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J Med Sci, Volume 48, No. 4, 2016 October: 226-239
226
J Med Sci, Volume 48, No. 4, 2016 October: 226-239
Corresponding author: etinurweningsholikhah@ugm.ac.id
Indonesian medicinal plants as sources of
secondary metabolites for pharmaceutical
industry
Eti Nurwening Sholikhah
Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah
Mada, Yogyakarta, Indonesia
DOI: http://dx.doi.org/10.19106/JMedSci004804201606
ABSTRACT
Medicinal plants are widely used in traditional medicine in both underdeveloped and
developing countries in the word until now. Some secondary metabolites isolated from
medicinal plants have been developed as modern drugs. New antimalarial artemisinin is
an example of modern medicine that developed from Artemisia annua L, a plant used
in China since 4,000 years ago. Indonesia is endowed with a rich natural resource.
The biodiversity comprises thousands plant species. Therefore, Indonesian ora and
fauna are a remarkable opportunity for the development of secondary metabolites for
pharmaceutical industry. The Indonesian National Agency for Drug and Food Control,
Republic of Indonesia (Badan Pengawas Obat dan Makanan, Republik Indonesia = BPOM
RI) classies traditional medicine into three classes, namely jamu (Indonesian indigenous
traditional medicine), standardized herbal medicine and phytopharmaca based on its
scientic evidences. The BPOM also determined 9 medicinal plants for focusing research
for drug development. This paper discusses some secondary metabolites and their
pharmacological activities of the following 9 selected Indonesian medicinal plants namely
Piper retrofractum Vahl, Andrographis paniculata Ness, Curcuma xanthorrhiza, Psidium
guajava L, Syzigium polyanthi, Morinda citrifolia, Guazuma ulmifolia Lamk, Zingiber
ofcinale, and Curcuma domestica collected from various publications. Furthermore,
several modern drugs derived from medicinal plants are also discussed.
ABSTRAK
Tanaman obat telah digunakan secara luas dalam pengobatan tradisional baik di negara-
negara belum dan sedang berkembang di dunia hingga saat ini. Beberapa metabolit sekunder
dari tanaman obat telah dikembangkan menjadi obat modern. Antimalaria artemisinin
adalah salah satu contoh obat moderen yang dikembangkan dari tanaman Artemisia annua
L, suatu tanaman obat yang digunakan di Cina sejak 4000 tahun yang lalu. Indonesia
dianugerahi oleh kekayaan alam yang melimpah dengan ribuan keanekaragaman hayati
yang terdiri dari ribuan spesies tanaman. Oleh karena itu ora dan fauna Indonesia sangat
terbuka lebar untuk dikembangkan untuk kepentingan industri farmasi. Badan Pengawas
Obat dan Makanan, Republik Indonesia (BPOM RI) mengelompokkan obat tradisional
dalam tiga kelas yaitu jamu, obat herbal terstandar dan tofarmaka berdasarkan bukti
ilmiahnya. Ada 9 tanaman Indonesia yang telah ditetapkan oleh BPOM RI untuk menjadi
fokus penelitian dan pengembangannya menjadi obat. Makalah ini mengulas tentang
kandungan metabolit sekunder dan aktivitas farmakologi dari ke 9 tanaman obat tersebut
dari berbagai publikasi yaitu cabe jawa (Piper retrofractum Vahl), sambiloto (Andrographis
paniculata Ness), temulawak (Curcuma xanthorrhiza), jambu biji (Psidium guajava L),
227
Sholikhah, Indonesian medicinal plants as sources of secondary
metabolites for pharmaceutical industry
salam (Syzigium polyantha), mengkudu (Morinda citrifolia), jati belanda (Guazuma ulmifolia
Lamk), jahe (Zingiber ofcinale), dan kunyit (Curcuma domestica). Selain itu, beberapa
obat modern yang telah berhasil dikembangkan dai tanaman obat juga dibahas.
Keywords: medicinal plants - pharmacological activities - pharmaceutical industry
-secondary metabolite - traditional medicine
INTRODUCTION
Recently, medicinal plants are widely
used in traditional health care in both
developing and developed countries. Various
traditional medicine (TM) from different
cultures in the word used medicinal plants as
the backbone for thier health care system. In
Indonesia, the use of TM has been embedded
on the national culture since centuries ago.
As a mega biodiversity country, Indonesia
is endowed with a rich natural resource
including TM materials as a national asset that
needs to be explored, researched, developed
and optimized for their utilization. Therefore,
the national asset has a value and comparative
advantage as a major base in the capital
utilization and development efforts to be
competitive commodity.1
Some attempts have been conducted
both at the global and regional level for the
harmonization of standards and quality of
TM. Therefore, the TM can be traded across
countries with the same standards and quality.
World Health Organization (WHO) has
issued some policies concerning traditional
medicine, such as WHO Traditional Medicine
Strategy 2002-2005,2 National Policy on
Traditional Medicine and Regulation of
Herbal Medicine,3 and Development of
Traditional Medicine in the South-East Asia
Region.4 These policies have been adopted by
WHO member countries including Indonesia
in the development their TM potencies.
As medicine, the use of TM must meet the
requirements of safety and effectivenes. The
TM must be implemented based on scientic
evidences to improve human health outcomes,
including physical, mental and social well-
being. Therefore UNESCO’s International
Bioethics Committee included the subject of
TM in its work program for 2010-2011.5
Plant secondary metabolites play an
important role in determining of biological
activities of medicinal plants used in TM.
Therefore, identication and isolation of
the secondary metabolites are important to
standardize and to increase quality of the
TM. Over 24,000 stuctures of secondary
metabolites have been isolated and evaluated
its biological activities. Some of them have
antinutritional and toxic effect on mammals.6
Moreover, some of plant secondary metabolites
are successfully developed as modern drugs.
At least 119 bioactive compounds from plant
secondary metabolites that were being used as
drugs. Some of these drugs are still obtained
commercially, for the most part, by extraction
from only about 90 species of medicinal
plants.7 With more than 250 000 species of
medicinal plants known to exist on this word,
common sense dictates that many more useful
drugs remain to be discovered from this
medicinal plants.
Some examples of modern drugs developed
from medicinal plants are new antimalarial
artemisinin from Artemisia annua L, a plant
used in China for many centuries,8 inotropic
digitalis glycosides from Digitalis purpurea,9
anticancer of vinca alkaloids (vincristine and
vinblastie, vindesine, and vinorelbine) from
J Med Sci, Volume 48, No. 4, 2016 October: 226-239
228
Catharanthus roseus10-12, antimuscarinic
belladonna alkaloids (atropine, hyoscine or
scopolamine) from Atropa belladonna,13 and
antirheumatic colchicine commonly produced
by plants like Colchicum autumnale and
Gloriosa superb.14
Indonesia has the biodiversity comprises
thousands plant species. Therefore,
Indonesian ora is a remarkable opportunity
for the development of secondary metabolites
for pharmaceutical industry. The BPOM
classies the TM into three classes, namely
traditional jamu , standardized herbal
medicine jamu and phytopharmaca jamu
based on its scientic evidences. Traditional
jamu is Indonesian indigenous traditional
medicine that its use just based on empirical
experiences. Whereas, standardized herbal
medicine jamu is dosage form of natural
medicine which has been proven for its safety
and pharmacological effect at preclinical
study, and the material has been standardized
and phytopharmaca jamu is dosage form of
natural medicine which has proven for its
safety and pharmacologycal effect preclinical
and clinical study, and its material and product
have been standardized.15
The BPOM also decided 9 plants to be
research focus for drug development. These
plants were investigated their biological
activities by Indonesian and foreign
researchers. Furthermore, the secondary
metabolites of these plants were isolated and
identied. However, their development both
as TM or modern drugs remains stagnant. This
paper discusses some secondary metabolites
and their pharmacological activities of the
9 selected Indonesian medicinal plants that
potentially developed as TM or modern drugs.
Several modern drugs derived from medicinal
plants are also discussed.
DISCUSSION
Indonesian medicinal plants as source of
secondary metabolites
1. Piper retrofractum Vahl (Cabe Jawa)
Piper retrofractum Vahl (Piperaceae) is
Indonesian indogenous plant. As a garden
medicinal plant, it grows well in secondary
forests lowland. The synonim of P. retrofractum
Vahl is P. longum. This plant is known locally
as cabe jawa, cabe jamu (in Java), cabe solak
(Madura) and cabia (Sulawesi). Piper longum
oils contain few secondary metabolites
monoterpene hydrocarbons, a moderate
content of sesquiterpenes and high content of
aliphatic hydrocarbons.16 Piperidine alkaloids
(FIGURE 1) from P. retrofractum Vahl.
protect against high-fat diet-induced obesity.17
FIGURE 1. Piperidine alkaloids isolated from P. retrofractum Vahl
229
Sholikhah, Indonesian medicinal plants as sources of secondary
metabolites for pharmaceutical industry
2. Andrographis paniculata Ness
(Sambiloto)
Andrographis paniculata Ness is very
well known in Indonesia as a medicinal plant
because of its bitter taste. It is known locally
as sambiloto. Andrographis paniculata
Ness is traditionally used to treat various
diseases such as high blood pressure, fever,
malaria, diabetes, gastrointestinal disorders,
inammation, dysentery and cancer. The main
active compound is andrographolide (FIGURE
2). However it also contains avonoids such as
5,7,2’, 3’-tetrametoksiavanon, 5-hydroxy-7,
2’, 3’-trimetoksiavon,18 5-hydroxy-7’,
2’,6-trimetoksiavon and 14-deoxy-15,12-
11-isopropiliden-dehidroandrografolid.19
Andrographolide has been proven to have a
variety of pharmacological activities such as
anti-inammatory, antibacterial, antidiabetic,
and anticancer. Shi et al.19 reported that
andrographolide inhibits invasion and migration
of colorectal cancer cells by inhibiting the
activity of MMP-7 expression, whereas Lee et
al.20 proved andrographolide inhibits invasion
and migration of lung cancer cells (A-549)
by inhibiting P13K/Akt signaling pathways.
Some andrographolide derivatives have been
successfully synthesized and tested for their
anticancer activity by several researchers. Jada
et al.21 reported that benzylidene derivatives
of andrographolide inhibit growth of breast
and colon cancer cells in vitro by inducing
G(1) arrest and apoptosis.
FIGURE 2. Andrographolide isolated from A. panicu-
lata Ness
3. Curcuma xanthorrhiza (Temu Lawak)
Curcuma xanthorriza has been used
traditionally by Indonesian people to cure
acne, increased appetite, anti-cholesterol, anti-
inammatory, anemia, antioxidant, cancer
prevention, and antimicrobial. It is well known
as temu lawak. Curcuma xanthorriza has a
variety of pharmacological activities such as
analgesic, antidiabetic, antihyperlipidemic
and stimulants. Beside curcumin, some
other specic active compound found in C.
xanthorriza, i.e. xanthorrizol, ar-tumerone
and α-curcumin (FIGURE 3). Xanthorrizol as
the main compound in C. xanthorriza has been
proven as antioxidant and anti-inammatory.22
Activity and cytotoxic mechanism of
xanthorrizol in some cancer cells in vitro
have been reported by several investigators.
Ismail et al.23 reported xanthorrizol induce
apoptosis of HeLa cells via the up-regulation
of bax and p53. Xanthorrizol also showed
antiproliferative activity in breast cancer
cells MCF-7 via apoptosis induction through
modulation of bcl-2, p53 protein and PARP-
1.24
FIGURE 3. Some active compounds isolated from C.
xanthorriza.
Another study conducted by Handayani
et al.25 proved that xanthorrizol has
antiproliferative activity on hepatoma HepG2
cell by inducing apoptosis through p53, Bcl-
2 and caspase-dependent signaling pathway.
Xanthorrizol also reported to inhibit the
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230
proliferation of HCT116 colon cancer cells
line by inhibiting the cell cycle in the G0/G1
phase and G2/M regulation through inhibition
of cyclin A, B1, and D1 and cyclin-dependent
kinase 1 (CDK1), CDK2 and CDK4. It also
has p21, p27 and cyclin-dependent kinase
inhibitors activity.26
4. Psidium guajava L (Jambu Biji)
Psidium guajava, commonly known as
guava or jambu biji in Indonesia is belonging
to family of Myrtaceae, native plant of tropical
America and has long spread to southeast Asia.
Guava is a fruit rich in bioactive compounds
that may be used in various way to offer to the
population the possibility of preventing certain
chronic disease at low cost because of its
antioxidant activity.27 Guava leaf extracts are
rich sources of natural antioxidants and could
be developed into functional food or drug
against diseases and for a variety of benecial
chemo-preventive effects.28 Guava extract
exerted a potent anti-nociceptive effect.29
Begum et al.30 reported that two triterpenoids,
20b-acetoxy-2a,3b-dihydroxyurs-12-en-
28-oic acid (guavanoic acid) and 2a,3b-
dihydroxy-24-p-z-coumaroyloxyurs-12-en-
28-oic acid (guavacoumaric acid) along with
FIGURE 4. Asiatic acid isolated from P. guajava
5. Syzigium polyanthi (Salam)
Syzigium polyanthi with its synonym
Eugenia polyantha or Indonesian bay leaf is
one of spice used in Indonesia. It is known as
salam in Java. It has antioxidant activity.31
Three phenolic pancreatic lipase inhibitors
(FIGURE 5) were isolated from E. polyanthi.
Although the activities of the isolated
compounds were mild, the abundant content
of hydroxychavicol in this spice makes it quite
attractive as a food additive for the treatment
and prevention of obesity.32
FIGURE 5. Three phenolic pancreatic lipase inhibitors isolated from E. polyanthi.
2a-hydroxyursolic acid, jacoumaric acid,
isoneriucoumaric acid, asiatic acid, ilelatifol
D, and b-sitosterol-3-O-b-d-glucopyranoside
have been isolated from P. guajava leaves. The
asiatic acid (FIGURE 4) showed spasmolytic
activity.30
231
Sholikhah, Indonesian medicinal plants as sources of secondary
metabolites for pharmaceutical industry
6. Morinda citrifolia (Mengkudu)
Morinda citrifolia has been used in
traditional Polynesian medicine for over 2000
years. Its Indonesian name is mengkudu. It is
reported to have a broad range of therapeutic
effects, including antibacterial, antiviral,
antifungal, antitumor, antihelmint, analgesic,
hypotensive, anti-inammatory, and immune
enhancing effects.33 Morinda citrifolia is an
evergreen shrub whose ripe fruit has a strong
butyric acid smell and avor. The leaves and
especially the fruit are consumed in different
forms by various communities throughout the
world, the root is used as a dye.34 Morinda
citrifolia aquous extract as well as its biomarker
scopoletin (FIGURE 6) may be benecial as
a potential preventive and therapeutic agent
for gastro-esophageal inammatory diseases,
mainly through its antisecretory and prokinetic
activities including an inhibitory activity
on serotonin, free radicals, and cytokine-
mediated inammation.35,36 A known major
component (scopoletin) in M. citrifolia was
chosen as a marker and monitored in the
plasma and in different organs over time
by HPLC analysis.33 Other contents are
alizarin, aucubin, aracetin, asperulocidic
acid, citrifolinoside B, damnacanthal,
1,3-dihydroxy-6-methyl anthraquinone,
5,6-dihydroxylucidin, 2-methyl-4-
hydroxy-5,7-dimethoxyanthraquinone,
3-hydroxymorindone, 8-hydroxy-8-methoxy-
2-methyl-anthraquinone, lucidin, 2-methyl-
3,5,6-trihydroxyanthraquinone, morenone
FIGURE 6. Scopoletin isolated from M. citrifolia
7. Guazuma ulmifolia Lamk (Jati Belanda)
In traditional medicine, the bark of
G. ulmifolia Lamk, with local name jati
belanda, is used in the treatment of diarrhea,
hemorrhages, fever, inammatory diseases,
and as stimulant for uterine contractions.
Dried leaves are brewed into tea in some
countries and used for gastrointestinal
diseases and dysentery. The aerial parts of G.
ulmifolia Lamk have shown a gastroprotective
effect against the injurious effect of NSAIDs
(non-steroidal anti-inammatory drugs)
mainly by anti-inammatory and radical-
scavenging mechanisms.37 Fraction obtained
from G. ulmifolia Lamk bark produces
signicant antihypertensive effects. The
phenolic compounds such as oligomeric
procyanidins were detected in the PCF
by FAB+-MS and HPLC–DAD–ESI/
MS analysis.38 The chemical structure of
polymeric proanthocyanidin and oligomeric
proanthocyanidin were shown in FIGURE 7.39
1, morenone 2, morindanidrine, morindine,
morindone, physcion, ruberythric acid,
rubiadin, rubiadin monomethyl ether,
soranjidiol, and ursolic acid.34
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232
FIGURE 7. Oligomeric proanthocyanidin and polymeric proanthocyanidin isolated from G. ulmifolia
8. Zingiberofcinale(Jahe)
Zingiber ofcinale or called jahe in Java, is
known as seasoning. Traditionally, it also used
as a carminative and stimulant, to increase
appetite, treat the digestive tract disorder such
as nausea and vomit, to treat common cold,
cough, diarrhea, malaria, fever and arthritis.
Some scientic research have proven that it
has some pharmacological activity such as
immunomodulator and antimicrobial,40 in vitro
antihelminth,41 antinausea and vomiting,42
antioxidant,43 and anticancer.44
Phytochemical studies of Z. ofcinale showed
that it contains some chemical compounds from
various groups such as paradol, dihydroparadol,
gingerol, acetyl gingerol derivatives, shogaol,
3-dihydroshogaol, gingerdiol, mono-and diacetyl
gingerdiol derivatives, 1-dehydrogingerdione,
diarylheptanoide and metal ether derivatives.45
The chemical structure of some active compound
of Z. ofcinale can be seen in FIGURE 8.
Among some active compounds, gingerol is
compound which is often used by researchers
as a marker for extract standardization.
FIGURE 8. Some active isolated from Z. ofcinale.
233
Sholikhah, Indonesian medicinal plants as sources of secondary
metabolites for pharmaceutical industry
9. Curcuma domestica (Kunyit)
Curcuma domestica with its synonim
C. longa is one of the ginger family,
Zingiberaceae that widely distributed in
Asia.46,47 Curcuma domestica has been used
as seasoning, food coloring and traditional
medicine. In Indonesia it is well known as
jahe. As a traditional medicine, C. domestica
has been used to treat various diseases such as
diabetes, leprosy, gastrointestinal disorders,
tonic, laxative, rheumatic, antiseptic, hepatic
disorders, and cancer. Curcuma domestica
contains curcumin and its derivatives such as
bis-demetoxycurcumin, demetoxycurcumin.
It contains active compounds such as
curcumarol, α-, β-and ar-turmerone, and
zingiberene (FIGURE 9).
FIGURE 9. Some active compounds of Curcuma domestica
Curcumin and its derivatives have been
widely demonstrated to have great potential
to be developed as anticancer. From several
studies summarized by Aggrawal et al.48
showed that curcumin can inhibit the in
vitro proliferation of various cancer cells
such as T and B cell leukemia, colon cancer,
skin cancer, breast cancer BT20, SKBR3,
MCF7, T47D and ZR75-1. Various in vivo
studies in experimental animal also showed
that curcumin has chemopreventive and
chemotherapeutic activities in animal models
of cancer. Curcumin has been shown to
inhibit tumor initiation induced by benzo(a)
pirene and 7,12dimetilbenz (a) antrasen in
mice. Curcumin is reported to suppress mouse
skin tumor induced by forbol ester, suppress
carcinogenesis in skin cancer, stomach, colon,
liver and breast cancer in mice.49
Modern drugs developed from medicinal
plants
1. Artemisinin
Artemisinin was isolated from Artemisia
annua L, a plant used in China for many
centuries. Artemisinin is a sesquiterpene
lactone that bears a peroxide grouping
and, unlike most other antimalarials, lacks
J Med Sci, Volume 48, No. 4, 2016 October: 226-239
234
a nitrogen-containing heterocyclic ring
system.8 Subsequent studies of the structure
activity relationship led to the discovery
of dihydroartemisinin, artemether and
artesunate. Artemisinin and these three
derivatives (FIGURE 10) are being used
around the world as effective new antimalarial
drugs against falciparum malaria, including
multi-drug-resistant Plasmodium falciparum.
At the present time new artemisinin analogues
or derivatives are being developed. In
addition, recent studies also indicate that
some artemisinin derivatives have other
biological activities including antiparasitic
and anticancer activities.50
FIGURE 10. Artemisinin and its derivatives
2. Digitalis glycosides
Digoxin and digitoxin (FIGURE 11)
known as cardiac glycosides is one example
of a modern drug glycoside isolated from
the plant digitalis (Digitalis purpurea).9,51
Digoxin and digitoxin are cardiac glycoside
with positive inotropic activity. They increase
force and velocity of myocardial systolic
contraction (positive inotropic action), slow
heart rate, decrease conduction velocity
through AV node, and decrease the degree of
activation of the sympathetic nervous system
and renin-angiotensin system.52
FIGURE 11. Digoxin and digitoxin
235
Sholikhah, Indonesian medicinal plants as sources of secondary
metabolites for pharmaceutical industry
3. Vincristine and vinbalastine
Some anticancer used in cancer therapy
rstly isolated from medicinal plants. Vinca
alkaloids (vincristine and vinblastie) were
isolated from Catharanthus roseus.10-12
Vinblastine and vincristine (FIGURE 12)
are alkaloids which used for treatment of
leukemias, lymphomas, and testicular cancer.
A closely related derivative, vinorelbine, has
important activity against lung cancer and
breast cancer.52
FIGURE 12. Vinblastine (R=CH3) and vincristine
(R=CHO).
4. Atropine and hyoscine (scopolamine)
Atropine is major alkaloids of Atropa
belladonna. Further alkaloids in the leaves
are apoatropine, tropine, scopolamine,
aposcopolamine, 3-α-phenyl-acetoxytropane,
and tropinone.13 Atropine (FIGURE 13)
inhibits action of acetylcholine or other
cholinergic stimuli at postganglionic
cholinergic receptors, including smooth
muscles, secretory glands, and central nervous
system (CNS) sites. Hyoscine (scopolamine)
(FIGURE 13) competitively inhibits action
of acetylcholine at muscarinic receptors.
Principal effects are on iris and ciliary body
(pupil dilations and blurred vision), secretory
glands (dry mouth), drowsiness, euphoria,
fatigue, decreased nausea, and vomiting.
Atropine and scopolamine differ quantitatively
in antimuscarinic actions, particularly in their
ability to affect the CNS. Atropine has almost
no detectable effect on the CNS at doses that
are used clinically. In contrast, scopolamine
has prominent central effects at low therapeutic
doses. Because atropine has limited CNS
effects, it is preferred to scopolamine for most
purposes.52
FIGURE 13. Atropine and hyoscine (scopolamine)
5. Colchicine
Colchicine is also known as methyl ether
of colchicines. It is secondary metabolite
commonly produced by plants like Colchicum
autumnale and Gloriosa superba, It is
originally used to treat rheumatic complaints,
especially gout.14 Colchicine is one of the
oldest available therapies for acute gout. It is
considered second-line therapy due to a narrow
therapeutic window and a high rate of side
J Med Sci, Volume 48, No. 4, 2016 October: 226-239
236
effects, particularly at higher doses. The exact
mechanism of action of colchicine in gout is
not completely known. However, it involves
in a reduction of lactic acid production by
leukocytes leads to a decrease in uric acid
deposition, and a reduction in phagocytosis,
with abatement of the inammatory response.52
FIGURE 14. Colchicine
CONCLUSION
Many secondary metabolites have been
isolated from Indonesian medicinal plants.
Some of them have potential biological activities
to further development for pharmaceutical
industry both as TM or modern drugs. To
develop the Indonesian medicinal plant as
national product that can be competitive in
multinational market, studies these plants
for its safety, efcacy and standardization are
necessary. Working collaboration between
botanists, phytochemists, pharmacologists,
organic chemists and others are important to
pursue goal targeted.
ACKNOWLEDGMENT
Author would like to thank Prof. Dr.
Mustofa from Department of Pharmacology
and Therapy, Faculty of Medicine,
Universitas Gadjah Mada for his suggestions
and corrections during preparing of this
manuscript.
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