dillapiole	C12H14O4	222	P. saxifrage P. serbica	[46] [47]
52	nothoapiole	C13H16O5	252	P. serbica	[47]

).

3.2. Terpenoids

Terpenoids are a kind of active ingredient with diverse skeletons with manifold bioactivity and extensive distribution. The formula complies with the (C₅H₈)_n rule by polymerization of isoprene units in different linking ways. The long-term research by phytochemistshave certified that the volatile oil containing a large number of terpenoids has pervasively existed in Pimpinella, which released crucial activities of antibacterial, anti-inflammatory, and antidepressant activities. Notably, besides unique phenylpropanoids, the considerable quantity of specific C-12 sesquiterpene is another phytochemical marker distinguishing Pimpinella from other genera, such as geijerene- (107) and azulene- (109) type terpenes.

The volatile oil of P. anisum seed has attracted attention for its extensive biological activities such as antitumor, anti-inflammatory, and insecticidal agents. Numerous studies have characterized the ingredients in P. anisum, from which 46 monoterpenoids and sesquiterpenoids, including the principal ingredient linalool (101), were identified [6,50,51,52,53]. Many researchers have analyzed the essential oil extracted from the foreign-sourced Pimpinella genus. A. V-Negueruela et al. [44] disposed of the aboveground parts of P. junoniae in Spain to obtain the oil, and α-zingiberene (20.6%) and α-pinene (17.9%) were the most abundant among 26 volatile constituents. N. Tabanca et al. [36,45] evaluated essential oils extracted from roots, stems, leaves, and fruits of four Pimpinella species (P. aurea, P. corymbosa, P. peregrine and P. puberula) on GC-MS, and a total of 95 terpenoids were identified. Meanwhile, further data comparison discovered that the main components of each plant in different parts possess differentiation, while only the oil from the root had a higher similarity, containing large quantities of epoxy pseudoisoeugenyl-2-methyl butyrate (26.8–42.8%). A series of Pimpinella plant’s in vitro activity exploration, including the Turkish medicines P. anisetum [48], P. flabellifolia [48], and P. enguezekensis [51], the Iranian medicinal plants P. affinis [52] and P. khorasanica [19], the Indian herb P. monoica [15], and the Tunisian wild vegetable P. saxifrage [46], exhibited good antioxidant and antibacterial capacities, and GC-MS reports revealed terpenoids were dominant for their therapeutic effect. Recently, researchers also conducted profound studies on the oil of domestic Pimpinella plants. X. W. Xu [53] and E. M. Suleimen et al. [54] extracted the oil of P. diversifolia and P. thellungiana and identified 19 and 16 terpenoids, respectively.

In addition to terpenoids identified from volatile oils, S. Y. Lee’s long-term research on chemical constituents of P. brachycarpa [13], two new sesquiterpenes (152–153) and ten known terpenes (88–91, 128, 154–158) were isolated from the methanol extract of aerial parts. Ozbek et al. [16,17] obtained a new trinorguaian-type sesquiterpenoid (114) and a newly discovered triterpenoid glycoside (219) from P. cappadocica and P. rhodantha, respectively. Six triterpenoids (213–218) were isolated from P. anisum aqueous extract [55,56]. Pimpinelol (205) [10], a novel irregular sesquiterpene lactone from P. haussknechtii could significantly restrain the vitality of human breast cancer cells by inducing endoplasmic reticulum stress (Figure 4,

Table 3. Species of Pimpinella plants.

No.	Type	Name	Formula	Mol. Wt.	Species	Reference
53	Monoterpenoid	α-pinene	C10H16	136	P. aurea P. corymbosa P. peregrina P. puberula P. junoniae P. anisetum P. flabellifolia P. anisum P. affinis P. monoica P. thellungiana	[36] [44] [48] [57] [52] [15] [54]
54	Monoterpenoid	β-pinene	C10H16	136	P. aurea P. corymbosa P. puberula P. flabellifolia P. anisum P. monoica P. thellungiana	[36] [48] [6] [15] [54]
55	Monoterpenoid	camphene	C10H16	136	P. aurea P. corymbosa P. flabellifolia	[36] [48]
56	Monoterpenoid	pinocarvone	C10H14O	150	P. aurea	[36]
57	Monoterpenoid	pinocarveol	C10H16O	152	P. aurea P. thellungiana	[36] [54]
58	Monoterpenoid	myrtenal	C10H14O	150	P. corymbosa P. thellungiana	[36] [54]
59	Monoterpenoid	trans-verbenol	C10H16O	152	P. corymbosa P. peregrine P. monoica	[36] [15]
60	Monoterpenoid	myrtenol	C10H16O	152	P. aurea	[36]
61	Monoterpenoid	safranal	C10H14O	150	P. anisum	[57]
62	Monoterpenoid	1,8-cineole	C10H18O	154	P. anisum	[57]
63	Monoterpenoid	1,4-cineole	C10H18O	154	P. thellungiana	[54]
64	Monoterpenoid	α-fenchene	C10H16	136	P. monoica	[15]
65	Monoterpenoid	camphor	C10H16O	152	P. anisum	[58]
67	Monoterpenoid	borneol	C10H18O	154	P. anisum P. monoica	[58] [15]
68	Monoterpenoid	1-methoxy-4-methylbicyclo[2.2.2]octane	C10H18O	154	P. thellungiana	[54]
69	Monoterpenoid	α-phellandrene	C10H16	136	P. flabellifolia P. anisum	[48] [57]
70	Monoterpenoid	β-phellandrene	C10H16	136	P. aurea P. puberula P. junoniae P. anisum	[36] [44] [58]
71	Monoterpenoid	Limonene	C10H16	136	P. aurea P. corymbosa P. puberula P. anisetum P. flabellifolia P. anisum P. enguezekensis P. affinis P. monoica	[36] [48] [57] [51] [52] [15]
72	Monoterpenoid	α-terpinene	C10H16	136	P. aurea P. puberula P. anisum P. monoica	[36] [50] [15]
73	Monoterpenoid	γ-terpinene	C10H16	136	P. aurea P. flabellifolia P. anisum P. enguezekensis P. monoica	[36] [48] [6] [51] [15]
74	Monoterpenoid	Terpinolene	C10H16	136	P. aurea P. junoniae P. anisum P. monoica	[36] [44] [58] [15]
75	Monoterpenoid	terpinen-4-ol	C10H18O	154	P. aurea P. junoniae P. flabellifolia P. anisum	[36] [44] [48] [57]
76	Monoterpenoid	α-terpineol	C10H18O	154	P. junoniae P. flabellifolia P. anisum P. monoica	[44] [48] [57] [15]
77	Monoterpenoid	trans-p-menth-2-en-1-ol	C10H18O	154	P. aurea	[36]
78	Monoterpenoid	cis-p-menth-2-en-1-ol	C10H18O	154	P. aurea	[36]
79	Monoterpenoid	trans-p-mentha-2,8-dien-1-ol	C10H16O	152	P. puberula P. flabellifolia	[36] [48]
80	Monoterpenoid	cis-p-mentha-2,8-dien-1-ol	C10H16O	152	P. puberula P. flabellifolia	[36] [48]
81	Monoterpenoid	p-mentha-1,8-dien-4-ol	C10H16O	152	P. aurea	[36]
82	Monoterpenoid	carvone	C10H14O	150	P. puberula P. anisum P. enguezekensis	[36] [6] [51]
83	Monoterpenoid	perilla aldehyde	C10H14O	150	P. puberula	[36]
84	Monoterpenoid	trans-carveol	C10H16O	152	P. puberula P. anisum	[36] [57]
85	Monoterpenoid	cis-carveol	C10H16O	152	P. anisum	[57]
86	Monoterpenoid	cis-1,2-limonene epoxide	C10H16O	152	P. puberula	[36]
87	Monoterpenoid	piperitone oxide	C10H16O2	168	P. thellungiana	[54]
88	Monoterpenoid	3-hydroxy-5,6-epoxy-7-megastigmen-9-one	C13H20O3	224	P. brachycarpa	[13]
89	Monoterpenoid	(1R,6R,9R)-6,9,11-trihydroxy-4-megastigmen-3-one	C13H20O4	240	P. brachycarpa	[13]
90	Monoterpenoid	grasshopper ketone	C13H20O3	224	P. brachycarpa	[13]
91	Monoterpenoid	loliolide	C11H16O3	196	P. brachycarpa	[13]
92	Monoterpenoid	sedanolide	C12H18O2	194	P. puberula	[36]
93	Monoterpenoid	δ-3-carene	C10H16	136	P. aurea P. corymbosa P. puberula P. anisum P. enguezekensis	[36] [59] [51]
94	Monoterpenoid	traginone	C12H18O	178	P. puberula	[36]
95	Monoterpenoid	bornyl acetate	C12H20O2	196	P. aurea P. puberula	[36]
96	Monoterpenoid	trans-β-damascenone	C13H18O	190	P. puberula	[36]
97	Monoterpenoid	cyclodecadiene	C10H16	136	P. diversifolia	[53]
98	Monoterpenoid	β-myrcene	C10H16	136	P. aurea P. corymbosa P. puberula P. anisetum P. flabellifolia P. anisum P. affinis P. monoica	[36] [48] [59] [52] [15]
99	Monoterpenoid	trans-β-ocimene	C10H16	136	P. aurea P. anisum P. monoica	[36] [58] [15]
100	Monoterpenoid	cis-β-ocimene	C10H16	136	P. anisum P. affinis P. monoica	[58] [52] [15]
101	Monoterpenoid	Linalool	C10H18O	154	P. junoniae P. flabellifolia P. anisum P. enguezekensis P. affinis P. diversifolia	[44] [48] [50] [51] [52] [53]
102	Monoterpenoid	sabinene	C10H16	136	P. aurea P. corymbosa P. puberula P. flabellifolia P. anisum P. monoica	[36] [48] [57] [15]
103	Monoterpenoid	trans-sabinene hydrate	C10H18O	154	P. aurea	[36]
104	Monoterpenoid	cis-sabinene hydrate	C10H18O	154	P. aurea	[36]
105	C12-sesquiterpenes	isogeijerene	C12H18	162	P. corymbosa P. puberula	[36]
106	C12-sesquiterpenes	isogeijerene C	C12H18	162	P. puberula	[36]
107	C12-sesquiterpenes	geijerene	C12H18	152	P. aurea P. corymbosa P. peregrina P. puberula P. anisetum P. anisum P. affinis P. khorasanica P. thellungiana	[36] [48] [50] [52] [19] [54]
108	C12-sesquiterpenes	pregeijerene	C12H18	162	P. corymbosa P. puberula P. affinis P. khorasanica	[36] [52] [19]
109	C12-sesquiterpenes	3,10-dihydro-1,4-dimethylazulene	C12H14	158	P. puberula	[36]
110	C12-sesquiterpenes	4,10-dihydro-1,4-dimethylazulene	C12H14	158	P. corymbosa	[36]
111	C12-sesquiterpenes	1,4-dimethylazulene	C12H12	156	P. corymbosa	[36]
112	C12-sesquiterpenes	8-epi-dictamnol	C12H18O	178	P. puberula	[36]
113	C12-sesquiterpenes	dictamnol	C12H18O	178	P. puberula P. affinis	[36] [52]
114	C12-sesquiterpenes	1α, 5α-dimethyl-4α, 10α-bicyclo [0,3,5] dec-8-en-5β-methoxy-1β-ol	C13H22O2	210	P. cappadocica	[16]
115	Sesquiterpenes	β-elemene	C15H24	204	P. aurea P. corymbosa P. anisum P. diversifolia	[36] [50] [53]
116	Sesquiterpenes	γ-elemene	C15H24	204	P. flabellifolia P. monoica	[48] [15]
117	Sesquiterpenes	δ-elemene	C15H24	204	P. corymbosa P. anisum P. enguezekensis P. affinis	[36] [50] [51] [52]
118	Sesquiterpenes	elemol	C15H26O	222	P. puberula	[36]
119	Sesquiterpenes	β-caryophyllene	C15H24	204	P. aurea P. corymbosa P. peregrina P. puberula P. anisetum P. anisum P. monoica P. diversifolia	[36] [48] [57] [15] [53]
120	Sesquiterpenes	9-epi-β-caryophyllene	C15H24	204	P. peregrina	[36]
121	Sesquiterpenes	isocaryophyllene	C15H24	204	P. peregrina	[36]
122	Sesquiterpenes	isocaryophyllene oxide	C15H24O	220	P. corymbosa P. peregrina	[36]
123	Sesquiterpenes	caryophyllene oxide	C15H24O	220	P. aurea P. corymbosa P. peregrina P. puberula P. monoica P. diversifolia P. thellungiana	[36] [15] [53] [54]
124	Sesquiterpenes	α-humulene	C15H24	204	P. corymbosa P. peregrine P. monoica P. diversifolia	[36] [15] [53]
125	Sesquiterpenes	caryophylladienol II	C15H24O	220	P. peregrine	[36]
126	Sesquiterpenes	caryophyllenol II	C15H24O	220	P. puberula	[36]
127	Sesquiterpenes	12-hydroxy-β-caryophylleneacetate	C17H26O2	262	P. aurea P. corymbosa	[36]
128	Sesquiterpenes	(2R*,6S*)-2,6-dihydroxyhumlaobtusa	C15H24O2	236	P. brachycarpa	[13]
129	Sesquiterpenes	α-cubebene	C15H24	204	P. corymbosa P. junoniae P. monoica	[36] [44] [15]
130	Sesquiterpenes	β-cubebene	C15H24	204	P. corymbosa P. junoniae P. affinis P. monoica P. diversifolia	[36] [44] [52] [15] [53]
131	Sesquiterpenes	γ-muurolene	C15H24	204	P. aurea P. corymbosa P. peregrine P. junoniae P. enguezekensis	[36] [44] [51]
132	Sesquiterpenes	α-cadinene	C15H24	204	P. corymbosa	[36]
133	Sesquiterpenes	δ-cadinene	C15H24	204	P. corymbosa P. anisetum P. anisum P. monoica P. diversifolia	[36] [48] [58] [15] [53]
134	Sesquiterpenes	γ-cadinene	C15H24	204	P. junoniae P. monoica	[44] [15]
135	Sesquiterpenes	α-amorphene	C15H24	204	P. aurea	[45]
136	Sesquiterpenes	cadina-1,4-diene	C15H24	204	P. corymbosa	[36]
137	Sesquiterpenes	1-epi-cubenol	C15H26O	222	P. corymbosa	[36]
138	Sesquiterpenes	cis-cadin-4-en-7-ol	C15H26O	222	P. aurea	[45]
139	Sesquiterpenes	T-cadinol	C15H26O	222	P. corymbosa	[36]
140	Sesquiterpenes	α-cadinol	C15H26O	222	P. corymbosa P. anisum	[36] [59]
141	Sesquiterpenes	T-muurolol	C15H26O	222	P. corymbosa	[36]
142	Sesquiterpenes	germacrene D	C15H24	204	P. aurea P. corymbosa P. peregrina P. puberula P. anisetum P. anisum P. enguezekensis P. affinis P. monoica P. thellungiana	[36] [48] [50] [51] [52] [15] [54]
143	Sesquiterpenes	α-calacorene	C15H20	200	P. corymbosa P. anisum P. monoica	[36] [58] [15]
144	Sesquiterpenes	4,11-selinadiene	C15H24	204	P. saxifraga	[46]
145	Sesquiterpenes	β-selinene	C15H24	204	P. saxifrage P. anisum	[46] [57]
146	Sesquiterpenes	α-selinene	C15H24	204	P. monoica	[15]
147	Sesquiterpenes	thujopsan-2-α-ol	C15H26O	222	P. aurea	[45]
148	Sesquiterpenes	Thujpsadiene	C15H22	202	P. saxifraga	[46]
149	Sesquiterpenes	cyclopropa[a]naphthalene	C15H24	204	P. diversifolia	[53]
150	Sesquiterpenes	7-epi-α-eudesmol	C15H26O	222	P. aurea	[45]
151	Sesquiterpenes	β-chamigrene	C15H24	204	P. anisum P. diversifolia	[57] [53]
152	Sesquiterpenes	(3S,7S,9S)-3,9-dihydroxygermacra-4(15),10(14),11(12)-triene	C15H24O2	236	P. brachycarpa	[13]
153	Sesquiterpenes	(3R,7S,9S)-3,9-dihydroxygermacra-4(15),10(14),11(12)-triene	C15H24O2	236	P. brachycarpa	[13]
154	Sesquiterpenes	(3R,7R,9R)-3,9-dihydroxygermacra-4(15),10(14),11(12)-triene	C15H24O2	236	P. brachycarpa	[13]
155	Sesquiterpenes	6β,14-epoxyeudesm-4(15)-en-1β-ol	C15H24O2	236	P. brachycarpa	[13]
156	Sesquiterpenes	6β-methoxyeudesm-4(15)-en-1β-ol	C16H28O2	252	P. brachycarpa	[13]
157	Sesquiterpenes	(7R*)-opposit-4(15)-ene-1β,7-diol	C16H28O	236	P. brachycarpa	[13]
158	Sesquiterpenes	7β-methoxy-4(14)-oppositen-1β-ol	C17H30O	250	P. brachycarpa	[13]
159	Sesquiterpenes	α-copaene-11-ol	C15H24O	220	P. corymbosa	[36]
160	Sesquiterpenes	α-ylangene	C15H24	204	P. anisetum P. anisum	[48] [58]
161	Sesquiterpenes	α-copaene	C15H24	204	P. aurea P. corymbosa P. peregrine P. junoniae P. anisum P. monoica P. thellungiana	[36] [44] [58] [15] [54]
162	Sesquiterpenes	trans-α-bergamotene	C15H24	204	P. peregrine P. junoniae P. anisum	[36] [44] [59]
163	Sesquiterpenes	cis-α-bergamotene	C15H24	204	P. peregrina	[36]
164	Sesquiterpenes	trans-β-bergamotene	C15H24	204	P. peregrina	[36]
165	Sesquiterpenes	trans-α-bergamotol	C15H24O	220	P. corymbosa	[36]
166	Sesquiterpenes	α-zingiberene	C15H24	204	P. corymbosa P. junoniae P. anisetum P. anisum P. enguezekensis P. khorasanica P. diversifolia	[36] [44] [48] [50] [51] [19] [53]
167	Sesquiterpenes	trans-α-bisabolene	C15H24	204	P. corymbosa	[36]
168	Sesquiterpenes	β-bisabolene	C15H24	204	P. corymbosa P. peregrina P. puberula P. junoniae P. aurea P. anisetum P. anisum P. enguezekensis P. khorasanica P. diversifolia P. thellungiana	[36] [44] [45] [48] [50] [51] [19] [53] [54]
169	Sesquiterpenes	β-sesquiphellandrene	C15H24	204	P. peregrine P. junoniae P. diversifolia P. thellungiana	[36] [44] [53] [54]
170	Sesquiterpenes	α-bisabolol	C15H26O	222	P. aurea P. corymbosa P. peregrine P. junoniae P. thellungiana	[36] [44] [54]
171	Sesquiterpenes	β-bisabolol	C15H26O	222	P. aurea	[45]
172	Sesquiterpenes	β-bisabolenol	C15H24O	220	P. aurea	[36]
173	Sesquiterpenes	xanthorrhizol	C15H22O	218	P. junoniae	[44]
174	Sesquiterpenes	α-curcumene	C15H22	202	P. junoniae P. anisum P. khorasanica P. thellungiana	[44] [57] [19] [54]
175	Sesquiterpenes	γ-curcumene	C15H24	202	P. thellungiana	[54]
176	Sesquiterpenes	dehydro aromadendrene	C15H22	204	P. monoica	[15]
177	Sesquiterpenes	aromadendrene	C15H24	204	P. anisetum P. diversifolia	[48] [53]
178	Sesquiterpenes	spathulenol	C15H24O	220	P. corymbosa P. junoniae P. aurea P. anisetum P. thellungiana	[36] [44] [45] [48] [54]
179	Sesquiterpenes	isospathulenol	C15H24O	220	P. thellungiana	[54]
180	Sesquiterpenes	β-gurjunene	C15H24	204	P. junoniae	[44]
181	Sesquiterpenes	bicyclogermacrene	C15H24	204	P. aurea P. corymbosa P. peregrina P. flabellifolia	[36] [48]
182	Sesquiterpenes	α-guaiene	C15H24	204	P. diversifolia	[54]
183	Sesquiterpenes	cis-β-guaiene	C15H24	204	P. junoniae	[44]
184	Sesquiterpenes	trans-β-guaiene	C15H24	204	P. junoniae	[44]
185	Sesquiterpenes	4,6-guaiadiene	C15H22	202	P. corymbosa P. peregrina	[36]
186	Sesquiterpenes	salvial-4(14)-en-1-one	C15H24O	220	P. thellungiana	[54]
187	Sesquiterpenes	clavukerin B	C12H16	160	P. corymbosa	[36]
188	Sesquiterpenes	kessane	C15H26O	222	P. aurea	[36]
189	Sesquiterpenes	α-cedrene	C15H24	204	P. monoica P. diversifolia	[15] [53]
190	Sesquiterpenes	2-epi-α-funebrene	C15H24	204	P. monoica	[15]
191	Sesquiterpenes	diepi-α-cedrene	C16H28	220	P. anisum	[50]
192	Sesquiterpenes	daucene	C15H24	204	P. monoica	[15]
193	Sesquiterpenes	α-himachalene	C15H24	204	P. corymbosa P. anisum P. enguezekensis	[36] [50] [51]
194	Sesquiterpenes	β-himachalene	C15H24	204	P. anisum	[50]
195	Sesquiterpenes	γ-himachalene	C15H24	204	P. corymbosa P. anisetum P. anisum	[36] [48] [50]
196	Sesquiterpenes	himachalol	C15H26O	222	P. corymbosa P. peregrina P. aurea	[36] [45]
197	Sesquiterpenes	α-longipinene	C15H24	204	P. anisum P. thellungiana	[58] [54]
198	Sesquiterpenes	guaioxide	C15H26O	222	P. aurea	[36]
199	Sesquiterpenes	humulene epoxide II	C15H24O	220	P. peregrina	[36]
200	Sesquiterpenes	epi-cubebol	C15H24O	220	P. corymbosa	[36]
201	Sesquiterpenes	bicycloelemene	C15H24	204	P. aurea P. corymbosa	[36]
202	Sesquiterpenes	isofuranogermacrene	C15H20O	204	P. diversifolia	[53]
203	Sesquiterpenes	β-bourbonene	C15H24	204	P. corymbosa P. junoniae P. anisum	[36] [44] [58]
204	Sesquiterpenes	dehydrocostus lactone	C15H18O2	230	P. puberula	[36]
205	Sesquiterpenes	Pimpinelol	C15H20O5	280	P. haussknechtii	[10]
206	Sesquiterpenes	trans-β-farnesene	C15H24	204	P. peregrine P. junoniae P. khorasanica P. diversifolia	[36] [44] [19] [53]
207	Sesquiterpenes	cis-β-farnesene	C15H24	204	P. aurea P. corymbosa P. peregrine P. thellungiana	[36] [54]
208	Sesquiterpenes	cis, cis-farnesol	C15H26O	222	P. junoniae	[44]
209	Sesquiterpenes	trans, trans-farnesol	C15H26O	222	P. junoniae	[44]
210	Sesquiterpenes	sinensal	C15H22O	218	P. peregrina	[36]
211	Sesquiterpenes	nerolidol	C15H26O	222	P. anisum P. diversifolia	[59] [53]
212	Sesquiterpenes	cis,trans-α-farnesene	C15H24	204	P. thellungiana	[54]
213	Triterpenoids	ursolic acid	C30H48O3	456	P. anisum	[56]
214	Triterpenoids	oleanolic acid	C30H48O3	456	P. anisum	[56]
215	Triterpenoids	betulinic acid	C30H48O3	456	P. anisum	[56]
216	Triterpenoids	lupeol	C30H50O	426	P. anisum	[56]
217	Triterpenoids	α-amyrin	C30H50O	426	P. anisum	[55]
218	Triterpenoids	β-amyrin	C30H50O	426	P. anisum	[55]
219	Triterpenoids	saikogenin F-3-O-{β-D- glucopyranosyl-(1→2)-[β-D-xylopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)]-β-D-fucopyranoside}	C53H86O22	1075	P. rhodantha	[17]

).

3.3. Flavonoids and Their Glycosides

Flavonoids are the focused topic of natural product excavation currently, and the majority of flavonoids in Pimpinella plants exhibited satisfactory antioxidant power in accordance with previous studies. Moreover, flavonoids showed more diversified bioactivities related to different functional groups, including phenolic hydroxyl, glycoside, and isopentyl. So far, more than 36 flavonoids have been isolated from this genus.

A series of investigations focused on the chemical compositions of TCM’s P. thellungiana in the past 40 years identified eight flavonoid glycosides (220–227) [60,61,62,63,64]. X. Chang [49] and J. Lu [12] systematically conducted the componential survey on P. candolleana and P. brachycarpa, respectively, and isovitexin (228), quercetin-3-O-rhamnoside (229), luteolin (244), and 1-hydroxy-2, 3, 5-trimethoxy xathone (255) were isolated. H. Ozbek et al. [16,17] obtained a series of flavonoid glycosides (230–239, 251–252) with preferable antioxidant activity from Turkish P. cappadocica and P. rhodantha during in 2015–2016, including one novel β-hydroxy dihydro chalcone glycoside structure, ziganin (251) and three first-discovered acylated-flavonol glycosides, erzurumin (236), ilicanin (237), and quercetin-3′-methylether-3-O-α-L-(2″,3″-di-O-trans-coumaroyl)rhamnopyranoside (238), which enriched the flavonoid library of the Pimpinella genus. In 2020, the phytochemical profile of another traditional medicinal plant in Turkey, P. anthriscoides, was characterized by G. Zengin, et al. and four unique flavonoids, luteolin-7-O-glucoside (240), chrysoeriol-7-O-glucoside (241), diosmetin-7-O-rutinoside (242), and chrysoeriol (243), were identified [65]. A 2021 reporton analysis of P. anisum seed revealed the presence of eight flavonoids, including myricetin (245), quercetin (246), apigenin (247), kaempferol (248), chrysin (249), galangin (250), naringenin (253), and epigenin (254) [66] (Figure 5,

Table 4. Flavonoids and their glycosides of Pimpinella plants.

No.	Name	Formula	Mol. Wt.	Species	Reference
220	apigenin-7-O-glucoside	C21H20O10	432	P. thellungiana	[60]
221	apigenin-7-O-β-D-butylglucuronide	C25H26O10	502	P. thellungiana	[60]
222	apigenin-7-O-methylglucuronide	C20H22O11	460	P. thellungiana	[61]
223	luteolin-7-O-methylglucuronide	C22H20O12	476	P. thellungiana	[61]
224	apigenin-7-O-glucuronide	C21H18O11	446	P. thellungiana	[62]
225	luteolin-7-O-glucuronide	C21H18O12	462	P. thellungiana	[62]
226	schaftoside	C26H28O14	564	P. thellungiana	[63]
227	quercetin-3-O-glucuronide	C21H18O13	478	P. thellungiana	[64]
228	isovitexin	C21H20O10	432	P. candolleana	[49]
229	quercetin-3-O-rhamnoside	C21H20O11	448	P. brachycarpa	[12]
230	kaempferol-3-O-rhamnoside	C22H22O10	446	P. cappadocica	[16]
231	quercetin-3-O-galactoside	C21H20O12	464	P. cappadocica	[16]
232	kaempferol-3-O-(2″-O-glucopyranosyl)-galactoside	C27H30O16	610	P. cappadocica	[16]
233	quercetin-3-O-glucoside	C21H20O12	464	P. cappadocica	[16]
234	rhamnositrin-3-O-(2″-O-glucopyranosyl)-galactoside	C28H30O18	624	P. cappadocica	[16]
235	quercetin-3-O-(2″-O-glucopyranosyl)-galactoside	C27H30O17	626	P. cappadocica	[16]
236	kaempferol-3-O-(2″-O-β-D-glucopyranosyl-6″-O-caffeoyl)-β-D-galactopyranoside (erzurumin)	C36H36O19	772	P. cappadocica	[16]
237	quercetin-3-O-(2″-O-β-D-glucopyranosyl-6″-O-caffeoyl)-β-D-galactopyranoside (ilicanin)	C36H36O20	788	P. cappadocica	[16]
238	quercetin-3′-methylether-3-O-α-L-(2″,3″-di-O-trans-coumaroyl)-rhamnopyranoside	C40H34O15	754	P. rhodantha	[17]
239	quercetin-3-O-α-L-(2″,3″-di-O-trans-coumaroyl)-rhamnopyranoside	C39H34O13	740	P. rhodantha	[17]
240	luteolin-7-O-glucoside	C21H20O11	302	P. anthriscoides	[65]
241	chrysoeriol-7-O-glucoside	C22H22O11	462	P. anthriscoides	[65]
242	diosmetin-7-O-rutinoside	C28H32O15	608	P. anthriscoides	[65]
243	chrysoeriol	C16H12O6	300	P. anthriscoides	[65]
244	luteolin	C15H10O6	286	P. candolleana	[49]
245	myricetin	C15H10O8	318	P. anisum	[66]
246	quercetin	C15H10O7	302	P. anisum	[66]
247	apigenin	C15H10O5	270	P. anisum	[66]
248	kaempferol	C15H10O6	286	P. anisum	[66]
249	chrysin	C15H10O4	254	P. anisum	[66]
250	galangin	C15H10O5	270	P. anisum	[66]
251	(βR)-β, 3, 4, 2′, 6′ -pentahydroxy-4′-O-β-D-glucosyldihydrochalcone (ziganin)	C21H24O12	468	P. rhodantha	[17]
252	3-hydroxy-p-phlorizin	C21H24O11	452	P. rhodantha	[17]
253	naringenin	C15H12O5	272	P. anisum	[66]
254	pinocembrin	C15H12O4	256	P. anisum	[66]
255	1-hydroxy-2, 3, 5-trimethoxyxathone	C16H14O6	302	P. candolleana	[49]

).

3.4. Coumarins

Coumarins are widely distributed in Umbelliferae, Rutaceae, Asteraceae, Leguminosae, and Solanaceae, and 25 coumarins have been found in the Pimpinella genus in phytochemical relevant studies. The domestic scholar B. L. Qiao et al. [67], separated five components from the ethyl acetate extract of P. thellungiana, which were identified as coumarins after structural identification, bergapten (256), marmesin (257), scoparone (258), scopoletin (259), and isofraxidin (260). Subsequently, P. Pradhan and his team weresurprised to find a novel skeleton of natural furanthochromone dimers or oligomers, including visnagin (261), pimolin (262), visnagintrimer (263), visnagin tetramer (264), visnagin pentamer (265), and khellin (266), from chloroform extract of seeds in P. monoica [68,69]. Additionally, the phytochemical profile of P. anthriscoides was characterized and aegelinol (267), psoralen (268), imperatorin (269), is oimperator in (270), 3-(1,1-dimethylallyl)herniarin (271), peucedanin (272), and xanthyletin (273) were identified [65]. Some investigations [70,71,72,73] found that abundant linear coumarins (274–280) existed in the root and seed extract of P. anisum, among which isopimpinellin (274) and methoxsalen (275) were associated with the inhibitory activity of the cytochrome P450 1A2 isozyme in healthy adults. In addition, umbelliprenin (276) was proven to be an original skin-whitening agent (Figure 6,

Table 5. Species of Pimpinella plants.

No.	Name	Formula	Mol. Wt.	Species	Reference
256	bergapten	C12H8O4	216	P. thellungiana	[67]
257	marmesin	C14H4O4	246	P. thellungiana	[67]
258	scoparone	C11H10O4	206	P. thellungiana	[67]
259	scopoletin	C10H8O4	192	P. thellungiana	[67]
260	isofraxidin	C11H10O5	222	P. thellungiana	[67]
261	visnagin	C13H10O4	230	P. monoica	[69]
262	pimolin	C26H20O8	460	P. monoica	[68]
263	visnagintrimer	C39H30O12	690	P. monoica	[69]
264	visnagin tetramer	C52H40O16	920	P. monoica	[69]
265	visnagin pentamer	C65H50O20	1150	P. monoica	[69]
266	khellin	C14H12O5	260	P. monoica	[69]
267	aegelinol	C14H14O4	246	P. anthriscoides	[65]
268	psoralen	C11H6O3	186	P. anthriscoides	[65]
269	imperatorin	C16H14O4	270	P. anthriscoides	[65]
270	isoimperatorin	C16H14O4	270	P. anthriscoides	[65]
271	3-(1, 1-dimethylallyl) herniarin	C15H16O3	228	P. anthriscoides	[65]
272	peucedanin	C15H14O4	258	P. anthriscoides	[65]
273	xanthyletin	C14H12O3	228	P. anthriscoides P. anthriscoides	[65] [65]
274	isopimpinellin	C13H10O5	246	P. anisum	[70]
275	methoxsalen	C12H8O4	216	P. anisum	[70]
276	umbelliprenin	C24H30O3	366	P. anisum	[71]
277	7-. prenyloxycoumarin	C14H14O3	230	P. anisum	[72]
278	auraptene	C19H22O3	298	P. anisum	[72]
279	umbelliferone	C9H6O3	162	P. anisum	[72]
280	pimpinellin	C13H10O5	246	P. anisum	[73]

).

3.5. Sterols

Phytosterols are nutritional compounds from Pimpinella plants equipped with capabilities of cholesterol-reducing, blood pressure-lowering, and anti-inflammatory properties. Surprisingly, the variety and activity of sterols in P. anisum are research worthy. R. K. Saini, et al. acquired phytosterol profiling of P. anisum seeds by GC-MS measure [74]. It was surveyed that the total sterol content in seeds oil was 551.9 mg/100 g, and five sterols were identified, including the dominant ingredient α-spinasterol (282) (109 mg/100 g oil; 19.9% of the total sterols), campesterol (281), stigmasta-5,7,22-trien-3-ol (283), Δ7-avenasterol (284), and Δ5-avenasterol(285). Consistent with Saini’s results, S. Balbino, I. B. Rebey and M. Kozlowska, et al. [58,75,76] isolated affluent phytosterol compounds, i.e., Δ7-stigmastenol (286), Δ5, 23-stigmastadienol (287), Δ7-campesterol (288), sitostanol (289), cycloartenol (290), and 24-methylenecycloartenol (291) from P. anisum, recommending it as a natural source of salutary phytosterols. Furthermore, b-sitosterol (292) and g-sitosterol (293) were isolated from P. thellungiana and exhibited hypotensive activity [41]. Stigmasta-5, 22-dien-3-olacetate (294), daucosterol (295), and stigmasterol (296) were uncovered in P. candolleana, which displayed effective antioxidant and α-glucosidase inhibitory [49,75]. 24ζ-Methyl-5R-lanosta-25-one (297) and pregnenolone (298) provided an antioxidant property derived from P. brachycarpa [76] (Figure 7,

Table 6. Sterols of Pimpinella plants.

No.	Name	Formula	Mol. Wt.	Species	Reference
281	campesterol	C28H48O	400	P. anisum	[74]
282	α-spinasterol	C29H48O	412	P. anisum	[74]
283	stigmasta-5,7,22-trien-3-ol	C29H46O	410	P. anisum	[74]
284	Δ7-avenasterol	C29H48O	412	P. anisum	[74]
285	Δ5-avenasterol	C29H48O	412	P. anisum	[74]
286	Δ7-stigmastenol	C29H50O	414	P. anisum	[55]
287	Δ5,23-stigmastadienol	C29H48O	412	P. anisum	[55]
288	Δ7-campesterol	C28H48O	400	P. anisum	[77]
289	sitostanol	C29H52O	416	P. anisum	[77]
290	cycloartenol	C30H50O	426	P. anisum	[78]
291	24-methylenecycloartenol	C31H52O	440	P. anisum	[78]
292	b-sitosterol	C30H52O	428	P. thellungiana P. candolleana P. brachycarpa	[41] [75] [76]
293	g-sitosterol	C29H50O	414	P. thellungiana	[41]
294	stigmasta-5, 22-dien-3-olacetate	C31H50O2	454	P. candolleana	[49]
295	daucosterol	C35H60O6	576	P. candolleana	[49]
296	stigmasterol	C29H48O	412	P. candolleana	[75]
297	24ζ-methyl-5R-lanosta-25-one	C30H52O	428	P. brachycarpa	[76]
298	pregnenolone	C21H32O2	316	P. brachycarpa	[76]

).

3.6. Organic Acids

Organic acids are widely distributed in leaves, roots, and fruits, and as aromatic plants, organic acid is a crucial element of volatile oil in the Pimpinella genus. Its structural types included aliphatic polycarboxylic acid, aromatic benzoic, and caffeic acid with anti-inflammatory and antioxidant biological properties. Six reports [34,42,63,79,80,81] were performed by chemical separation, HPLC fingerprint characterization, and UHPLC-Q-Orbitrap HRMS rapid identification, and a total of 17 organic acids (299–315) were identified from P. thellungiana with abundant quinic acid derivatives. In other reports, five new quinic acid derivatives, 1-O-trans-caffeoyl-5-O-trans-coumaroylquinicacid (316), 1-O-trans-caffeoyl-5-O-7,8-dihydro-7α-methoxy caffeoy lquinic acid (317), 1-O-7,8-dihydro-7α-methoxycaffeoyl-5-O-trans-caffeoylquinic acid (318), 1,5-di-O-cis-coumaroylquinic acid (319), and 1,5-O-trans-dicaffeoylquinic acid (320), together with 10 known quinic acid derivatives (306–310, 313, and 321–324) with anti-neuroinflammatory activity, were isolated from the methanol extract of P. brachycarpa [82]. A. Topcagic, et al. identified 12 phenolic acids (325–336) from P. anisum during the analysis of volatile oil [66]. Moreover, 3-phenyllactic acid (337) and citric acid (338)were obtained from P. anthriscoides and had a proven antioxidant and inhibiting α-amylase, α-glucosidase, AChE, and BChE effect [65]. Long-chain fatty acids, tetradecanoic acid (339), linoleic acid (340), and stearic acid (341) were isolated from the volatile oil of P. diversifolia leaves [53], while dodecanoic acid (342) and pentadecanoic acid (343) were identified from P. aurea oil [36] (Figure 8,

Table 7. Organic acids of Pimpinella plants.

No.	Name	Formula	Mol. Wt.	Species	Reference
299	oleic acid	C18H34O2	282	P. thellungiana	[42]
300	palmitic acid	C16H32O2	256	P. thellungiana P. aurea	[42] [36]
301	2-methylbutanoic acid	C5H10O2	102	P. thellungiana	[34]
302	shikimic acid	C7H10O5	174	P. thellungiana	[79]
303	3,4-dihydroxybenzoic acid	C7H6O4	154	P. thellungiana P. aurea	[34] [36]
304	gallic acid	C7H6O5	170	P. thellungiana P. aurea	[80] [36]
305	3-O-trans-caffeoylquinic acid	C16H18O9	354	P. thellungiana	[63]
306	5-O-trans-caffeoylquinic acid	C16H18O9	354	P. thellungiana P. brachycarpa	[63] [82]
307	4-O-trans-caffeoylquinic acid	C16H18O9	354	P. thellungiana P. brachycarpa	[63] [82]
308	3,5-O-trans-dicaffeoylquinic acid	C25H24O12	516	P. thellungiana P. brachycarpa	[63] [82]
309	3,4-O-trans-dicaffeoylquinic acid	C25H24O12	516	P. thellungiana P. brachycarpa	[63] [82]
310	4,5-O-trans-dicaffeoylquinic acid	C25H24O12	516	P. thellungiana P. brachycarpa	[63] [82]
311	4-O-feruloylquinic acid	C17H20O9	368	P. thellungiana	[81]
312	1-O-feruloylquinic acid	C17H20O9	368	P. thellungiana	[81]
313	5-O-trans-coumaroylquinic acid	C16H18O8	338	P. thellungiana P. brachycarpa	[81] [82]
314	3-O-trans-caffeoyl-5-feruloylquinic acid	C26H26O12	530	P. thellungiana	[81]
315	4-O-trans-caffeoyl-5-feruloylquinic acid	C26H26O12	530	P. thellungiana	[81]
316	1-O-trans-caffeoyl-5-O-trans-coumaroylquinicacid.	C25H24O11	500	P. brachycarpa	[82]
317	1-O-trans-caffeoyl-5-O-7, 8-dihydro-7α-methoxycaffeoylquinic acid	C26H28O13	548	P. brachycarpa	[82]
318	1-O-7, 8-dihydro-7α-methoxycaffeoyl-5-O-trans-caffeoylquinic acid	C26H28O13	548	P. brachycarpa	[82]
319	1-O-trans-coumaroyl-5-O-cis-coumaroylquinic acid	C25H24O10	484	P. brachycarpa	[82]
320	1,5-di-O-cis-coumaroylquinic acid	C25H24O10	484	P. brachycarpa	[82]
321	1,5-O-trans-dicaffeoylquinic acid	C25H24O12	516	P. brachycarpa	[82]
322	5-O-cis-caffeoylquinic acid	C16H18O9	354	P. brachycarpa	[82]
323	4-O-trans-coumaroylquinic acid	C16H18O8	338	P. brachycarpa	[82]
324	5-O-cis-coumaroylquinic acid	C16H18O8	338	P. brachycarpa	[82]
325	5-hydroxyferulic acid	C10H10O5	210	P. anisum	[66]
326	ferulic acid	C10H10O4	196	P. anisum	[66]
327	sinapinic acid	C11H12O5	224	P. anisum	[66]
328	caffeic acid	C9H8O4	180	P. anisum	[66]
329	p-coumaric acid	C9H8O3	164	P. anisum	[66]
330	trans-cinnamic acid	C9H8O2	148	P. anisum	[66]
331	rosmarinic acid	C18H16O8	360	P. anisum	[66]
332	3-hydroxybenzoic acid	C7H6O3	138	P. anisum	[66]
333	salicylic acid	C7H6O3	138	P. anisum	[66]
334	4-hydroxybenzoic acid	C7H6O3	138	P. anisum	[66]
335	vanillic acid	C8H8O4	168	P. anisum	[66]
336	syringic acid	C9H10O5	198	P. anisum	[66]
337	3-phenyllactic acid	C9H10O3	166	P. anthriscoides	[65]
338	citric acid	C6H8O7	192	P. anthriscoides	[65]
339	tetradecanoic acid	C14H28O2	228	P. diversifolia	[53]
340	linoleic acid	C18H32O2	280	P. diversifolia	[53]
341	stearic acid	C18H36O2	284	P. diversifolia	[53]
342	dodecanoic acid	C12H24O2	200	P. aurea	[36]
343	pentadecanoic acid	C15H30O2	242	P. aurea	[36]

).

4. Pharmacology

Since the beginning of this century, due to the extensive use of the genus Pimpinella in traditional medicine, numerous scientific studies have demonstrated several ethnopharmacological properties from its extracts or compounds, including antibacterial, anti-inflammatory, insecticidal, antioxidant, and inhibitory enzyme activities [83]. In addition, some novel pharmacological activities such as antitumor, antidepressant, blood pressure lowering, hypoglycemic, and liver protection have been gradually exploited recently. In our review, the effect of the Pimpinella species during the recent 8 years (2015–2022) was summarized, and specific pharmacological studies were discussed in the following paragraphs, as presumptively presented in

Table 8. The pharmaceutical effects of Pimpinella species.

Pharmaceutical Activity	Part	Extract/ Compound	Experimental Model	Species	Reference
Antioxidant	Seed	Essential oil (in vivo)	Favism rats	P. anisum	[7]
	Seed	Ethanol extract (in vivo)	GN induced nephrotoxicity in rats	P. anisum	[84]
	Seed	Essential oil	DPPH radical scavenging activity	P. anisum	[50] [85] [86]
	Seed	Nanostructuredessential oil	DPPH and ABTS scavenging activity	P. anisum	[87]
	Seed	Water extract	DPPH and ABTS scavenging activity; FRAP	P. anisum	[56]
	Seed	N-hexane extract	DPPH and ABTS scavenging activity; FRAP and β-carotene bleaching tests	P. anisum	[11]
	Seed	Polysaccharide	DPPH radical scavenging activity	P. anisum	[9]
	Seed	Fatty acids and phenolic compounds	DPPH and ABTS scavenging activity	P. anisum	[66] [78]
	Aerial part	Flavonoid glycosides (230–237)	DPPH radical scavenging activity; FRAP	P. cappadocica	[16]
	Aerial part	Flavonoid glycosides (238–239)	DPPH radical scavenging activity; FRAP	P. rhodantha	[17]
	Fruit	Essential oil	DPPH radical scavenging activity; β-carotene bleaching inhibition	P. enguezekensis	[51]
	Aerial part	Essential oil	DPPH and ABTS scavenging activity; phosphomolybdenum and FRAP	P. anthriscoides	[65]
	Aerial part	Ethyl acetate extract	DPPH scavenging activity (IC50 = 53.07µg/mL)	P. alpina	[88]
	Aerial part	Ethyl acetate extract	DPPH radical scavenging activity (IC50 = 74.9 µg/mL)	P. affinis	[89]
	Seed	3% essential oil	DPPH radical scavenging activity (IC50 =6.81 µg/mL), β-carotene bleaching inhibition (IC50 = 206 µg/mL), FRAP (EC50 =35.20 µg/mL)	P. saxifraga	[46] [90]
Antibacterial	Seed	Polysaccharide	E. coli, P. aeruginosa, B. cerus, and S. aureus (50 mg/mL)	P. anisum	[9]
	Fruit	Essential oil	P. aeruginosa	P. anisum	[90]
	Seed	Essential oil	P. aeruginosa	P. anisum	[8]
	Seed	Essential oil	S. aureus and E. coli biofilms	P. anisum	[91]
	Seed	Essential oil	E. coli, P. aeruginosa, K. pneumonia, S. epidermidis, E. faecalis, S. pyogenes, B.cerus and S. aureus	P. anisum	[92]
	Seed	Essential oil	E amylovora with MIC of 31.25 μg/ml	P. anisum	[93]
	Seed	Oil-based hydrogel	C. albicans, C.glabrata and C. Parapsilosis.	P. anisum	[94]
	Aerial part	Essential oil	F.solani, S.brevicaulis, A spp., A. fumigatus and F. oxysporum (MIC = 50–490 μg/mL)	P. anisum	[95]
	Seed	Combination oil with terbinafine	T. rubrum and T. mentagrophytes	P. anisum	[96]
	Seed	Essential oils	T. rubrum	P. anisum	[97]
	Seed	Essential oil	A. niger, A. oryzae, M. pusillus and F. oxysporum	P. anisum	[98]
	Seed	Essential oil	C. perfringens with MIC of 10 μg/ml	P. anisum	[99]
	Seed	Essential oil	A. niger, A. oryzae, and A. ochraceus	P. anisum	[100]
	Seed	Essential oil	A. carbonarius	P. anisum	[101]
	Seed	Oil-based PLA films	L. monocytogenes and V. parahaemolyticus	P. anisum	[102]
	Seed	Nanostructured oil	Y. enterocolitica, B. cereus, E. coli, and L. monocytogenes	P. anisum	[103] [104]
	Seed	Nanostructured oil	14 food infesting fungi: A. sydowii, A. repens, A. fumigatus, A. niger, A. candidus, A. luchuensis, F. oxysporum, C. herbarum, F. poae, M. sterilia, C. lunata, A. humicola and A. alternata at its MIC dose (0.08–0.5μL/mL)	P. anisum	[105]
	Seed	Nanostructured oil	S. aureus, E. coli, C. albicans, and A. niger	P. anisum	[87]
	Seed	Essential oil	S. aureus and E. coli	P. alpine	[88]
	Aerialpart	Essential oil	B.cereus, S. typhimurium, M. luteus	P. saxifraga	[46]
	Fruit	Essential oil	A. lwoffii, E. coli, K. pneumonia, B. cereus, C. perfringens, S. pneumonia, C. krusei and C. albicans (MIC: 5–75 mg/mL)	P. enguezekensis	[51]
	Aerial part	Essential oil	S. parasitica (MIC: 2 μg/mL, MFC: 4 μg/mL)	P. affinis	[52]
	Aerial part	Essential oil	S. aureus, L. monocytogenes, B. cereus, S. typhimurium, P. aeruginosa, E. cloacae, E. coli, A. fumigatus, A. ochraceus, A. niger, A. versicolor, T. viride, P. funiculosum, P. ochrochloron, and P. verrucosum	P. anthriscoides	[65]
Anti-inflammatory activity	Seed	Combination oil with terbinafine	LPS stimulated neutrophils	P. anisum	[96]
	Fruit	Anethole (40)	Croton oil-induced ear edema and carrageenan-induced pleurisy model	P. anisum	[106]
	Fruit	0.3% essential oil	LPS-treated HBEpC and HTEpC cells	P. anisum	[107]
	Fruit	Anethole (40)	PM2.5 induced BEAS-2B and HepG2	P. anisum	[108]
	Seed	BLAB tea	Oval bumin-induced allergic rhinitis model mice	P. anisum	[109]
	Seed	Polysaccharide	Model of foot swelling induced by carrageenan in mice	P. anisum	[9]
Antitumor activity	Seed	Essential oil	Cytotoxicity against Hep G2 cells	P. anisum	[110]
	Seed	Agnps containing aqueous extract	Cytotoxicity against human neonatal skin stromal cells and HT115 cells	P. anisum	[111]
	Seed	Agnps containing aqueous extract	Cytotoxicity against colorectal cancer cell lines	P. anisum	[112]
	Fruit	Pimpinelol (205)	Cytotoxicity against MCF-7 cell, IC50: 1.06 μM	P. haussknechtii	[10]
Hypoglycemic activity	Seed	Aqueous extract	Inhibitory activity against α-amylase and α-glucosidase, (IC50=692.6±5.2 and 73.9±2.2 μg/mL)	P. anisum	[11]
	Seed	Aqueous extract	Against pancreatic damage in STZ-induced diabetic rats	P. anisum	[113]
	Seed	Methanolic extract	Wound healing activity in STZ-induced diabetic rats	P. anisum	[114]
Hypotensive activity	Herb	Ethyl acetate and ethanol extract	Inhibition effect on angiotensin-converting enzyme (0.5–10mg/mL)	P. brachycarpa	[115]
	Seed	Aqueous extract	Calcium channel antagonist	P. anisum	[116]
Insecticidal activity	Seed	Essential oil	Insecticidal effect against C. quinquefasciatus (LC50 = 25.4 μL/L) and S. littoralis (LD50 = 57.3 μg/larva)	P. anisum	[117]
	Seed	Essential oil	Insecticidal effect against L. dispar	P. anisum	[118]
	Seed	Essential oil	Insecticidal effect against P.truncatus and T. granarium	P. anisum	[119]
	Seed	Essential oil	Insecticidal effect against L. decemlineata	P. anisum	[120]
	Seed	Essential oil	Insecticidal effect against B. aeneus	P. anisum	[121]
	Seed	Essential oil	Insecticidal effect against T. castaneum and P. interpunctella	P. anisum	[122]
	Seed	Essential oil	Insecticidal effect against M. incognita	P. anisum	[123]
	Seed	Essential oil	Insecticidal effect against aphids	P. anisum	[124]
	Seed	Essential oil	Insecticidal effect against Ipstypographu	P. anisum	[125]
	Seed	Essential oil	Insecticidal effect against P. citri	P. anisum	[126]
	Seed	Essential oil	Insecticidal effect against A. obtectus	P. anisum	[127]
	Seed	Essential oil	Acaricidal and reduce AchEin two-spotted spider mite	P. anisum	[86]
	Seed	Essential oil nano-emulsions	Insecticidal effect against S. oryzae and T. castaneum	P. anisum	[128]
	Seed	Essential oil nano-emulsions	Insecticidal effect against B. oleae	P. anisum	[129]
	Seed	Essential oil nano-emulsions	Insecticidal effect against M. persicae	P. anisum	[130]
	Seed	Essential oil nano-emulsions	Insecticidal effect against T. confusum	P. anisum	[131]
	Seed	Essential oil nano-emulsions	Insecticidal effect against T. castaneum	P. anisum	[132] [133]
	Seed	Essential oil	Insecticidal effect against Aedes aegypti	P. anisum	[134]
	Seed	Essential oil	Insecticidal effect against Musca domestica	P. anisum	[135]
	Seed	Essential oil	Insecticidal effect against Ixodes ricinus	P. anisum	[136]
	Seed	Essential oil	Insecticidal effect against Trypanosoma brucei	P. anisum	[46]
	Seed	Essential oil	Insecticidal effect against Culexquinquefasciatus	P. anisum	[137] [138]
	Seed	P-anisaldehyde (47)	Insecticidal effect against horn fly, H.irritansirritans	P. anisum	[139]
	Seed	P-anisaldehyde (47)	Insecticidal effect against lone star tick, A. americanum	P. anisum	[140]
	Seed	Essential oil-loaded zein nanocapsules	Insecticidal effect against mosquito	P. anisum	[141]
Enzymes inhibitory activity	Aerial part	95% ethanol extract	Inhibitory effects on CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes	P. brachycarpa	[142]
	Aerial part	Essential oil	Tyrosinase, α-amylase, α-glucosidase, AChE and BChE	P. anthriscoides	[65]
	Seed	Water extract	Inhibitory effects on GSTA1–1(IC50 = 3.40 ± 0.83μg/mL)	P. anisum	[143]
	Seed	Essential oil	Inhibitory effects on xanthine oxidase (IC50 = 2.37 ± 0.23 μg/mL)	P. anisum	[144]
	Seed	Ethanol extract	Selective modulators of RALDHs	P. anisum	[145]
	Root	Bergapten (256) isopimpinellin (274) methoxsalen (275)	Inhibitory effects on CYP 1A2	P. anisum	[70]
	Seed	Phenolic extract	Inhibitory effects on AChE and BChE (IC50 = 0.07 and 0.34 μg/mL)	P. anisum	[56] [66]
Anti depressant activity	Seed	70% ethanol total extract (100 mg/kg)	Antidepressant and anxiolytic effects on Swiss Albino mice	P. anisum	[145]
	Seed	Essential oil	Memory impairment, anxiety, and depression in scopolamine-induced rats	P. peregrina	[18]
	Seed	Essential oil	Inhibition of brain cerebral cortex and hippocampus inflammation	P. anisum	[146]
	Seed	Essential oil	Inhibition of brain cerebral cortex and hippocampus antioxidant effects	P. anisum	[147]
	Herb	Extract	Clinical treatment of depression in patients with IBS	P. anisum	[148]
Uterine relaxant activity	Seed	50%hidroalcoholic extract	Uterine contraction induced by oxytocin, Bay K8644, carbachol, or generated spontaneously	P. anisum	[140]
Wound healing effect	Seed	Polysaccharide	Reparation of laser burn wounds in mice	P. anisum	[9]
Migraine headache	Herb	Essential oil	Clinical treatment of migraine	P. anisum	[141]
Premenstrual syndrome	Herb	Extract	Clinical treatment of premenstrual syndrome	P. anisum	[142]
Skin whitening effect	Herb	Umbelliprenin (276)	Melan-a cells of mice	P. anisum	[71]

(Figure 9).

4.1. Antioxidant Activity

Plant-derived compounds have promising antioxidant activities (1–2). Within the past eight years, twenty studies have revealed the antioxidant properties in Pimpinella species, concentrating on P. anisum (60% of all studies). Seeds (70%) and aboveground parts (25%) were considered to be admirable candidates as antioxidants, and aromatics and flavonoids were identified as the dominant components. Experiments were divided into two categories: in vivo level and in vitro level. In vitro activity screening was a rapid and efficient antioxidant assay, with the precedence of animal studies constituting 90% of all tests.

Since 2015, only two in vivo tests were reported relating to the antioxidant activity of P. anisum. Favism is a metabolic disease of acute hemolytic anemia induced by bean consumption. In 2016, Kori, et al. demonstrated that pretreatment with P. anisum oil could block the oxidative stress effect of the causative agent to achieve a favism-protective effect by arresting the hydrolysis-of vicine ran convict to their aglylate free radical compounds (divicine and isouramil), and this effect related to anethole [7]. Ashtiyani’s et al, study was aimed at exploring the alleviating effect of a P. anisum ethanol extract on gentamicin (GN)-induced Wistar rat model of nephrotoxicity by interfering with oxidative stress [84]. bThe results showed that P. anisum reversed the GN-induced increase in levels of plasma creatinine, BUN, MDA, and excretion of sodium and potassium and improved FRAP and GN-induced tubule damage.

On the other hand, the in vitro antioxidant performance of P. anisum was evaluated by utilizing different radical scavenging activities, such as DPPH and ABTS, reducing capacity assay (FRAP and PMCA), and β-carotene/linoleic acid determination. Many types of research showed satisfactory antioxidant properties of ethanol extract [84], aqueous extract [56], n-hexane extract [11], and volatile oil [50,85,86] of P. anisum seeds by various tests. As expected, further data comparison indicated that the DPPH clearance rate of oil exceeded 77% at the optimal concentration, superior to other types of extracts, and is recommended as a natural antioxidant. Furthermore, another analysis of oxidative–correlative components revealed that P. anisum oil possessed a positive correlation with the total amount of phenols and polysaccharides [9] and a negative correlation with the total amount of sterols [78].

Meanwhile, many studies clarified the antioxidant effect of different Pimpinella species abroad, providing a logical basis for the rational choice of the Pimpinella plant. Ozbek et al. also proved the superior antioxidant activities of P. cappadocica [16] and P. rhodantha [17], which were consistent with the flavonoid glycosides content, while the antioxidant capacities of P. enguezekensi [51] and P. anthriscoides [65], newly discovered species in eastern Anatolia, that were attributed to high trans-anethole concentration. The antioxidant characterizations of ethyl acetate extracts from Indonesian P. alpine [88] and Iranian P. affinis [89] were conducted by in vitro screening with IC₅₀ values of 53.07 and 74.90 µg/mL, respectively. A study in 2019 [46] discovered that 3% of P. saxifraga oil exhibited significant antioxidant activity and DNA protection potential, correlating with the proportion of phenolic compounds [90], which indicated it could be used as a new natural antioxidant candidate added to the sodium alginate coating in the preservation of cheese.

4.2. Antibacterial Activity

Bacterial infection is the main cause of morbidity and mortality throughout the world. Since antiquity, scientists have been interested in its bacteriostatic potential due to the characteristic volatile compositions in the Pimpinella species. In Table 8, most data concerning P. anisum oil presented that phenyl propanes, especially anethole and its isomers, were the predominant components accounting for 98% of its content [149]. Various test procedures were conducted, such as disk diffusion, agar diffusion, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) using in vitro conditions to explore the antagonistic activity of microorganisms of extracts from different species.

Since 2015, 19 reports have multidimensionally characterized the antimicrobial activity of P. anisum, accounting for 79%. The essential oil from P. anisum has been triumphantly developed as a target preparation, and with advances in biological materials, the combination of PLA film materials, nano emulsions, and gel materials with oil has been affirmed as a new dosage form, which could greatly improve its antibacterial ability. In terms of antibacterial experiments, many studies demonstrated that oil and polysaccharide from P. anisum seeds and fruits exhibit antibacterial activity against a battery of gram-negative and gram-positive bacterium (Table 8) [8,9,91,92,150]. Noteworthily, fire blight was a devastating disease of commercial crops of Rosaceae, ascribing to the highly infectious bacteria Erwiniaamylovora, and Akhlaghi et al. found that P. anisum oil showed above-average antibiotic ability with a MIC of 31.25 μg/mL [93].

In antifungal experiments, P. anisum oil-hydrogel formulation was successfully prepared by the freeze-drying method, which was suitable for vaginal delivery systems and showed restraining activity against Candida albicans, C. glabrata, and C. parapsilosis [94]. Currently, aromatic plants have attracted interest for scientists as sources of natural antimicrobials due to the increased resistance of pathogenic fungi. Khosravi et al., confirmed P. anisum oil was sensitive to Fusarium solani emerging from patients with onychomycosis with a MIC ranging from 50 to 490 μg/mL [95].

In another dermatophyte infections study [96], combined treatment with terbinafine and P. anisum oil showed that oil enhanced the activity of terbinafine against Trichophytonrubrum and T. mentagrophytes with a 4-fold reduction in the MIC. The combination therapy had a synergistic effect on reducing the concentration of antifungal drugs and the appearance of resistant strains than monotherapy. A. J. Obaid et reported that P. anisum oil down-regulated the keratinase gene expression of T. rubrum by 0.079 compared with control (1.00), conducing to target determination during drug development [97].

In recent years, with the continuous improvement of consumer requirements for food safety, the application of P. anisum oil as a natural antibacterial agent has been greatly promoted in the food domain. Many microbiology experiments [98,99] demonstrated that P. anisum oil exerted an inhibitory effect on the growth of the food-born germ Clostridium perfringens and several mycete by controlling of mycelium growth and spore germination [100]. Khoury et al. further integrated with qRT-PCR to reveal the modulation of 5 µL/mL P. anisum oil on the ochratoxin A production during grape brewing by down-regulating the expression of Aspergillus carbonarius biosynthesis-related genes (acOTApks, acOTAnrps, acpks gene) and growth-regulating genes (laeA and vea gene) [101]. Noori et al., research in 2021 showed a concentration-dependent inhibitory effect on Listeria monocytogenes and Vibrio parahaemolyticus by adding P. anisum oil to a novel polylactic acid (PLA)-based composite film for food packaging [102]. Ultrasound-assisted P. anisum oil-based nanoemulsion prevented microbial contamination induced by 5 bacteria and 14 food-contaminating fungi compared with pure extract and is recommended as a green food antiseptic [87,105,106,107].

In addition to P. anisum, many studies exhibited the antimicrobial potentials of different Pimpinella species from around the world, including, P. alpine [88], P. saxifrage [46], P. enguezekensis [51], P. affinis [52], and P. anthriscoides [65], which showed the moderate bacteriostatic effect against a battery of microorganisms, suggesting development as an alternative for P. anisum.

4.3. Anti-Inflammatory Activity

The cause of body inflammation is either infection or physical/chemical damage. In that case, blood starts oozing out into tissues from blood vessels (5–6). P. anisum has been approved by the Committee of Herbal Products of the European Medicines Agency (EMA) for a therapeutic schedule of mild indigestion and an expectorant for coughs due to its traditional effects on respiratory disorders. As the literature ascertained, the genus Pimpinella exerted an anti-inflammatory effect by regulating the expression of proinflammatory cytokines (IL-1, IL-8, and TNF-α), and anethole (40) from the volatile oil was the prime ingredient [96]. However, there was little research on its anti-inflammatory mechanism in respiratory tissues. T. P. Domiciano et al. previously provided preclinical evidence that anethole (40) inhibited the production or release of PGE₂ and NO in acute inflammation in animals [106]. R. Iannarelli et al. [107] further revealed that P. anisum oil acted as a remarkable anti-inflammatory by reducing the expression of IL-1 and IL-8 in LPS-induced tracheal epithelial HBEpC and HTEpC lines and promoting the secretion of Muc5ac. Another study on the respiratory system examined the effects of anethole (40) on the inflammatory status of lung and liver cells after exposure to airborne pollution of particulate matter (PM). In PM_2.5-induced BEAS-2B and HepG2 cells, anethole (40) reduced the levels of IL-6 and IL-8 by 96% and 87%, respectively, demonstrating it is a natural therapeutic agent to counteract PM-induced inflammation [108]. Recently, based on analysis of ovalbumin (OVA)-induced allergic rhinitis (AR) model mice, C. S. Liao’s team found that the anti-inflammatory response of BLAB tea containing P. anisum was relevant to the suppression activity on the accumulation of inflammatory cells and the release of Th2 and histamine in the nasal mucosa, NALF, and serum, and induction of the production of Th1 and Treg [109]. Another P. anisum study [9] indicated that polysaccharide extract mediated anti-inflammatory effects by improving edema and reducing MDA and SOD levels of oxidative stress indexes in muscle in carrageenan-induced foot swelling in mice.

4.4. Anti-Tumor Activity

It is important to note that the antitumor activities of genus Pimpinella have been verified at the cellular level and in animal studies, while few studies report on clinical applications. Terpenoids from P. anisum seed are the dominant antitumor compounds. A 2015 study showed that treating HepG2 cells with P. anisum oil for 24 h caused concentration-dependent and significant cytotoxicity [110]. Nowadays, silver nanoparticles (AgNPs) provide a new pathway for the utilization of natural products and the importance of drug release. Alsalhi et al., designed a green synthetic route in 2016 to prepare AgNPs containing a P. anisum aqueous extract, which exerted obvious antitumor effects on human neonatal skin stromal cells and colon cancer cells [111]. S. Devanesan et al. conducted an in-depth study on the pharmacological mechanism of AgNPs in the colorectal cancer cell (CRC) [112]. Interestingly, synthetic AgNP could selectively destroy CRC via the inhibition of proliferation, arresting the cell cycle at the G2/M phase, and inducing apoptosis, indicating that composite nanomedicines may pioneer new approaches for prospective anticancer therapy. A. Mahmoud et al. reported a novel sesquiterpene lactone pimpinelol (205) from P. haussknechtii and demonstrated reduction viability against human breast cancer cell line (MCF-7 cells, IC₅₀: 1.06 μM) by inducing protein aggregation and endoplasmic reticulum stress at the cytokine levels [10].

4.5. Hypoglycemic Activity

Diabetes is a lifelong metabolic disease characterized by hyperglycemia, leading to a variety of deadly complications. Previous reports have confirmed that the ethanol extract of P. brachycarpa possesses the capacity for precaution of hyperglycemia and remission of oxidative stress in type II diabetic mice [14]. Since 2015, studies paid attention to P. anisum in controlling hyperglycemia and preventing diabetes complications. Preliminarily, M. Bonesi et al. evaluated the inhibitory activity of P. anisum seed on two key enzymes associated with type II diabetes, and it exhibited moderate inhibition against α-amylase and α-glycosidase with IC₅₀ values of 692.6 ± 5.2 and 73.9 ± 2.2 μg/mL, respectively [11]. Secondly, a 2020 study using a streptozotocin (STZ)-induced diabetic rat model observed that β-cell structure was significantly improved, insulin immune response was enhanced, and pancreatic acinus and amylase levels were reduced in the P. anisum-treated group compared to diabetic-control. The authors attributed the beneficial effects of P. anisum extract to its hypoglycemic and antioxidant properties, as oxidative stress plays a critical role in the development and progression of diabetes. In this study, the P. anisum-treated group significantly reduced SOD and CAT and increased their levels of lipid peroxidation marker MDA, which plays a role in lowering blood glucose. In addition, in immunohistochemical experiments, it could be observed that compared with diabetic control groups, the caspase 3 immunoreaction (22.34 ± 1.27 vs. 52.96 ± 2.32) and beclin 1 immunoreaction (31.55 ± 1.05 vs. 46.85 ± 1.30) were significantly decreased in the P. anisum-treated group (p < 0.001). These results indicated that P. anisum could significantly down-regulate the autophagy regulation marker beclin 1 and apoptosis marker caspase 3 in the pancreas, also relating to its antioxidant properties. Finally, M. Hashemnia et al. explored the potential of P. anisum on skin ulceration complications induced by diabetes from a new perspective of wound healing [114]. P. anisum reversed oxidation changes of MDA and GSH in wound skin (p < 0.05) and significantly reduced the wound size and the number of inflammatory cells while enhancing the re-epithelialization rate, collagen content, and fibroblast reaction, promoting festering wound reparation in diabetic rats.

4.6. Hypotensive Activity

A report in 2017 demonstrated that the ethyl acetate and ethanol extract of P. brachycarpa has a significant antihypertensive function in hypertensive model rats [115]. Further invitro exploration revealed it exhibited a dose-dependent inhibitory effect on an angiotensin-converting enzyme in the range of 0.5–10 mg/mL, and 80% ethanol extract presented the highest inhibitory rate. However, the effective ingredients and mechanism of hepatoprotective activity need to be further clarified. Another study in 2019 confirmed that an aqueous extract of P. anisum seed had the beneficial effect of lowering arterial blood pressure in rats and further explored its mechanism by estimation of different models [116]. V.B.C. Pontes et al. successively eliminated the actions of diuresis, angiotensin receptor antagonism, and β-receptor blockade of P. anisum. Additionally, it proved to act as a calcium channel antagonist to act as a hypotensive agent by inhibiting Ca²⁺ influx.

4.7. Insecticidal Activity

Since the 20th century, the wide application of pesticides has led to the rapid development of agriculture and a booming increase in output. However, the increasing pests’ resistance and soaring pollution in the environment and food caused by synthetic pesticides have motivated researchers to explore natural botanicals as sources of new insecticides, such as Pimpinella essential oils.

A 2018 study [117] used P. anisum oil to explore the toxicity of agricultural pests and the safety of beneficial insects, and the results displayed noteworthy insecticidal effects against two pathogenic insects, Culex. quinquefasciatus (LC₅₀ = 25.4 μL/L) and Scaphoideus littoralis (LD₅₀ = 57.3 μg/L). Nevertheless, it was not toxic to beneficial insects in comparison with α-cypermethrin at the same lethal concentration. Similar inferences were drawn from another nine studies by contact and fumigation tests [118,119,120,121,122,123,124,125,126]. A.Hatege kimana et al. revealed another pathway in the eradication of the pest (Acanthoscelidesobtectus) by reducing fecundity (egg production) and fertility (egg hatch ability/progeny production) [127]. Ulteriorly, in vitro tests observed activity decline of AchE in two-spotted spider mites after P. anisum management, which was attributed to the high-content ingredients, such as E-anethole, isoeugenol, and α-pinene [86]. In addition, green insecticides with the cooperation of emerging eco-friendly substances and natural ingredients are perceived as a strategy. K. A. Draz et al. prepared P. anisum oil of nanoemulsions (2500 mg/L) to eliminate the emergence of Sitophilus oryzae and Triboliumcastaneum by 94.6% and 84.5%, respectively, which exceeded the values compared to that of pure oil; it had no adverse impact on the germination rate of wheat [128]. Concurrently, various attempts [129,130,131,132,133] have proved P. anisum-nanoformulation possessed considerable repellent and toxic activities against Bactroceraoleae and other crop pests.

In addition to the management of crop pests, P. anisum oil had an excellent performance on larval elimination and cutting-off transmission against pests spreading epidemic diseases. Numerous studies have provided convictive evidence of larval killing and oviposition deterrent activities of P. anisum on pestiferous pests, the vector of dengue, human African trypanosomiasis, and filariasis [48,136,137,138,139,140]. A. T. Showler et al. further demonstrated p-anisaldehyde was a botanical ingredient inhibiting the reproduction of pests [139,140]. To develop efficient mosquitocide, S. S-Gomez et al. encapsulated P. anisum oil in nanoparticles loaded with zein to overcome the defects of high degradability and low persistence and successfully applied it to mosquito larvicide [141]. Overall, Pimpinella oil not only combated insect vectors but also prevented crops and other organisms from toxic damage, representing a milestone in the commercial development of green-based insecticide formulations.

4.8. Enzymes Inhibitory Activity

O. H. Chan’s research declared that the ethanol extract of P.brachy carp regulated the enzymes CYP1A2, 2B6, and 3A4 by concerted inhibition, while it affected the enzymes CYP2C19 and 2D6 by competitive inhibition [142]. Furthermore, G. Zengin et al. evaluated the enzymatic inhibition of Turkish P. anthriscoides on tyrosinase, α-amylase, α-glucosidase, AChE, and BChE by invitro tests [65]. Since 2015, six studies focused on exploring the P. anisum-derived enzyme inhibitor. On one hand, scientists actively probed plant extracts, and a sol-gel GSTA1–1macroarray high-throughput screening tool was independently developed for celerity determination of the GST-inhibitory activity of P. anisum (IC₅₀ = 3.40 ± 0.83 μg/mL) [143]. Gout was induced by excessive accumulation of uric acid due to xanthine oxidase (XO), which has the function of oxidizing hypoxanthine to xanthine and uric acid in an overactive state. L. Bou-Salah et al. revealed that P. anisum oil inhibited the activity of human-original XO (IC₅₀ = 2.37 ± 0.23 μg/mL), discussing new tactics for gout treatment [144]. RALDHs were assigned to convert retinaldehyde to retinoic acid (RA), acting as the dominant mechanism in RA signaling pathways and relevant cancers. The current study indicated that ethanol extracts of P. anisum selectively and intensively inhibited RALDH3 expression, while it did not modulate RALDH1 and RALDH2, highlighting the selectivity of that in the regulation of RALDHs and the RA-governed metabolic process [145]. On the other hand, studies on P. anisum ingredients found that abundant bergapten (256), iso-pimpinellin (274), and methoxsalen (275) were inhibitors of CYP-1A2, which are involved in drug metabolism and carcinogenic bioactivity [70]. However, phenolic ingredients exerted remarkable inhibition against AChE and BChE with IC₅₀ values of 0.07 and 0.34 μg/mL, respectively [56,66].

4.9. Antidepressant Activity

Depression and anxiety disorders are commonly believed to be stress-related mood disorders, invariably accompanied by various diseases and premature aging in severe cases. Many studies have manifested that the antidepressant effect of genus Pimpinella extracts is associated with neurotransmitters, genetic polymorphisms, endocrine system abnormalities, and cytokine levels [151]. A reversion of anxiety and depression and amelioration of memory formation in model mice by total extract of P. anisum [152] (100 mg/kg) and volatile oil of P. peregrine [18] could be observed according to researchers. However, precise elucidation of the mechanism was needed. Therefore, the in-depth study focusing on P. anisum oil by Koriem et al. [146] found that levels of 5-HT, DA, NE, GABA, and IL-10 were significantly reduced (p < 0.001) and the levels of inflammatory cytokines IL-1β, IL-6, TNF-α, and Ki-67 were significantly increased (p < 0.001) after oral administration of P. anisum oil compared with chronic mild stress (CMS) model rats, bringing the cerebral cortical and hippocampal levels close to normal. As is known, the inflammatory factors mainly occurred in allergy conditions. TNF-α represented an inflammatory factor in neurons where IL-1β produced inflammation through monocytes and macrophages; IL-6 and IL-10 had a vital role in the neuronal response to injury, while Ki-67 represented a nuclear protein, which was associated with cellular multiplication. These results confirmed the efficacy of P. anisum oil in the treatment of depression by inhibiting the inflammation of the cerebral cortex and hippocampus. It is worth noting that El-Shamy et al. concluded with conflicting results compared to Koriem et al., using the same animal models and experimental procedures as they attributed the depression-improving effect to its antioxidant activity [147]. The reason was decreased levels of GSH-Px, GST, GSH, and CAT, while increased levels of MDA and NO were observed in the cerebral cortex and hippocampus. Additionally, M-jahromi et al. [148] selected 120 patients with depression suffering from irritable bowel syndrome (IBS) to provide clinical evidence of the antidepressant effect of P. anisum. The P. anisum-treated group preferentially alleviated mild or moderate depressive symptoms in IBS patients compared to control and placebo groups making it a prospective and economical option for depressive patients.

4.10. Other Activities

In addition to the above pharmacological activities related to traditional usage, many novel pharmacological properties have been excavated from the genus Pimpinella. For example, the ethanol extracts of P. anisum combated uterine contractions by inhibiting L-type Ca²⁺ channels and blocking Ca²⁺ influx [153], and the polysaccharide extract accelerated wound healing [9]. Mosavata and his team implemented placebo-controlled trials to demonstrate that P. anisum ameliorated the distress of migraine [154] and premenstrual syndrome [155]. Moreover, umbelliprenin (276) in P. anisum has been proven to be a potential skin-whitening agent [71]. These data were anticipant of genus Pimpinella for drug exploitation in the treatment of various diseases.

5. Conclusions and Perspective

In this review, the traditional uses, chemical constituents, and modern pharmacological activities of the genus Pimpinella were summarized. Conclusively, genus Pimpinella principally contained phenyl propanoids, terpenoids, flavonoids, coumarins, sterols, and organic acids with a broad spectrum of biological activities, such as antioxidant, antibacterial, anti-inflammatory, antitumor, hypoglycemic, hypotensive, insecticidal, inhibitory enzyme, and antidepressant activities. Some Pimpinella cultivars could be applied as natural sources of edible vegetables, and essential oil was the important raw material for the production of green insecticides and condiments of alcoholic beverages.

This review is prepared to provide an overview of the knowledge of the last eight years (from 2015 to 2022) and to make suggestions for filling the gaps available in the literature for this genus. However, there were still some shortcomings during the overview of the genus Pimpinella, and suggestions were made for filling the gaps available in the literature for this genus. The mechanism, target, toxicity, and clinical application of the pharmacology needed to be further studied and discussed. Firstly, the species Pimpinella were abundant with similar appearance in China, and most were used as folk medicine. Detailed identification and quality standard were conducted only in P. anisum and P. thellungiana. Hence, it is urgent to establish a complete quality standard for Pimpinella plants to prevent the mixed-use phenomenon. Secondly, despite the increasing demand for pharmacological research on the genus Pimpinella recently, such as antioxidant, anti-inflammatory, antitumor, anti-depressant, and hypoglycemic effects, more attention should be paid to the relevant clinical research. The therapeutic properties recorded in medical books of various countries of all ages should be appreciated. For example, the traditional curative effect of P. anisum in the gastrointestinal tract and digestive function documented in many places has not been confirmed by uniting with modern scientific methods, which provides new directions for the future. Finally, P. anisum’s essential oil, aqueous, or organic solvent extracts are often applied for pharmacological investigation. To better clarify the pharmacological activity of P. anisum, the bioactivity-oriented separation method can be adapted to excavate the bioactive components and maximize utilization.