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REVIEW
Star anise (Illicium verum): Chemical compounds, antiviral
properties, and clinical relevance
Jayanta Kumar Patra
1
| Gitishree Das
1
| Sankhadip Bose
2
|
Sabyasachi Banerjee
3
| Chethala N. Vishnuprasad
4
|
Maria del Pilar Rodriguez-Torres
5
| Han-Seung Shin
6
1
Research Institute of Biotechnology &
Medical Converged Science, Dongguk
University-Seoul, Goyang-si 10326, Republic
of Korea
2
Department of Pharmacognosy, Bengal
School of Technology, Sugandha, Hooghly
712102, West Bengal, India
3
Department of Phytochemistry, Gupta
College of Technological Sciences, Asansol,
West Bengal, India
4
Centre for Ayurveda Biology and Holistic
Nutrition, The University of Trans-Disciplinary
Health Sciences and Technology (TDU),
Bengaluru, Karnataka, India
5
Laboratorio de Ondas de Choque (LOCH),
Centro de Física Aplicada y Tecnología
Avanzada (CFATA), Universidad Nacional
Autónoma de México Campus UNAM Juriquilla
Boulevard Juriquilla no. 3001 Santiago de
Querétaro, Qro., C.P. 76230, Mexico
6
Department of Food Science &
Biotechnology, Dongguk University-Seoul,
Goyang-si 10326, Republic of Korea
Correspondence
Dr. Jayanta Kumar Patra, Research Institute of
Biotechnology & Medical Converged Science,
Dongguk University-Seoul, Goyang-si 10326,
Republic of Korea.
Email: jkpatra@dongguk.edu
Medicinal herbs are one of the imperative sources of drugs all over the world. Star
anise (Illicium verum), an evergreen, medium-sized tree with star-shaped fruit, is an
important herb with wide distribution throughout southwestern parts of the Asian
continent. Besides its use as spice in culinary, star anise is one of the vital ingredients
of the Chinese medicinal herbs and is widely known for its antiviral effects. It is also
the source of the precursor molecule, shikimic acid, which is used in the manufacture
of oseltamivir (Tamiflu
®
), an antiviral medication for influenza A and influenza
B. Besides, several other molecules with numerous biological benefits including the
antiviral effects have been reported from the same plant. Except the antiviral
potential, star anise possesses a number of other potentials such as antioxidant, anti-
microbial, antifungal, anthelmintic, insecticidal, secretolytic, antinociceptive, anti-
inflammatory, gastroprotective, sedative properties, expectorant and spasmolytic,
and estrogenic effects. This review aimed to integrate the information on the cus-
tomary attributes of the plant star anise with a specific prominence on its antiviral
properties and the phytochemical constituents along with its clinical aptness.
KEYWORDS
antiviral, Illicium verum, oseltamivir, shikimic acid, star anise, Tamiflu
1|INTRODUCTION
Plants are a vital part of the ancient system of medicine for treating
numerous infectious and non-infectious diseases across the globe.
The rich repository of bioactive compounds such as phenols, terpe-
noids, alkaloids, and so forth make them an important source of drug
(Sasidharan, Chen, Saravanan, Sundram, & Latha, 2011). Generally,
the use of herbal remedies for treating various disease conditions is
more common in rural places where the accessibility to the foods
and also medical services is limited (Bukar, Dayom, & Uguru, 2016).
People usually consume plants in different forms, namely, infusions,
spices, and medicinal smoke. Also, some of the plants are used as
seasoning substances to add flavor to the foods provide health bene-
fits (Bagchi & Srivastava, 2003).
Star anise (SA: Illicium verum Hook. f.), better known as Chinese
SA, belongs to the Magnoliaceae family and is an aromatic plant. It
has a star shape, and its fruit is a very important element as a spice in
the Oriental cuisine. It is a highly regarded medicinal plant with a num-
ber of medicinal properties in the countries like China and Vietnam
(Figure 1), and it is a commonly used spice. Several biologically impor-
tant phytochemicals have been reported from SA. It also possesses
antimicrobial, antiviral, and antioxidant properties (George, 2012).
Jayanta Kumar Patra and Gitishree Das are combined first author.
Received: 14 October 2019 Revised: 25 December 2019 Accepted: 1 January 2020
DOI: 10.1002/ptr.6614
Phytotherapy Research. 2020;1–20. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons, Ltd. 1
Apart from the Chinese uses, the fruits are also referred in ayurveda,
traditional Indian system of medicine, as useful in dyspepsia, flatu-
lence, spasmodic colonalgia, dysentery, cough, asthma, rheumarthritis,
facial paralysis, and so forth. Additionally, the essential oils from SA
are composed of prenylated C
6
–C
3
compounds, lignans, sesquiter-
penes, and flavonoids, each with different types of compounds which
are also important with respect to its vast medicinal properties.
Among all of them, the anethole compounds are responsible for its
characteristic taste. Besides, compounds like α-pinene, β-pinene,
myrcene, α-phellandrene limonene, γ-terpineol, linalool, α-terpineol,
estragole, trans-anethole, α-cubebene carryophyllene oxide, and
α-humulene present in the essential oil of SA are also reported to
have contained a number of biological activities (Aly, Sabry,
Shaheen, & Hathout, 2016; Luís et al., 2019; Wang, Hu, Huang, & Qin,
2011). In addition, a number of procedures have been established for
the extraction of the bioactive compounds from this plant species,
and, among which, the hydro-distillation, steam distillation, solvent
extraction, supercritical fluid CO
2
extraction, hydro-distillation-
headspace solvent microextraction, and microwave-assisted extrac-
tion process are the most common ones (Rocha & Candido Tietbohl,
2016). SA has attracted the scientific community due to the presence
of a specific compound called the shikimic acid that acts as a chemical
precursor in the manufactor of oseltamivir (Tamiflu
®
), an avian flu
drug (Ohira, Torii, Aida, Watanabe, & Smith Jr, 2009; Xu et al., 2017).
The aim of this review is to present the general characteristics, chemi-
cal properties, and antiviral properties of I.verum (SA) along with a
future perspective on its usage.
2|SA IN FOOD
SA is the ripe, dried fruit of I.verum. Its whorl is formed by six to eight,
one-seeded, boat-shaped, woody, wrinkled, ridged, reddish-brown fol-
licles whose inner structure is characterized by a smooth, lustrous,
and light-brown texture (Zhang, Ji, & Yu, 2018). Its seed is light brown
and ovoid in shape. SA has been used for long in Chinese cuisine as a
spice, but it is not only limited to China but also to Vietnam and India
for the preparation of broths and meat. SA is part of the popular five-
spice powder mix. It contains SA, cassia, clove, fennel, and Sichuan
pepper in equal parts. Besides, it has been a part of the alcoholic bev-
erages such as pastis and absinthes, together with its uses in teas, fruit
compotes, and jams in the Western countries. The inclusion of anise
as a part of a healthy diet could have benefits as in the prevention of
disease in combination with other food types, for example, other
plants, fruits, and vegetables.
3|BOTANICAL DESCRIPTION
The I.verum, which belongs to the division Magnoliophyta, class Mag-
noliopsida, order Austrobaileyales, and family Illiciaceae, is a modest
semblance herb of around 8 to 15 m in height and 30 cm thick with
flat-out, felicitous trunks and emphatic, bald-headed branchlets
(Chouksey, Sharma, & Pawar, 2010). The normal existence of the herb
is 80–100 years. The bark is white to bright gray. Its 6–12 cm tall
leaves are simple, leathery, alternate, plenary, bright, bald-headed,
generally packed in groups toward the finish of the branches
(Chouksey et al., 2010). The flowers bloom huge and are androgynous,
1–1.5 cm in diameter, white-pink to red or greenish-yellow, axillary,
and single (Chouksey et al., 2010). The fruit looks like capsule, but the
entirety is star formed, radiating 5 to 10-pointed pontoon-molded
segments about eight on average. Every arm of the fruit looks like a
seed pod. The fruits have thick skin and are rust shaded with their
dimension up to 3 cm long (Chouksey et al., 2010). The fruits were
picked since it gets ripen when the essential oil is at its maximum. The
seeds are sparkling brown or ruddy with high oil content (Chouksey
et al., 2010; Fritz, Ölzant, & Länger, 2008; Prajapati, Purohit,
Sharma, & T, K., 2006). In the ayurvedic system of medicine, it is com-
monly used in the rasa: katu, Guna: Lakhu, Teekshna, Virya: Ushra,
Vipaka: Katu (Chouksey et al., 2010).
4|CHEMICAL CONSTITUENTS
Fruits comprise a greater number of alkaloids, essential oil, and tannins
(9% to 10%), containing both cis- and trans-anethole (85% to 90%),
limone, α-pinene, safrol, β-phellandrene, α-terpineol, and farnesol
(Chouksey et al., 2010; Dzamic et al., 2009; Tuan & Ilangantileket,
1997). Some little number of nitrogenous components and 14 hydrocar-
bon components along with 22 oxygenated hydrocarbon derivatives are
there like ρ-allylanisole, anisylacetone, anisaldehyde, ρ-cumicaldehyde,
ρ-allylpen, palmitic acid, linoleic acid (1–4 methoxyphenyl)-prop-2-one
FIGURE 1 Medicinal potential of star anise
2PATRA ET AL.
TABLE 1 Chemical constituents of star anise
Chemical constituents Structure Applications References
Cis-anethole Antimicrobial, antifungal, anthelmintic,
antioxidant, antinociceptive, gastroprotective,
anti-inflammatory, sedative activity and
insecticidal activities, spasmolytic effect on
contracted smooth muscles, secretolytic and
expectorant effects, estrogenic effects, and
reproductive toxicity
(Chouksey et al., 2010; Marinov & Valcheva-
Kuzmanova, 2015)
Trans-anethole
α-Pinene Gastroprotective effect, selective anti-
inflammatory and anticatabolic effects,
antinociceptive, antimicrobial activities
(Chouksey et al., 2010; de Almeida Pinheiro et al.,
2015; Him, Ozbek, Turel, & Oner, 2008; Rufino
et al., 2014; Silva et al., 2012)
α-Phellandrene Antimicrobial activity, anti-inflammatory action,
mast cell stabilization, antinociceptive effect,
antifungal activities
(Chouksey et al., 2010; _
Is¸can et al., 2012; Lima
et al., 2012; Siqueira et al., 2016; J.-h. Zhang,
Sun, Chen, Zeng, & Wang, 2017)
Limonene Botanical insecticide, spasmolytic, antitumor,
anticancer, and anti-inflammatory activities.
(Andrade & de Sousa, 2013; Chouksey et al.,
2010; de Sousa, Mesquita, de Araújo Ribeiro, &
de Lima, 2015)
ρ-Cymene Anxiolytic, antioxidant, anticancer,
antinociceptive, anti-inflammatory, and
antimicrobial effects
(Chouksey et al., 2010; Marchese et al., 2017)
Linalool Local anesthetic activity, antimicrobial activity,
anti-inflammatory, antinociceptive,
antihyperalgesic activities
(Chouksey et al., 2010; Peana, Moretti,
Watson, & Preedy, 2008)
(Continues)
PATRA ET AL.3
TABLE 1 (Continued)
Chemical constituents Structure Applications References
Terpinen-4-ol Antimicrobial effect, anti-inflammatory, and
antioxidant acitivities
(Chouksey et al., 2010; Mondello, De Bernardis,
Girolamo, Cassone, & Salvatore, 2006)
α-Terpineol Antioxidant, antiulcer, anticancer,
antihypertensive, antinociceptive.;
anticonvulsant activities
(Chouksey et al., 2010; Khaleel, Tabanca, &
Buchbauer, 2018)
Shikimic acid Antioxidant, anticoagulant, antithrombotic,
antibacterial, anti-inflammatory and analgesic
activities
(Chouksey et al., 2010; Estevez, & A., & J Estevez,
R., 2012)
Estragole/methyl chavicol/ρ-allylanisole CNS depressant, antioxidant activity,
antimicrobial, anesthetic, and modulation of
the immune responses.
(Chouksey et al., 2010; Wiirzler, Silva-Filho,
Aguiar, Cavalcante, & Cuman, 2016)
Anisyl acetone Antioxidant and antibacterial activities. (Chouksey et al., 2010; Yang et al., 2012)
ρ-Anisaldehyde Antifungal effect, antibacterial, anti-HIV,
anticancer, antineoplastic, anti-inflammatory,
tuberclostatic, antimalarial activities
(Chouksey et al., 2010; Mbah et al., 2017)
β-Caryophyllene Anticancer, anti-inflammatory, anticarcinogenic,
antimicrobial, antioxidative and analgesic
activities
(Chouksey et al., 2010; Fidyt, Fiedorowicz,
Strządała, & Szumny, 2016)
Foeniculin Insecticides (Chouksey et al., 2010; Garneau et al., 2000)
(Continues)
4PATRA ET AL.
TABLE 1 (Continued)
Chemical constituents Structure Applications References
Linoleic acid Antibacterial activity, anti-inflammatory, acne
reductive, skin-lightening and moisture
retentive property, cardiovascular-protective,
anticancer, neuro-protective, anti-osteoporotic,
and antioxidative effects
(Chouksey et al., 2010; Dilika, Bremner, & Meyer,
2000; Kim, Nam, Kim, Hayes, & Lee, 2014)
Palmitic acid Anti-inflammatory activity, antioxidant,
hypocholesterolemic, nematicide, pesticide,
antiandrogenic flavor, haemolytic, 5-alpha
reductase inhibitor
(Aparna et al., 2012; Chouksey et al., 2010;
Kumar, Kumaravel, & Lalitha, 2010)
Hexadecanoic acid methyl ester Antioxidant, hypocholesterolemic, nematicide,
pesticide, antiandrogenic, haemolytic activities.
(Balamurugan, Evanjaline, Parthipan, & Mohan,
2017; Chouksey et al., 2010)
δ-3-Carene Anti-inflammatory, antihistamine, antifungal
activity, antibacterial, sedative and expectorant
effects
(Ocete, Risco, Zarzuelo, & Jimenez, 1989; Singh,
Maurya, DeLampasona, & Catalan, 2006)
α-Terpinene Antioxidant (Rudbäck et al., 2012; Singh et al., 2006)
1,8-cineole / eucalyptol Antinociceptive property, vasodilator,
bronchodilator, anti-inflammatory activity,
hepatoprotective, gastroprotective,
antibacterial, antimycotic and antitumorogenic
activities
(Bhowal & Gopal, 2015; Singh et al., 2006)
γ-Terpinene Antimicrobial, cytotoxic, anti-inflammatory
activities
(Singh et al., 2006; Soukoulis & Hirsch, 2004)
Trans-linalool oxide Antioxidant and antimicrobial activity (Luís, Duarte, Pereira, & Domingues, 2017; Singh
et al., 2006)
Terpinolene Anticancer, antibacterial, antioxidant,
antifungal and sedative properties
(Aydin, Türkez, & Tas¸demir, 2013; Eftekhar,
Yousefzadi, Azizian, Sonboli, & Salehi, 2005;
Grassmann, Hippeli, Spitzenberger, & Elstner,
2005; Ito & Ito, 2011; Singh et al., 2006)
(Continues)
PATRA ET AL.5
TABLE 1 (Continued)
Chemical constituents Structure Applications References
Terpinen-1-ol Antibacterial, antifungal, antitumor, cytotoxic,
anticancer activities
(Shapira, Pleban, Kazanov, Tirosh, & Arber, 2016;
Singh et al., 2006)
Borneol Analgesic, anesthetic, sedative, anxiolytic
activities
(Granger, Campbell, & Johnston, 2005; Singh
et al., 2006)
α-Copaene Antimicrobial activity, anti-proliferative,
antioxidant, anti-genotoxic and cytotoxic
activities
(Martins et al., 2015; Singh et al., 2006; Turkez,
Togar, Tatar, Geyıkoglu, & Hacımuftuoglu,
2014)
Trans-α-Bergamotene Cytotoxic activity (Monajemi, Oryan, Haeri-Roohani, Ghannadi, &
Jafarian, 2010; Singh et al., 2006)
Δ-Cadinene Anticancer activity (Hui, Zhao, & Zhao, 2015; Singh et al., 2006)
1,4-cineole Fumigant insecticide and CNS depressant (Singh et al., 2006)
γ-Terpineol Flavoring ingredient
β-Terpineol Flavoring ingredient
(Continues)
6PATRA ET AL.
TABLE 1 (Continued)
Chemical constituents Structure Applications References
Acetaldehyde In the production of sedatives and tranquilizers,
flavoring agents
Methyl p-anisate Flavoring agent
Trans-β-Farnesene Scent preparation.
4-Methoxypropiophenone Fragrance agent
m-Methoxy mandelic acid Not reported
t-Muurolol Antifungal activity
Margaric acid Antiproliferative activity
Phenol Oral analgesic, antiviral, antifungal activities (Wei et al., 2014)
Benzoic acid Antifungal activity
4-Ethyl benzaldehyde Flavoring ingredient
(Continues)
PATRA ET AL.7
TABLE 1 (Continued)
Chemical constituents Structure Applications References
Benzyl alcohol Local anesthetic, antimicrobial, insect repellent,
flavoring agents.
4-Methoxy benzoic acid / p-anisic acid Antimicrobial activity
4-Methoxy benzaldehyde oxime Not reported
O-Nitrobenzoic acid Not reported
β-Copaene Antimicrobial activity (Sinha, 2019; Wei et al., 2014)
Longifolene Antifungal, anti-termite activities, flavoring agent,
natural autoxidation
(Mukai, Takahashi, & Ashitani, 2017, Mukai,
Takahashi, & Ashitani, 2018, Wei et al., 2014)
Bisabolene Anticonvulsant activity, flavoring agent (Orellana-Paucar et al., 2012; Wei et al., 2014)
ρ-Hydroxybenzoic acid Antiestrogenic, antimutagenic, antimicrobial,
antialgal, anti-platelet aggregating, antioxidant.
Nematicidal, hypoglycemic, anti-inflammatory,
antiviral activities
(Manuja, Sachdeva, Jain, & Chaudhary, 2013; Wei
et al., 2014)
β-Humulene Anti-inflammatory, antibiotic, antioxidant,
anticarcinogenic and local anesthetic activities
(Legault & Pichette, 2007; Wei et al., 2014)
(Continues)
8PATRA ET AL.
TABLE 1 (Continued)
Chemical constituents Structure Applications References
3-Hydroxybenzoic acid Anti-stress, anxiolytic and antidepressant,
antimicrobial agents
(Khan, Chatterjee, & Kumar, 2015; Kumar et al.,
2010; Wei et al., 2014)
3,6-Dimethyl-4H-furo[3,2-C]pyran-4-one Not reported (Wei et al., 2014)
3-Hydroxy-1,2-benzisoxazole Not reported
4-Methoxy cinnamaldehyde Flavoring agent
4-Ethyl-α-methyl benzyl alcohol Not reported
Cis-3,5-dimethoxy-β-methyl-β-nitrostyrene Not reported
Hydrazine carboxylic acid,2-methyl-
3,7-dimethyl-2,6-octadienal ester
Not reported (Yan et al., 2002)
9-Methyl-9H-fluorene Organometallic reagent (Bowen, Aavula, & Mash, 2002;
Wei et al., 2014)
1H-Benzimidazol-4-ol-5-ethoxy-1
(methylphenyl)
Not reported (Huang et al., 2013)
(Continues)
PATRA ET AL.9
TABLE 1 (Continued)
Chemical constituents Structure Applications References
2,2-Diisobutyl-1,3-benzodioxole Not reported (Wei et al., 2014)
Bendazol Hypotensive, vasodilator, antispasmodic action,
anti-parasitic activities
Trans-2-Ethoxy-β-methyl- β-nitrostyrene Not reported
N-(4-hydroxyphenyl)-2-methylbenzamide Not reported
9,12-Octadecadienoic acid (Z,Z)-, methyl ester
/ methyl linoleate
Flavoring ingredient
Phenol-3-[2-(2-phenylethyl)amino]ethyl Not reported (Huang et al., 2013; Wei et al., 2014)
Spiro[4.5]dec-1-ene Not reported (Yan et al., 2002)
(Continues)
10 PATRA ET AL.
TABLE 1 (Continued)
Chemical constituents Structure Applications References
α-Farnesene Flavoring ingredient
2-Methyl-3-phenylpropanal Not reported
Phenyl ethanolamine Cardiovascular activity
Surfynol 102 Surfactant
Acetic acid geranyl ester Flavoring ingredient
p-Allylphenol/Chavicol Odorant
Hexyloleate Not reported
2-(2-Aminopropoxy)-3-methyl benzeneethanol Not reported
Bicyclo 2.2.1 heptane-2,3-dione,6-(acetyloxy)-
1,5,5-trimethyl, endo
Not reported
(Continues)
PATRA ET AL.11
TABLE 1 (Continued)
Chemical constituents Structure Applications References
Acethydrazide Antibiotic, cytotoxic activities
1,10-(1-Ethyl-2-methyl-1,2-ethenediyl)bis
(4-methoxybenzene)
Not reported (Huang et al., 2013)
1-Acetoxy-6-(1-hydroxy-1-methylethyl)-
3,9-dimethyl-2z,8-deca-diene
Not reported
Nopol Flavoring ingredient
γ-Elemene Antitumor (S. Wang et al., 2012; Yan et al., 2002)
3-Undecene Not reported
Germacrene D Antibacterial property, cytotoxicity, olfactory
receptor neuron activator.
(Essien et al., 2016; Yan et al., 2002)
Trans-Nerolidol Flavoring agent, antineoplastic, leishmanicidal,
anti- parasitic, and antifungal activities
(Arruda, D'Alexandri, Katzin, & Uliana, 2005; S.-J.
Lee et al., 2007; Yan et al., 2002)
(Continues)
12 PATRA ET AL.
TABLE 1 (Continued)
Chemical constituents Structure Applications References
Geranyl isobutyrate Flavoring agent
Veranisatin A Analgesic activity (Nakamura, Okuyama, & Yamazaki, 1996)
Veranisatin B Analgesic activity
ρ-Cumic aldehyde Not reported
PATRA ET AL.13
and foeniculin (Wang, Jiang, & Wen, 2007; Yamada, Takada,
Nakamura, & Hirata, 1965; Yan, J.-h., Xiao, X.-x., & Huang, K.-l., 2002).
The new phenylpropanoid glucosides, such as seco-cycloartane; alkyl
glucosides, 3,4-seco(242)-cycloartane-4(28),24(diene)3,26-dioic acid, and
phenylpropanoid 26- methyl ester of nigranoic acid, were also recog-
nized from dichloromethane leaves extract of I. verum (Lee, Li, Lee,
Song, & Son, 2003; Sy & Brown, 1998).
Another study of phytochemical assessment claims that the
I. verum fruit contains β-pinene, β-sitosterol, a-phellandrene, p-
cymene, β-myrcene, limonene, car-3-ene, cineol, 4(10)-thujene, linal-
ool, and 4-terpineol (Asolkar, Kakkar, & Chakre, 1992; Rashid &
Zuberi, 2016; Rastogi & Mehrotra, 1993). The presence of safrole, as
well as hydroquinone ethyl ether, was also detected. The fatty acid
mix contains myristic, stearic, and linoleic acids (Asolkar et al., 1992;
Rastogi & Mehrotra, 1993). It also contains copaene, anisketone,
sesquicitronellene, caryophyllene, farnesene, methyl-3-methoxy-ben-
zoate, methyl isoeugenol, p-hydroxy benzoic acid, nerolidol, and m-
methoxy-a-benzyl benzene acetic acid (Asolkar et al., 1992; Rashid &
Zuberi, 2016; Rastogi & Mehrotra, 1993). A number of bioactive com-
pounds found in the I.verum are listed in Table 1, many of which are
reported by Chouksey et al. (2010).
4.1 |Isolation of volatile oils
The volatile oils isolated from I.verum by hydro-distillation process
are α-pinene, sabinene, limonene, δ-3-carene, α-phellandrcene,
1,8-cineole, γ-terpinene, p-cymene, linalool, β-caryophyllene,
estragole, α-terpineol, cis-anethole, trans-anethole, anisaldehyde
(Bernard, Perineau, Delmas, & Gaset, 1989), terpinen-4-ol,
α-terpinene (Rudbäck, Bergström, Börje, Nilsson, & Karlberg, 2012),
terpinolene (Amanzadeh, Ashrafi, & Mohammadi, 2006), terpinen-
1-ol, borneol (Chen et al., 2014), α-copaene (Martins et al., 2015),
δ-cadinene (Pérez-López, Cirio, Rivas-Galindo, Aranda, & de Torres,
2011), 4-methoxypropiophenone, β-copaene, bisabolene (Aslam,
Ahmad, & Raja, 2017), O-nitrobenzoic acid, α-farnesene, germacrene
D (Özek et al., 2018), trans-nerolidol (Sriti Eljazi et al., 2018), geranyl
isobutyrate (Wangchuk, Keller, Pyne, Taweechotipatr, &
Kamchonwongpaisan, 2013), chavicol (Charles & Simon, 1990), and
ρ-cumic aldehyde.
4.2 |Isolation of shikimic acid
From ethanolic extract of SA, the solvent was removed by the help of
a rotary flash evaporator under reduced pressure. The residue was
again dissolved in water and heated up to 80C. Five drops of
37–40% formaldehyde solution was mixed to the warm solution and
cooled. A glass filter funnel was used to remove the precipitate which
contains a layer of celite to obtain a clear orange solution. Again it is
passed through an anion exchanger (Amberlite IRA-400) to collect the
yellow eluent and acetic acid. Then, the acetic acid was eliminated by
high vacuum rotary evaporator that afforded an orange-colored solid.
It was then dispersed in methanol and heated. To afford a solid mass,
filtration and subsequent elimination of the methanol was continued.
In the next step, the solid mass was recrystallized to get a bright white
crystalline solid called shikimic acid (Payne & Edmonds, 2005).
4.3 |Isolation of anisyl acetone
Isolation of anisyl acetone was performed by GC/MS analysis using
helium (He) as carrier gas (Meier, Kohlenberg, & Braun, 2003).
4.4 |Isolation of foeniculin
The isolation of foeniculin is done by using high-performance
counter-current chromatography (HPCCC), notably, high-speed
counter-current chromatography is considered, from essential oils of
SA, whose presence was confirmed by GC–MS analysis (Skalicka-
Woźniak, Walasek, Ludwiczuk, & Głowniak, 2013).
4.5 |Isolation of linoleic acid
The isolation of linoleic acid is done by treating the extract of the mixed
acids with sufficient urea to reduce the content of saturated and oleic
acids in the initial liquids to about 5%; then go for low-temperature crys-
tallization from acetone at −75C then gives a precipitate enriched in
linoleic acid (Gunstone, McLaughlan, Scrimgeour, & Watson, 1976).
4.6 |Isolation of palmitic acid
Directly, n-hexane is mixed to the crude methanolic extract with vig-
orous stirring; it was then filtered and while the residue was permitted
to dry and the same technique was repeated with ethyl acetate, n-
butanol, and lastly the residue acquired is methanol fraction. Ethyl
acetate, methanol, n-hexane, and n-butanol fractions acquired were
concentrated in hot air sterilizing chamber. Column chromatography
was then performed using petroleum benzene as mobile phase
followed by 9:1 ratio of petroleum benzene and ethyl acetate as elut-
ing solvent. The eluents were reviewed by TLC using methanol and
chloroform at 1:9 ratio. The isolated colorless powder was then ana-
lyzed with UV–Vis, IR,
1
H NMR and
13
C NMR spectroscopies for
appropriate characterization of palmitic acid (Bulama, Dangoggo,
Halilu, Tsaf, & Hassan, 2014).
4.7 |Isolation of hexadecanoic acid methyl ester
Methanolic extract was fractionated using flash column chromatography
using mixtures of hexane and ethyl acetate. Oil was acquired with hexane
inethylacetate.GC–MS and spectroscopic analyses confirm the hex-
adecanoic acid methyl ester presence (Ajoku, Okwute, & Okogun, 2015).
14 PATRA ET AL.
4.8 |Isolation of methyl linoleate
It was extracted with n-hexane, then quantified by HPTLC and applied
directly to flash chromatography using hexane:acetone (40:60) in
order to isolate methyl linoleate as pale-yellow viscous oil (Jubie,
Dhanabal, & Chaitanya, 2015).
5|ANTIVIRAL EFFECTS OF ACTIVE
CONSTITUENTS FROM SA
SA is rich in flavonoids, alkaloids, tri-terpenoids, saponins, tannins, and
anthraquinones along with a repository of reducing sugars, amino
acids, and proteins. Several biologically important phytochemicals
reported from SA have shown to have antiviral effects and were stud-
ied against several viral pathogens. Shikimic acid (3,4,5-trihydroxy-
1-cyclohexene-1-carboxylic acid), a natural organic compound and an
important intermediate in the biosynthesis of various phytochemicals,
is one of the most widely studied molecules from SA in the context of
its antiviral effects. It is the key intermediate of the shikimic acid path-
way and has gained relevance as a substrate for the chemical synthe-
sis of the drug oseltamivir phosphate (OSP), known commercially as
Tamiflu (Candeias, Assoah, & Simeonov, 2018). This drug is an
efficient inhibitor of the surface protein neuraminidase (NA) enzyme
of the seasonal influenza virus types A and B, avian influenza virus
H5N1, and human influenza virus H1N1 (Bradley, 2005). Although SA
pods were one of the main sources of shikimic acid, the yield was only
up to 17% (dry basis content) and was not sufficient to meet the high
demand for the OSP drug to manage the major influenza outbreaks.
As an alternate, advancements in biotechnology had helped in design-
ing innovative strategies of synthesizing shikimic acid using genetically
modified Escherichia coli (Bilal et al., 2018; Martínez, Bolívar, &
Escalante, 2015).
While shikimic acid is the most important bioactive from SA, stud-
ies have reported several other molecules as well with prominent ant-
iviral effects. In a study wherein two new compounds, illiverin A and
tashironin A, reported from the roots of I.verum along with seven
other known compounds, namely, 4-allyl-2-(3-methylbut-2-enyl)-1,-
6-methylenedioxybenzene-3-ol; illicinole, 3-hydroxy-4,5-methylenedi-
oxyallyl-benzene; (−)-illicinone-A; 4-allyl-4-(3-methylbut-2-enyl)-
1,2-methylenedioxycyclohexa-2,6-dien-5-one; 3,4-seco-(24 Z)-cycloart-4
(28),24-diene-3,26-dioic acid; and 26-methyl ester and tashironin, showed
that compounds (−)-illicinone-A and 26-methyl ester possessed moderate
anti-HIV activity with EC50 values of 16.0 and 5.1 μM, respectively (Song
et al., 2007). Similarly, studies carried out with essential oils from SA also
showed interesting results with respect to its antiviral effects. Studies
TABLE 2 Various compounds reported from other species from the genus Illicium with antiviral effects
Species
number Species Compound Activity against References
1Illicium
jiadifengpi
3,4-Dehydroneomajucin
1,2,3,4-Tetradehydroneomajucin
Hepatitis B (J. Liu et al., 2016)
2 2S-hydroxyl-jiadifenolide, jiadifenlactone acid,
Jiadifenolide, 2-oxo-3,4-dehydroxyneomajucin,
2-oxoneomajucin, neomajucin, majucin, (2S)-
hydroxyneomajucin, (2R)-2-hydroxyneomajucin
and (1R,2S)-1,2-epoxyneomajucin
Expression of HBeAg
and HBsAg
(J.-F. Liu et al.,
2015)
3Illicium
oligandrum
Oligandrin
spirooliganone B
Coxsackie virus B3 (CVB3)
Coxsackie virus B3 and influenza virus
A (H3N2)
(Lü et al., 2015;
Ma et al., 2013)
4Illicium henryi 10-Benzoyl-cycloparvifloralone HBV surface antigen
(HBsAg) secretion and
HBVe antigen (HBeAg) secretion
(Ji-Feng et al.,
2014)
5 Sesquiterpene lactones, henrylactones A–E(1–5),
together with ten known compounds:
Cycloparvifloralone (6), tashironin (7), tashironin
A (8), neoanisatin (9), anisatin (10), anislactone B
(11), 7-O-acetylanislactone B (12), merrillianolide
(13), cyclomerrillianolide (14) and pseudomajucin
(15)
Anti-hepatitis B virus (HBV) (J.-F. Liu et al.,
2010)
6(−)-Dihydrodehydrodiconiferyl alcohol tashironin Both HBsAg and HBeAg
HBV surface antigen
(HBsAg) secretion
(J.-F. Liu et al.,
2010;
J. F. Liu et al.,
2011)
7Illicium majus Majusanic acids E
Majusanic acids F
4-Epi-dehydroabietic acid
Majusanic acids B
Majusanic acid D
Coxsackie B3 virus (Y.-D. Wang et al.,
2013)
PATRA ET AL.15
carried out with the anise oil along with two other essential oils (dwarf-pine
oil and chamomile oil) against different types of thymidine-kinase such as
thymidine-kinase-positive (aciclovir-sensitive) and thymidine-kinase-
negative (aciclovir-resistant) herpes simplex virus Type 1 (HSV-1) showed
that all these essential oils have antiviral activity against the aciclovir-
sensitive HSV strain KOS and aciclovir-resistant clinical HSV isolates as
well as aciclovir-resistant strain Angelotti, through interrupting the adsorp-
tion of herpes viruses. This is different from the mode of action of aciclovir,
which is effective after attachment inside the infected cells. The report
indicated that these oils are capable of exerting a direct effect on HSV and
might be useful in the treatment of drug-resistant viruses (Christine Koch
et al., 2008). Astani, Reichling, and Schnitzler (2011) evaluated the antiviral
activity of SA essential oil against HSV-1 under in vitro condition. Likewise,
another study of anise essential oils on herpes simplex virus Type 2 (HSV-
2), carried out on RC-37 cells using a plaque reduction assay, showed an
inhibition with IC
50
value of 0.016% (Koch, Reichling, Schneele, &
Schnitzler, 2008). Compounds like anethole, 4-methoxy-benzaldehyde,
2-hydroxy-2-(4-methoxy-phenyl)-n-methyl-acetamide, cyclohexyl-ben-
zene, 1-(1-methylethenyl)-3-(1-methylethyl)-benzene, eucalyptol, γ-sitos-
terol, and so forth were also reported from SA with various bioactivities
(Peng et al., 2016). Similarly, there are various other compounds which
have been reported from other species from the genus Illicium which have
potential antiviral effect (Table 2). Ma et al. (2013) have reported isolation
of two novel antiviral compounds spirooliganones A and B, from the roots
of Illicium oligandrum. And among the two, the spirooliganone B was
highly effective against the coxsackie virus B3 and influenza virus A
(H3N2) with IC
50
values of 3.70–5.05 μM than the spirooliganone A com-
pound by a biosynthetic pathway which includes a hetero-Diels–Alder
reaction process of the epimers (Ma et al., 2013). Similarly Lü et al. (2015)
has also isolated the oligandrin and oligandric acid from the roots of
I. oligandrum and tested its promising antiviral activity against the
coxsackie virus B3 (CVB3), influenza virus A/Hanfang/359/95 (H3N2),
and influenza virus A/FM/1/47 (H1N1) (Lü et al., 2015). Liu et al. (2010)
have isolated five new sesquiterpene lactones, henrylactones A–E
along with 10 other known compounds from the stems and roots of
Illicium henryi and tested them for their antihepatitis B virus (HBV)
activities. Among them, tashironin compound exhibited significantly
high activity inhibiting the HBV surface antigen (HBsAg) secretion
and HBV e antigen (HBeAg) secretion using HBV transfected Hep
G2.2.15 cell line (J.-F. Liu et al., 2010). Liu et al. (2016), isolated two
compounds from the fruits of Illicium jiadifengpi,namely,
3,4-dehydroneomajucin and 1,2,3,4-tetradehydroneomajucin, with
potent antihepatitis B virus activities on the Hep G2.2.15 cell line.
Wang et al. (2013) have isolated around 13 compounds from the
roots of Illicium majus and have tested their antiviral potential against
the Coxsackie B3 virus.
6|PRE-CLINICAL AND CLINICAL STUDIES
ON BIOACTIVE COMPOUNDS FROM SA
A number of pre-clinical and clinical studies have been undertaken
to develop the antiviral drug using the shikimic acid isolated from
the Illicium anisatum, or SA (Bradley, 2005). These drugs have been
approved and commercialized in the name of Tamiflu (Bradley,
2005). The mixture of shikimic acid and quercetin has been reported
to be tested against the bird flu in China and Taiwan (Boota,
Rehman, Mushtaq, & Kazerooni, 2018). Besides, there are reports
that the essential oil from the SA and its isolated compounds
exhibited promising antiviral activity against the HSV-1 in the viral
suspension tests (Astani et al., 2011). There are more studies which
have been devoted to the development of drugs against herpes
(7401H HSV1; Allahverdiyev et al., 2013), along with products such
as vaginal gels to fight Candida species, although more significant
studies need to be achieved in order to step into the clinical trial
phases (Gafit¸{t\hskip-0.7ex\char "B8}anu et al., 2016) for these
pharmaceutical formulations. Apart from these, a number of com-
pounds have been isolated from different species of the genus
Illicium and have been tested against different types of viruses
which is summarized in Table 2.
7|CONCLUSION
SA (I.verum) is one of the important plant species which is a reposi-
tory of various types of bioactive molecules. Besides using it as a culi-
nary ingredient, various traditional medicines have reported about the
diverse applications of this plant in managing numerous disease condi-
tions. Nevertheless, the plant is most often commended for its ant-
iviral effects because of the oseltamivir (Tamiflu), which has been
commercially available as a treatment for flu. Besides, it would also be
more impactful to study the immunomodulatory and other virus resis-
tance mechanism that the body exerts against a number of viruses.
Such studies are important because the resistance to viral infections
need not be always through a direct inhibition of virus, but it can also
be through enhancing the body's resistance to the infections. In the
future research work, it is necessary to identify more active com-
pounds and their derivatives from this plant species for their potential
clinical trials for the evaluation of the applicable thwack of I. verum
against numerous human diseases. In this review, the antiviral effects
of SA have been indicated together with the botanical description,
number of phytoconstituents present, and isolation procedure of the
phytochemicals.
ACKNOWLEDGEMENTS
Authors are grateful to their respective institutions for support.
CONFLICT OF INTEREST
Authors declare no conflict of interest with the manuscript.
ORCID
Jayanta Kumar Patra https://orcid.org/0000-0003-4118-4355
Sankhadip Bose https://orcid.org/0000-0001-7327-1619
Sabyasachi Banerjee https://orcid.org/0000-0003-0983-4012
Maria del Pilar Rodriguez-Torres https://orcid.org/0000-0001-9107-
247X
16 PATRA ET AL.
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How to cite this article: Patra JK, Das G, Bose S, et al. Star
anise (Illicium verum): Chemical compounds, antiviral
properties, and clinical relevance. Phytotherapy Research.
2020;1–20. https://doi.org/10.1002/ptr.6614
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