Journal of Biologically Active Products from Nature

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Therapeutic Applications of Natural Products in

Herbal Medicines, Biodiscovery Programs, and
Biomedicine

Phurpa Wangchuk

To cite this article: Phurpa Wangchuk (2018) Therapeutic Applications of Natural Products in
Herbal Medicines, Biodiscovery Programs, and Biomedicine, Journal of Biologically Active Products
from Nature, 8:1, 1-20, DOI: 10.1080/22311866.2018.1426495

To link to this article: https://doi.org/10.1080/22311866.2018.1426495

Published online: 13 Mar 2018.

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 TBAP 8 (1) 2018 pp 1 - 20 1
ISSN Print: 2231-1866
ISSN Online: 2231-1874

Therapeutic Applications of Natural Products in Herbal

Medicines, Biodiscovery Programs, and Biomedicine

Phurpa Wangchuk
Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of
Tropical Health and Medicine, James Cook University, Cairns Campus, QLD 4878, Australia
Received 20 October 2017; accepted in revised form 09 January 2018

Abstract: Natural products had been one of the important sources of remedial agents for thousands of
years. From the data presented in this review, the utilization of biologically active natural products in traditional
medicines and drug discoveries is still alive and well. This review presents the medicinal applications of natural
products in both the traditional and modern medicines and shed lights on historical connections of this two
medical system as well as identifies the potential sources of natural products that have been scantily explored
till date. More than 85-90 % of the world populations rely on traditional medicines that use natural products, for
their primary health services. Almost 73 % of the current pharmaceutical products/drugs are derived from
natural products including medicinal agents from traditional medicines. These drugs are discovered from different
sources including plants, animals and microbes. While plants had been the reliable sources of anticancer and
antiparasitic drugs, microbial sources especially the Streptpmyces (actinomycetes) had been known for their
antibiotic and anti-infective properties. More than 80-90 % of the world’s biodiversity including plants, marine
world, animals, microbes and extremophiles remain under-explored for medicinal applications and merits our
attention in near future.

Key words: Therapeutic applications, natural products, herbal medicine, biodiscovery,

biomedicine.
Introduction too at a great socio economic. This is because of
With the advancement in science and technol- the fact that the drugs available today are still not
ogy, remarkable progress has been made in the very effective particularly with respect to the fight
field of medicine including diagnosis, treatments against drug resistant pathogens and newly
and pharmaceutics. Recent drug discovery tech- emerging infections. This includes infectious dis-
niques based on Structure-Activity Relationships, eases such as AIDS, influenza, tuberculosis and
Computer Modelling, Combinatorial Chemistry, malaria as well as other chronic disorders like
High Throughput Screening and Spectroscopy cancer, autoimmune disorders and central nervous
(MS, NMR, and IR) have triggered and spear- system disabilities (e.g. Alzheimer’s disease). The
headed the discoveries of many natural and syn- lead cause of death is HIV-AIDS, followed by
thetic drugs. A recent world sales of pharmaceu- tuberculosis and malaria. A recent data shows that
ticals (excluding veterinary medicines) were val- the HIV virus had infected at least 21,000,000
ued at ca US$ 325 billion 1. Despite these devel- people worldwide 2 and over 14,000 new infec-
opments, of the known 30,000 human diseases or tions are estimated to occur on a daily basis, nearly
disorders, only one-third can be treated symptom- half of them in women 3 and strikingly affecting
atically with drugs (either in part or fully) and that Africa 4. While malaria continues to affect 1-3
*Corresponding author (Phurpa Wangchuk)
E-mail: < [email protected] > © 2018, Har Krishan Bhalla & Sons
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 2
million lives each year 5, ca. 2 billion people (in- vival of human species and even to this day they
cluding at least 15 million Americans) are affected have become indispensible treatment regimens in
by tuberculosis 6,7. If the strategies to combat both traditional and modern medicines. This re-
these infectious diseases (microbial) are not put view briefly presents the medicinal applications
in place, they will continue to be the leading cause of natural products in both the traditional and
of premature death in both developed and devel- modern medicines and sheds light on historical
oping nations as their resistance to many conven- connections of this two medical system, which
tional drugs is increasing. are often not recognised and appreciated. This
The emergence of drug resistance is of special review also identified the potential sources of natu-
concern to communities worldwide and there is ral products that have been scantily explored till
an urgent need to find concrete solutions for com- date, which could be prioritised in future drug dis-
bating such epidemics. One vital solution to pre- covery programs. The information and the chemi-
vent drug resistance is to use the currently avail- cal structures were mainly acquired from the da-
able drugs more judiciously and optimally. In gen- tabases including SciFinder Scholar, CHEMnet
eral, resistance is observed higher in areas of high Base and Wiley Online Library, Wikipedia and the
consumption of antibiotics and lower in areas of search engines including ScienceDirect, Scirus,
low consumption 8. A study conducted on con- Scopus and Google Scholar.
trolling resistance in community-acquired patho-
gens in Finland in the 1990s, revealed that there Application of natural products in traditional
was a 50 % reduction in the macrolide resistant medicines
group-A Streptococci when the use of macrolides The most remarkable of all the ancient inven-
such as erythromycin were reduced for treating tions was the art of utilising natural products for
the diseases 9. Therefore, choosing the correct treating various ailments, which was initially re-
drug, dose, dose interval and duration of therapy stricted to a few elites such as priests, medicine
may more efficiently provide clinical benefits while men, shamans, magicians and witch doctors 11.
contributing less to resistance than choosing the Many cultures used individual herbs or animals
drug with the narrowest spectrum 10. Engaging as medicines, few traditions propounded power-
evidence-based complementary and alternative ful combinations with different ingredients known
medicines for treating some chronic disorders as poultices, tinctures and mixtures. Even though
especially diabetes, cancer and autoimmune dis- the origin and the chronology of the use of natural
eases, and also developing more appropriate treat- products in medicines are often disputed by the
ment regimens including the super drugs would scholars, it is recorded that the Mesopotamians in
be other possibilities to overcome drug resistance 2600 B.C 14 were the first to apply herbs like oils
or drug shortages. of cypress, cedar, liquorice, myrrh and poppy juice
Super drugs could be developed synthetically, for treating different ailments, all of which are
but experience has taught us that the natural prod- still used today for the treatment of coughs and
ucts such as plants, animals and microorganisms colds, inflammation, and parasitic infections. It is
exhibit bewildering properties wherein their whole said that the Indian Vedic and Buddhism-based
parts or derivatives had been used for social, eco- Sowa Rigpa (also spelled as g.so-ba-rig-pa)
nomic, environmental, traditional and modern concepts of death and medicine dates to 2500 BC
medicines. Because Homo sapiens are herbivores 15
but the best known written documentation of
to some degree, they first encountered bioactive the Indian Ayurvedic system that documented the
agents in vegetal food items 11, and poisonous first use of Datura, Aconitum, Canabis and
plants and animals, which they used as poisons Sarcostemma 11 dates to 1000 BC (Susruta and
for hunting food, warfare, depredating wild ani- Charaka). The Egyptian’s Ebers Papyrus, which
mals and for gaining mastery over a hostile envi- originated in 1500 BC documented some of the
ronment 12-13. The bioactive agents present in the 700 drugs including formulas such as gargles,
natural products have played vital role in the sur- snuffs, poultices, infusions, pills and ointments 14.
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 3
The Chinese materia medica Wu-Shi Er-Bing Fang betan Sowa Rigpa (translated as the Art of Heal-
- dating back to 1100 BC 14,16 - contains 52 pre- ing Sciences 18) have become popular worldwide.
scriptions. The exact origin of Tibetan Sowa Rigpa is
In the Mediterranean countries, pharmacognosy shrouded in mystery. Many Tibetan Sowa Rigpa
reached a summit in Greece in Hippocrates’s era practitioners believe that their medical system was
(460-377 BC) 11. Theophrastus (ca 300 to 322 propounded and taught by Buddha 19,20. The offi-
BC), who was a philosopher and naturalist, was cial Tibetan medical website (http://www.men-
the first to deal with the history of plants, which tsee-khang-exports.org/history.php) shows that
later on helped in the classification of plants in- many medical texts including called Vimalagotra
cluding herbs. Pedanius Dioscorides, a Greek (translated as Immaculate Lineage), g.so-dpyad
physician (ca 40-90 AD) produced De materia ‘bum-pa (One hundred thousand verses of heal-
medica in 78 AD, which described more than 500 ing), g.ser-od dampai m.do (Supreme Golden
medicinal plants and their uses in detail. Galen Rays Sutra) that contained a separate chapter on
(ca 129-199 AD) founded “Galenics” and taught Nad-thams Cad Zhi-bar bYed-pai rGyud (The
pharmacy and medicine in Rome 17. Avicenna Ways of Completely Curing Diseases) and Dul-
(980-1037 AD), a Persian pharmacist, physician, ba rLung (Vinaya Sastra) were taught by Bud-
philosopher and a poet described 1400 drugs and dha mostly using disease and healing as meta-
medicinal plants which greatly contributed to the phors to illustrate his philosophy of the human
formation of a codified Graeco-Roman Medicine condition 21-22. The usage of herbs in these teach-
in the 5th century 11,14. The United States National ings couldn’t be verified. However, it was only in
Institutes of Health (NIH) - National Library of 718-785 A.D that Tibet saw the peak develop-
Medicine (NLM) (www.nlm.nih.gov/hmd/medi- ment of astrology, medicine and astronomical sci-
eval/arabic.html) highlights the history of medi- ence 15,23-24, and that the written text originated.
cines and gives due credence to the Arabs for not During that time, Tibet hosted several medical
only preserving much of the Greco-Roman ex- conferences at Samye inviting the renowned heal-
pertise during the Dark and Middle Ages (5th to ers of that time from China, India, Persia,
12th centuries), but also cross-fertilizing it with Byzantium and Himalayan countries like Nepal
Chinese and Indian herbs. and possibly Bhutan 22. It was reported that all
Though some medieval medical theories and the different medical systems were analysed at
practices are laughable and horrifying, many of this conference and the best practices were in-
them laid sound therapeutic foundations that at- corporated into Tibetan Sowa Rigpa. Pre-Bud-
tempted to explain diseases and healing proce- dhist Shamanistic views and the Bon tradition also
dures on rational principles. Generations of medi- influenced the way Tibetan Medicine evolved 25-
eval healers who embraced new ideas and spread 26
. Later on, this medical system spread to many
them across most of western countries contrib- countries such as Mongolia, Nepal (Mustang),
uted significantly to the development of modern India (Ladhak) and Bhutan 18,27. Many ancient
medicine. It is recorded that Paracelsus (1493- Sowa Rigpa physicians including those from
1541) administered dosage formulations separat- Bhutan obtained their higher degree medical train-
ing “Arkanum” from non-active ingredients of ing/education from the Tibetan Chagpori medical
drugs and this ground-breaking medieval medical college, which was established in 1696 in Lhasa.
knowledge gave rise to western medicine and Today, it is practiced worldwide and there exist
pharmacy. This historical connection between the formal certified medical education providers in
traditional and modern medicines is often forgot- USA, Europe, India, Mongolia and Bhutan-albeit
ten. While the European and African traditional in modified and innovated forms. Sowa Rigpa
medical system (including Egyptian medicine) re- treatment regimen includes five kinds of healing
main neglected, eroded or lost because of the methods: behavioural modification, herbal phys-
dominance of modern medicine, the Indian iotherapy, minor surgery and prescription of herbal
Ayurvedic, Chinese traditional medicine and Ti- medicine. The Sowa Rigpa medicine uses as
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 4
many as 2200 traditional drugs and more than 1000 cological uses of plants from different countries
natural products (bulk of them medicinal plants) appear daily in the high impact journals including
20,25
. Each drug is polyingredient in nature. Journal of Ethnopharmacology, BMC Journal of
In Bhutan, Tibetan Sowa Rigpa was cross-fer- Complementary and Alternative Medicine, Evi-
tilized with its ethnomedical system in the 8th cen- denced-Based Complementary and Alternative
tury A.D and later expanded by Zhadrung Medicine, and many other natural products jour-
Ngawang Namgyal in the 16th century. Though nals, which indicate that many traditional medical
Bhutanese Sowa Rigpa belong to the larger cor- (often called Complementary and Alternative
pus of Tibetan Sowa Rigpa, there are few ideas Medicine) practices are still alive worldwide.
and innovations invented and incorporated to the Currently, it is estimated that approximately 85-
system by the Bhutanese Drungtshos (Traditional 90 % of the world’s population use traditional
physicians). These differences include the use of medicines 27,32-33. WHO estimates showed that
locally available natural products in the formula- 75 % of the French population, 30 % of the Viet-
tions, golden needle therapy (not practiced in Ti- namese population, and 40 % of Indonesia’s popu-
betan Sowa Rigpa), physiotherapy, and profes- lation uses traditional medicines 34. In Germany,
sional and administrative functions. Bhutan’s lo- 77 % of pain clinics provide acupuncture, in Ja-
cal ethnomedical culture, traditions and belief sys- pan 72 % of registered western style doctors uses
tem influenced the way Bhutanese Sowa Rigpa kampo medicine 34 and in Bhutan, Bhutanese
evolved (in isolation from Tibetan Sowa Rigpa) Sowa Rigpa medicine covers 80 % of the
over many centuries. Its official integration with country’s hospitals and basic health units (BHU).
modern allopathic medical system in 1967 and the In terms of economic value, traditional therapies
constant adaptation and innovation to fit itself to contribute to US $ 60 billion a year and the USA
the current need of the country further influenced alone spends US $ 2.7 billion per year followed
the way Bhutanese Sowa Rigpa evolved recently by China with US $ 1.8 billion and Australia with
- making it unique to Bhutan. Currently, the $ 1 billion a year 34. Despite advancement in mod-
Bhutanese Sowa Rigpa uses 300 different types ern hospital services in many countries, such high
of natural products to produce more than 100 tra- demand for traditional medicine is incredible. The
ditional prescription drugs 28-29. Different natural main reasons for such a massive demand could
product ingredients including plants, animal parts, be that the traditional medicines are: a) central to
marine organisms, minerals, rare earth and pre- the cultural and social belief of the people, b) gen-
cious metals, soils and rocks are powdered, mixed erally believed to be health promoting and effec-
and formulated into different dosage forms as: pills tive in treating chronic disorders with minimal side
(39.81 %), tablets (30.10 %), ointments (3.88 %), effects 31, c) affordable for the people as they
syrups (1.94 %), capsules (12.62 %), powders can easily access the natural products from their
(3.88 %), crude extracts (0.97 %) and unestab- environment, d) modern medicines are expensive
lished dosage forms (6.80 %) 30. and therefore cannot be easily accessed by the
In USA, homeopathy (that includes hydro- poor people, and e) subjected to scientific studies
therapy, nutritional therapy, herbal therapy, manual and clinical trials making it more evidence-based
manipulation and midwifery), was founded by medicines and attracting respect from the people.
German physician Hahnemann (1755-1843) and Recent scientific investigation of the principles of
became popular in 1830s. The discovery of anti- drug action of Japanese traditional Sino-medicine
biotics and vaccines in the 20th century dramati- at the molecular level have resulted in obtaining
cally changed medical practice in USA, North many novel compounds and in uncovering new
Americas, Europe and North-West Asia. As a mechanisms of drug action 35. Similarly, clinical
result a separate field of ethno-medicine emerged trials of the Swiss PADMA products derived from
as an academic specialization focusing on tradi- Tibetan medicine proved successful in the treat-
tional healing systems 31. Hundreds of scientific ment of irritable bowel syndrome 36 and fibrinoly-
studies on the verification of ethnopharma- sis with stable intermittent claudication 37-38. The
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 5
traditional medical ideas and practices on ‘diet and natural products - recorded as many as 270,000
life style changes’ is gaining emphasis even in natural products/chemical entities 45. Many of
modern preventive medical approaches to com- these chemical entities form the backbone of
bat lifestyle diseases including diabetes, hyperten- modern drugs.
sion and inflammatory diseases. The traditional A recent review by Newman and Cragg 43 (the
physicians’ recognition (especially practiced in best and the comprehensive review so far) pro-
Tibetan and Bhutanese Sowa Rigpa) of the in- vides comprehensive information on new chemi-
evitability of death and their compassionate role cal entities that were discovered in between 1981-
to help the near-death patient to die peacefully 2014 (almost 34 years timeframe of drug discov-
and less traumatically have been applied in mod- ery) and also clearly segregates the classes of
ern medicine as ‘end of life care’. There are many new chemical entities (NCE) as biological mac-
medical conditions that could be treated effecti- romolecules, unaltered natural products, botani-
vely if the traditional and modern medical system cal drug with defined mixture, natural product
work together through an integrated app-roaches. derivatives, natural product pharmacophore based
Besides providing important health care ser- synthetic products, mimics of natural products,
vices, the traditional medicines are rich in herbal vaccines and purely synthetic drugs. Out of 1562
traditions. It is estimated that about 35-70,000 NCE discovered in this time frame of 34 years,
herbal plant species have at one time or another 73 % belong to natural products and their deriva-
been used in some culture for medicinal purposes tives (including unaltered, altered, inspired, mim-
with majority of them being in Asian medicines ics, natural products synthetics, biologics and bo-
39-40
. While Indians utilize 20 % of their plant tanicals mixtures) and only 27 % of the drugs were
flora as medicinal plants, Chinese uses 19 % of of purely synthetic origin. This indicates that de-
their total plant diversity. Vietnamese, Sri Lankan spite too much focus and funding discharged into
and Thai uses 17 %, 16.5 % and 15.5 % of their combinatorial and synthetic-based drug develop-
plant diversity, respectively. USA, Australia, In- ment, natural products are the major contributor
donesia and Malaysia have a high number of in the armoury of new drugs. This review high-
plant species but their utilization as medicinal lighted 68 medical indications/conditions and the
plants are low. Australia had utilized 7.8 % of its major disease areas that have been investigated
higher plant flora as medicinal plants and this (in terms of numbers of drugs approved) in the
knowledge remains in Aboriginal communities 41. pharmaceutical industry continue to be microbial
Overall, these medicinal plants contain valuable infections (bacterial, fungal and viral), cancer,
ethnobotanical information that navigates new hypertension, inflammation, diabetes and ulcer.
drug discoveries 42. While 23 % of total NCE were developed for treat-
ing bacterial, fungal and viral infections (antimi-
Therapeutic application of natural products crobials), 13 % of total NCE were developed for
in drug discoveries treating cancer. More than 78 % of these antimi-
Generally, screening of secondary metabolites crobials and 87 % of anticancer drugs were of
and development of drugs from natural products natural origins 43. It is however interesting to note
is a very hard task requiring much effort starting that higher percentage of approved drugs/disease
from material identification, collection, extraction, does not necessarily translate into higher sale pro-
isolation, purification and compound identification ceeds.
to pharmacological and clinical testing. However, The domineering contributions of natural prod-
the enormous chemical diversity and highly un- ucts in drug lead discovery and development was
usual structures provided by natural products is enhanced by the technological advancement in the
greater than that offered by most available com- areas of Genomics, Transcriptomics, Proteomics
binatorial approaches based on heterocyclic com- and Metabolomics. Metabolomics is the most re-
pounds 43-44. The Dictionary of Natural Products cent developments and it is being increasingly used
- an authoritative and comprehensive database on in novel drug discovery, drug target identification,
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 6
elucidating mechanism of drug action and inter- therefore they are often species specific. These
action, customizing precision and personalized secondary metabolites have drug-like character-
medicine/drug treatments and in monitoring thera- istics as highlighted in the Lipinski rule of five 48.
peutic outcomes of drug treatments 46. Nuclear The Lipinski rules states that the biologically ac-
Magnetic Resonance, Gas Chromatography Mass tive natural products/drug like compounds/drugs
Spectrometry, Infra Red Spectroscopy, Liquid should have: a) less than five hydrogen bond do-
Chromatography Mass Spectrometry and the nor groups (such as -OH and -NH), b) less than
High Performance Liquid Chromatography are ten H-bond acceptors in the molecule (such as
some of the major advanced equipment used in oxygen and nitrogen atoms), c) a molecular
metabolomics and the isolation of pure compounds weights less than 500 Dalton, and d) Log P value
from different biological sources. While these less than five units.
advanced equipment helped overcome many
hurdles and challenges faced in natural products- Plant sources
based drug discovery programs, the inadequate It is estimated that ca. 250,000 38 to 500,000
supply of lead compounds isolated from natural species of plants grow on earth 14,32-33 and 70 %
sources (often described as ‘valley of death’) re- of all the world’s biodiversity of vertebrates, higher
mains as immense problems faced by process plants and butterflies are harboured by 12 coun-
chemists in translating research laboratory discov- tries; Mexico, Colombia, Ecuador, Peru, Brazil,
eries to commercial items. A review by Newman Zaire, Madagascar, China, India, Malaysia, Indo-
47
demonstrates how this ‘valley of death’ could nesia and Australia 49. The 18 global biodiversity
be overcome in the development of natural prod- hotspots support nearly 50,000 endemic plant spe-
uct-based anti-tumor agents through the interplay cies 49. A high rate of endemism is predicted in
of chemists (natural product isolation experts, syn- oceanic islands like Australia and Madagascar,
thetic chemistry experts, pharmaceutical chem- extreme Himalayan mountain ranges like in
ists and process chemists), biologists (with exper- Bhutan (Fig. 1), and plant symbionts like orchids
tise in marine invertebrates, plants and microbes 50
. These endemic species were found to contain
and in tumor cell and animal-based assays). Gen- varieties of distinctly new chemical structures. It
erally, the starting materials of the biological is reported that only 10-15 % of terrestrial bio-
samples largely affect the supply of lead com- diversity, especially higher plants, were explored
pounds and therefore it is critical to identify the phytochemically for medicinal applications 33, and
sources of natural products more carefully. ca. 85 % to 90 % of this resources still remain
unstudied. A recent reviews by Atanasov et al.51
Sources of natural biologically active natural and Gechev et al.52 provides a fascinating insights
products into plant derived natural products, drug discov-
Sources of biologically active natural products eries and approaches.
include terrestrial plants, animals (especially mam- The main categories of plant-derived drugs that
mals, insects, spiders, reptiles and amphibians), are available today are: terpenes (34 %), glyco-
marine organisms and microorganisms. These sides (32 %), polyketides and others (18 %) and
sources contain primary metabolites (proteins, fats, alkaloids (16 %) 53 (Fig. 2). For examples,
nucleic acids and carbohydrates, which are re- artemisinin (1) (an antimalarial frontline drug) iso-
sponsible for normal growth, development, or re- lated from Artemisia annua belong to the class
production of an organism), and secondary me- of terpenes (sesquiterpene lactone), digoxin (2)
tabolites (organic small molecules including alka- isolated from Digitalis lanata (used for treating
loids, terpenoids, flavonoids, phenolics, glycosides, atrial fibrillation, atrial flutter and heart failure)
polyketides, peptides). The secondary metabolites belong the class of glycoside (cardiac glycoside);
are produced by the organisms to help them in lovastatin (3) (used for lowering cholesterol
adapting to its competitive environment and as (hypolipidemic agent)) preferably isolated fer-
defence mechanism against the predators, and mented Aspergillus terreus but also isolated from
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 7

Fig. 1. High altitude medicinal plant of Bhutan growing in extreme

vegetative and climatic conditions of the Himalayas

Fig. 2. Representative structure of plant drugs belonging to different phytochemicals classes

 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 8
oyster mushroom, Pleurotus ostreatus, belong to aceae) 56. The NAPRALERT database listed
the class of polyketide drugs; and atropine (4) ca.16,000 alkaloids 12,33 but only 600 of them have
(used as nerve agent and for treating uveitis, am- been analysed for their bio-medicinal properties
blyopia and pesticide poisoning) isolated from At- 12
. The most famous examples of plant alkaloids
ropa belladonna belong to the class of alkaloids. that are clinically used today as antitumor and an-
Alkaloids are under-explored for their medici- ticancer drugs belong to different classes as
nal applications despite containing interesting ni- taxanes, velban, oncovin and camtothecins (Fig.
trogenous structural system 54 that could be ex- 3). While taxol (5) (isolated from Taxus brevi-
ploited for therapeutic purposes. They are bio- folia) belong to the class of taxanes, vinblastine
synthesised through elaborate chemical reactions (6) and vincristine (7) (isolated from Catharanthus
(hence diversity in structures) that are quite often roseus) belong to the class of velban and oncovin,
different from laboratory synthesis 55. The alka- respectively. Camtothecin (8) (isolated from
loids serve the plants as a feeding deterrent and Camptotheca acuminata) belong to the class of
protect them from predators and fungal infections, camtothecins. A review by Amin et al.58 provides
and consequently they are observed in areas comprehensive description of the plant derived
where herbivores usually attack (inflorescence, anticancer agents.
young plants and peripheral cell layers of stems Other popular plant alkaloids used as drugs (Fig.
and roots) 12,56-57. This ecological asset provides 4) today are morphine (9) (isolated from Papaver
strong rationale for medicinal applications. It is somniferum and used as an analgesics), and
estimated that 10-15 % of all vascular plants con- galantamine (10) (isolated from Galanthus cau-
tain alkaloids (particularly observed in the fami- casicus and used for the treatment of mild to
lies - Apocyanaceae, Papaveraceae, Papilion- moderate Alzheimer’s disease). Recently, we
aceae, Ranunculaceae, Rutaceae and Solan- found that scoulerine (11) (isolated from the

Fig. 3. Structure showing representative classes of anticancer plant alkaloid drugs

 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 9

Fig. 4. Structure showing different plant alkaloids used as an

analgesic and for treating Alzheimer’s disease and malaria
Bhutanese medicinal plant, Corydalis dubia) sig- Plasmodium falciparum 62-63. Artemisinin (1) and
nificantly inhibited acetycholinesterase with two- its derivatives are the only drugs of choice cur-
fold better than the reference drug, galantamine rently used worldwide 64. Although malaria re-
(10) 59 (Fig.4). Acetycholinesterase is responsible search received well-deserved attention and fund-
for the termination of nerve impulse transmission ing for over a decade, it did not result into any
at the cholinergic synapses by rapid hydrolysis of novel antimalarial drugs or vaccines. Plants still
acetylcholine (ACh), which is a neurotransmitter play vital role in antimalarial drug development
linked to Alzheimer’s disease. The first well- and numerous secondary metabolites has been
known antimalarial plant alkaloid drug, quinine (12) reported as potential drug lead candidates 65-67.
(Fig.4), was the discovered in 1820 by Caventou Very recently, five antimalarial drug lead com-
and Pelletier from the bark of Cinchona offici- pounds with significant antiplasmodial activity
nalis 60. against the multi-drug resistant strain of Plasmo-
The first major research on plant extracts, which dium falciparum were discovered from the
was started in 1947-1980s by screening 600 spe- Bhutanese medicinal plants 42. However, this is
cies of plants belonging to 126 families 61, found only initial phase of drug discovery process and
that several plants (particularly belonging to the whether these compounds could be transformed
family of Simaroubaceae and Amaryllidaceae) had into effective antimalarial drug to combat multi-
significant bioactivity against avian malarias 56. drug resistance remains questionable.
With the discovery of many cheap antimalarial Having reviewed many published papers on
drugs, malaria was eliminated from Europe, North plant-derived drugs, we realised that the medici-
America, Australia, South America and Asia and nal applications of plant kingdom has been mostly
the search for new antimalarial agents became focused on flowering plants. Plant classes includ-
secondary for these countries. Consequently, there ing hornworts, mosses, liverworts, horsetails, ferns,
is only limited armoury of antimalarial drugs to- cycads, lycopods and lichens remains scarcely
day, which is a big concern worldwide due to the studied for medicinal plants and therefore has
emergence of multi-drug resistance strains of merits worthy of our attention in future.
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 10
Animal sources spiders and scorpions and very few have been
Medical and drug scientists understand that ani- studied for bioactive secondary metabolites 69. The
mal-derived drugs or excipients are not as appeal- scorpion venom-based tumor paint is recently
ing as plant drugs, but the search for synthetic approved by FDA for clinical trial on brain tu-
alternatives has often ended in frustration and thus mour patients 70. Out of 100, 000 species of spi-
the animal derived products still play important ders, only 30 have been studied till date for their
role in modern medicine. A number of current venoms 50 . Insect-fungi or often known as
drugs /excipients/creams/mixtures/ vaccines are entomopathogenic fungi constitute 700 known
sourced from porcine, bovine, hamster, murine, fungal species from 100 genera of insects71 and
hen, equine, canine, feline, sheep, fish and shell presents niche chemical diversity with potential
fish, guinea pig and mammalian cells. A for therapeutic applications. Venoms and poisons
Queensland health guideline for use of medicines/ of reptiles and amphibians are interesting category
pharmaceuticals of animal origin 68, listed more of lower animal groups that exhibit fascinating
than 135 medical products as animal natural prod- pharmacological activities worthy of pharmaceu-
ucts or their distant derivatives. Most of these tical applications. For examples (Fig. 5), teprotide
pharmaceutical products are obtained from blood, (13) (parent scaffold of captopril and isolated from
enzymes, intestines, pancreases, ovaries, kidneys, snake, Bothrops jararaca 72) is used as an anti-
meats, fats, milk, sheep’s wool, pressed tallow, hypertensive drug, and the epibatidine (14) (iso-
bee glue, insect secretion and chitins, humanized lated from a frog, Epipedobates tricolor 73) was
antibodies, proteins, murine/human chimeric mono- shown to be a novel non-opioid analgesic agent
clonal antibody, embryos, virus grown in hen eggs, with two hundred times the analgesic potency of
venoms and cartilages 68. The most popular ex- morphine (9).
amples of porcine products are gelatin (used in The recent medicinal applications of parasitic
capsule shells and as stabilisers anticoagulant) and helminths, explained by ‘hygiene hyposthesis’ have
heparin (anticoagulant injection). These animal- been well received worldwide. Shepherd et al. 74
derived pharmaceutical products are big concern and Johnston et al. 75 highlighted the potential of
for people with particular faith, culture and pa- excretory-secretory products of helminths, which
tients (with allergic reaction to the animal sub- comprises proteins and small molecules, as the
stances) and therefore informed consent and de- pharmacopoeia of immunomodulating agents.
cisions are essential while prescribing these medi- Another comprehensive and insightful review by
cations. us 76 highlighted the ability of hookworms and
Amongst the lower groups of animals, venoms other helminths to modulate inflammation, and how
and toxins secreting insects, amphibians, reptiles, some researchers are intentionally infecting hu-
butterflies, bees and wasps, snails, scorpions and man participants with low subclinical doses of lar-
spiders, produce novel bioactive compounds. vae to treat a range of diseases. Our group at the
There are 30 million species of insects including Centre for Biodiscovery and Molecular Develop-

Fig. 5. Representative structures of drug agents from animal sources

 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 11
ment of Therapeutics in Queensland have been 2004 for the treatment of pain 79. In 2007, an-
mining hookworm genomes, proteomes and small other marine natural product, trabectedin (16) (Fig.
molecules from hookworm to be used in the treat- 6) (isolated from sea squirt Ecteinascidia
ment of some autoimmune and allergic disorders turbinata) was the first marine anticancer drug
(including inflammatory bowel diseases, coeliac to be approved in the European Union 79. Aplidine
disease and asthma) that plague industrialized (17) (Fig. 6), obtained from the Mediterranean
countries. tunicate Aplidium albicans, is another potent an-
An important area where drug discovery re- titumor marine drug 80. Vidrabine (18) (Fig. 6),
search focus has been minimal is the lower class which is currently used as an antiviral drug against
of insect including wingless insects such as sil- herpes simplex and varicella zoster viruses, is a
verfish, centipedes, millipedes, small worms, and new generation sugar modified nucleoside ana-
winged insects including butterflies, moths, beetles, log of spongothymidine and spongouridine that
cockroaches, crickets, cicadas, dung flies, ants, were isolated from Caribbean sponge Tethya
hornets, grasshoppers and scale insects. These crypta 81.
insects (though scary and disgusting) have their Recently, jellyfish venom has been studied for
own ecological adaptations that may have niche their bioactive proteins and peptides 83 and these
secondary metabolites, which could be exploited presents potential therapeutic applications. A re-
for future drug discoveries. Drugs and pharma- cent review by Danielle and Wei 84 provides com-
ceutical products, if discovered from these sources, prehensive information on deep-sea marine fauna
would be particularly good news for those people including bryozoan, chordata, cnidarian, echino-
of particular faiths, religion and culture that forbid dermata, microorganisms, mollusca and prorifera,
the use of pharmaceuticals derived from porcine, and highlighted that most of their natural products
bovine and equine products. exhibited low micromolar cytotoxicity towards a
range of human cancer cell lines. It is therefore
Marine sources reasonable to say that marine fauna will be the
The marine world represents 70 % of earth’s source of our next generation anticancer drugs
surface, but only 5 % of the marine organisms that could possibly overtake plant derived cancer
have been explored chemically and a huge diver- drugs in near future.
sity of marine fauna and flora are yet to be inves-
tigated 77. The Dictionary of Marine Natural Prod- Microbial sources
ucts - a comprehensive and authoritative data- About 100 billion - trillion of microbial species
base on marine natural products - recorded more are estimated to be present on Earth 85. Over 1030
than 50,000 known natural products drawn from individual bacteria and more than 80,000 species
marine organisms 78. A number of good reviews of fungi with highly specialised nutritional niche
79-81
highlighted the isolation of bioactive agents, had been recorded till date 71,86-87. It is estimated
clinical trials, novel marine-based drugs and the that only 1 % of bacterial and 5 % of fungal spe-
challenges facing drug discoveries from the ma- cies have been examined or studied till date 14.
rine organisms. Approximately 300 patents on Fungi have been a frequent source of antibiotics,
marine natural products were issued between 1969 ever since the discovery of penicillin (19) (Fig. 7)
and 1999 82 and a number of compounds have from the filamentous fungus Penicillium notatum
progressed to clinical trials in the recent years. In by Alexander Fleming in 1928 96. Some popular
the mid 1980s, bryostatin-1 (15) (Fig. 6) was iso- drugs (Fig.7) derived from microbial sources in-
lated from Bugula neritina, a marine bryozoan, cludes ivermectin (20) (an anthelmintics and anti-
and was found to be effective against ovarian car- parasitic drugs derived from avermectin isolated
cinoma and non-Hodgkin’s’ lymphoma 14. A pep- from Streptomyces avermitilis), rapamycin (21)
tide discovered in a tropical cone snail, Conus (an immunosuppressive agent isolated from Strep-
magus, was the first marine-derived compound tomyces hygroscopicus), streptomycin (22) (an-
to be approved in the United States in December tibiotics isolated from Streptomyces griseus) 96.
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 12

Fig. 6. Structure of representative drugs derived from marine organisms

These drugs effectively managed the infectious metagemnomics and metabolomics studies of mi-
diseases and by 1980s many major infectious dis- crobes is expected to usher in a new era of su-
eases in the developed world were almost eradi- per-drugs that could be used for combating many
cated and half the major pharmaceutical compa- pathogens including the super-bugs.
nies in Japan and the USA stopped their antibac- It became evident to us that microbial sources
terial drug development programs 88. As a result produce structurally diverse secondary metabo-
drug-resistant pathogens were on the rise world- lites but not much effort was put in to tap them
wide 89-95 especially the Staphylococcus aureus for medicinal compounds. There is only limited
and enterococci, which has now developed into works on microbes (bacteria, fungi, virus) that
multi-drug resistant ‘super-bugs’ threatening to put reside or help endophytes, marine organisms,
an end to successful chemotherapy. Therefore, extremophiles, and the Antarctic mosses to sur-
there is urgent need to develop new drugs to com- vive in unusual environment, and their exploita-
bat those multi-drug resistant microbial infections tion could potentially furnish a new class of drugs.
and many researchers including ourselves believe The extremophiles (mostly bacteria) such as
that the solution to this drug resistance problem alkalophiles, halophiles, barophiles, thermophiles
lies within the chemodiversity of microbial spe- and psychrophiles are also under-explored for
cies themselves. Recent focus of the genomics, medicinal applications and they offer a potentially
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 13

Fig. 7. Structures of the representative drugs derived from microbial sources

diverse source of novel bioactive agents 43,96 wor- related genera yield same or structurally related
thy of exploration. compounds. For example, seven different genera
of plants in the Solanaceae contain tropane alka-
Search strategies for biologically active natu- loids 99, while 164 genera of 47 families produce
ral products and drugs both isoquinoline and indole alkaloids 100. Com-
Most of the bioactive natural products and the pletely random screening approach involves study-
drugs are obtained by using four natural products ing plant extracts based on personal interest and
screening strategies including biorational, the easy accessibility of the materials, which had
chemorational and random approaches 69, 97. no prior ethnopharmacological uses or chemo-typi-
Biorational approach includes ethnomedically di- cal rationality whatsoever.
rected screening (based on the ethnopharma- Among these three search strategies, the
cological uses of plants in traditional medicines) ethnodirected biorational approach had proven to
and random high throughput screening (based on be the shortest and the most effective search strat-
the observation of pest-plant analysis, host-para- egy for discovering drugs from nature. This is
site interactions plant characteristics and their mainly because their long history of clinical uses
ecological adaptation). Only one anti-HIV agent enhances the hit rate of a new drug lead candi-
was discovered as a result of random high date. For example, the National Cancer Institute,
throughput screening 98. The chemorational ap- USA, reported that the medicinal plant extracts
proach is based on chemotaxo-nomical consider- gave greater bioactivity hit rates than those ran-
ations such as alkaloid surveys, and investigation domly studied plant extracts 101. Similarly, out of
of specific families which are known to contain 800 Vietnamese and Lao medicinal plant extracts
similar compounds that showed prior biological that were investigated, more than 25 biologically
activities or had been identified as drug leads 97. active compounds were identified and of these
It has been found that species in a given genus or 13 were new anti-HIV agents and three were
 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 14
antimalarial agents 102. A recent study involving capnoidine and 14-O-acetylneoline, mitigated in-
Bhutanese medicinal plants also support this view- flammation in a murine model of ulcerative colitis
point of bioactivity hit rates and scientific find- 112
. All these high hit rate of bioactivity was made
ings. From nine Bhutanese medicinal plant spe- possible through the guidance provided by the eth-
cies investigated for their phytochemical and bio- nobotanical information of the medicinal plants.
logical activities in between 2002-2015, 181 These are only a handful of examples of ethno-
phytochemicals including five new phytochemicals directed biorational approach for screening me-
were identified using GCMS and NMR spectros- dicinal plants. There exist colossal scientific lit-
copy 42. Out of 55 compounds that were isolated erature (on the phytochemicals and biological ac-
from these nine plants, 32 compounds were tested tivities of medicinal plants) published by the Jour-
for their biological activities (antimicrobial, anti- nal of Ethnopharmacology, BMC Complementary
malarial, anti-inflammatory, anti-acetylcholinest- and Alternative Medicine, Evidence-based
erase and anthelmintic properties) and 15 of them Complementary and Alternative Medicine, Jour-
exhibited promising results. While five compounds nal of Natural Products, Phytochemistry,
demonstrated strong antimalarial activity against Phytotherapy Research, Natural Product Com-
multidrug resistant strains of Plasmodiam munications, Phytomedicine and other journals on
falciparum (patented) 103-109, one compound a monthly basis. Such published information helps
showed strong acetylcholinesterase activity two- the researchers and the pharmaceutical compa-
fold better than the drug, galantamine (10), which nies to select the most potential bioactive com-
is currently used for treating Alzheimer’s disease pounds as drug lead candidates. An analysis by
42
. Recently, we have shown that out of 10 com- Fabricant and Farnsworth 113 on the origin of the
pounds tested, four of them (Fig. 8): isomyristicin drugs developed between 1981 and 2001 showed
(23), bergapten (24), luteolin (25) and linalool ox- that 80 % of 122 plant-derived drugs were dis-
ide acetate (26) showed strong dual anthelmintic covered as a result of chemical studies directed
activities against Schistosoma mansoni and Tri- at isolating the biologically active substances from
churis muris 110-111. Bergapten and luteolin were the plants used in traditional medicines. Between
effective against the schistosomulum stage of S. 2000 and 2005, about five medicinal plant-based
mansoni, to which praziquantel is ineffective. Out drugs were introduced in the United States mar-
of seven alkaloids tested, two compounds, ket and another seven plant-derived compounds

Fig. 8. Structures of anthelmintic compounds identified from Bhutanese medicinal plants

 Phurpa Wangchuk / TBAP 8 (1) 2018 pp 1 - 20 15
are currently in clinical trials around the world 114- and the modern drug discoveries are praisewor-
115
. thy and inspirational. Traditional medicines, that
Although an ethnodirected biorational search use natural products as the bulk ingredients, pro-
strategy furnishes high hit rate of bioactivity, it is vide primary health care services to more than
crucial to have intimate understanding of the dis- 85-90 % of world’s population - while at the same
ease concepts of the culture whose pharmacopeia time providing useful ethnobotanical information
is under examination. The products used as medi- for effective modern drug discovery programs.
cines by local people are usually not those that Almost 73 % of current pharmaceuticals are natu-
are tested in the laboratory. Most of the effective ral products derivatives, which were discovered
brews or formularies are multi-ingredient com- using biorational, chemorational, and random high
pounds. Chemical reactions occur within these throughput screening protocols. The 2015 Nobel
mixtures or poultices and are most often associ- Prize for Physiology or Medicine to Omura and
ated with synergism making them more effective Campbell - for their discovery and development
than the single isolated lead compound. When the of the avermectin/ivermectin complexes from
medicinal plants are subjected to phytochemical Streptomyces avermitilis, a soil actinomycete, and
screening, researchers often target only one com- to Tu Youyou - for her discovery and develop-
pound, or a few limited compounds, which quite ment of artemisinin from Artemisia annua, de-
often turn out to be biologically inactive owing to picts the importance of both chemorational and
the loss of other active components during this ethnodirected biorational approaches to drug dis-
screening process. Therefore, the ethnomedical covery.
indication may not necessarily be productive when These recognitions will serve as an inspiration
screening is directed towards only specific phy- to further explore the rich biodiversity for medici-
tochemical isolations. nal applications. More than 80-90 % of the world’s
biodiversity including plants, marine organisms,
Conclusion and future prospects on natural animals, microbes and extremophiles remain un-
products der-explored and are worthy of investigation to
Nature is the best chemist. It’s overwhelmingly discover novel natural products, drug lead com-
perpetual contribution of biologically active natu- pounds and the drugs, which could be used for
ral products to the expansion of traditional medi- combating the drug resistant pathogens and newly
cines (complementary and alternative medicines) emerging infectious diseases.

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