Drugs from the Natural Bio Sources for Human Disease
M. Mohamed Mahroop Raja
From the past few decades to the future life natural products have played a vital role throughout the world in treating and preventing human disease. The value of natural product in this regard can be based on 3 criteria, (i) The rate of introduction of new chemical entities of wide structural diversity, (ii) The number of disease treated or prevented by these substances and (iii) Their frequency of use in treatment of disease. Microbes have made a phenomenon contribution to the health and well being of people throughout the world. In addition to many primary metabolites such as amino acid, vitamins and nucleotide they also capable of making secondary metabolites, which constitute 1/3 of the pharmaceutical in the market today and provides many essential products to the environment. The new millennium will see further advanced discovery that will keep the sentence Prevention is better than cure.
Received: April 25, 2010;
Accepted: May 11, 2010;
Published: September 02, 2010
For thousands of years, natural products have played an important role throughout
the world in treating and preventing human diseases. Natural product medicines
have come from various source materials including terrestrial plants, terrestrial
microorganisms, marine organisms, and terrestrial vertebrates and invertebrates
(Newman et al., 2000). Therapeutic drugs have
played a major role in increasing average life expectancy in the United States
in the last century. However, while many of the drugs are in use for the last
fifty years or more have been of synthetic or semi-synthetic origin, the pharmacopoeias
prior to that period were of natural origin. The medicinal value of plants has
been recognized by almost every society on this planet. In the nineteenth and
earlier centuries, natural product extracts, particularly those derived from
botanical species, provided the main source of folk medicines. However, in the
latter part of the nineteenth century, biologically-active organic molecules
began to be isolated in relatively pure form for medicinal use. For example,
Salicyclic acid, the precursor of aspirin, was isolated in 1874 from willow
bark. Various more potent painkillers, such as morphine and codeine, were isolated
from the opium poppy. The anti-malarial agent, quinine, was separated from cinchona
(china bark). The leaves of the purple foxglove plant provided an excellent
source of digitalis that was purified for use against heart disease. There are
numerous other examples. Although synthesis of the first synthetic pharmaceutical
drug, aspirin, occurred in the latter half of the nineteenth century, it was
not until the early 1900s that the recognition of aspirin as a universal pain
reliever was realized and this discovery spawned the era of therapeutic agents.
However, it was not until the recognition that many infectious diseases were
caused by microorganisms that the real impetus in the development of therapeutic
agents, both natural and non-natural, began to occur. Concurrent with the discoveries
in medical microbiology were major advances in synthetic organic chemistry and
biochemistry that provided further momentum in the area of therapeutic agents.
Synthetic sulfa drugs, the natural antibiotic, penicillin, from Penicillium
notatum (Alexander Fleming), the semi-synthetic antibiotic, tetracycline, produced
from natural chlortetracycline elaborated by Streptomyces aureofaciens (Benjamin
Duggar) and the anti-tubercular aminoglycoside, streptomycin, from Streptomyces
griseus (Salman Waksman) were all landmark discoveries of the 1930s and 1940s.
The importance of vitamins and diseases caused by their deficiencies were also
being uncovered during this period. During the next several decades advances
in X-ray crystallography, NMR spectroscopy and, mass spectrometry and developments
in electrophoresis, ultracentrifugation, HPLC and other technologies contributed
to the discovery of additional chemical entities with therapeutic activities
and to the development of some vaccines natural products with industrial applications
can be produced from primary or secondary metabolism of living organisms (plants,
animals or microorganisms). Owing to technical improvements in screening programs,
and separation and isolation techniques, the number of natural compounds discovered
exceeds 1 million. Among them, 50-60% is produced by plants (alkaloids, flavonoids,
terpenoids, steroids, carbohydrates, etc.) and 5% have a microbial origin. Of
all the reported natural products, approximately 20-25% show biological activity,
and of these approximately 10% have been obtained from microbes. Furthermore,
from the 22-500 biologically active compounds that have been obtained so far
from microbes, 45% are produced by actinomycetes, 38% by fungi and 17% by unicellular
bacteria (Berdy, 2005). The increasing role of microorganisms
in the production of antibiotics and other drugs for treatment of serious diseases
has been dramatic. However, the development of resistance in microbes and tumor
cells has become a major problem and requires much research effort to combat
it. Raja et al. (2010) reported new antibiotics
that are active against resistant bacteria are required. Bacteria have lived
on Earth for several billion years. During this time, they encountered in nature
a wide range of naturally occurring antibiotics. To survive, bacteria developed
antibiotic resistance mechanism (Hoskeri et al.,
REASONS FOR DEVELOPING NEW ANTIBIOTICS
New antibiotics that are active against resistant bacteria are required. Bacteria
have lived on the Earth for several billion years. During this time, they encountered
in nature a wide range of naturally occurring antibiotics. To survive, bacteria
developed antibiotic resistance mechanisms. Therefore, it is not surprising
that they have become resistant to most of the natural antimicrobial agents
that have been developed over the past 50 years. This resistance increasingly
limits the effectiveness of current antimicrobial drugs. The problem is not
just antibiotic resistance but also multidrug resistance. In 2004, more than
70% of pathogenic bacteria were estimated to be resistant to at least one of
the currently available antibiotics (Katz et al.,
2006) The so-called superbugs (organisms that are resistant to most of the
clinically used antibiotics) are emerging at a rapid rate.
S. aureus, which is resistant to methicillin, is responsible for many
cases of infections each year. The incidence of multidrug-resistant pathogenic
bacteria is increasing. The Infectious Disease Society of America (IDSA) reported
in 2004 that in US hospitals alone, around 2 million people acquire bacterial
infections each year. S. aureus is responsible for half of the hospital-associated
infections and takes the lives of approximately 100 000 patients each year in
the USA alone (Balaban and DellAcqua, 2005). The
bacteria produce a biofilm in which they are encased and protected from the
environment. Biofilms can grow on wounds, scar tissues and medical implants
or devices, such as joint prostheses, spinal instrumentations, catheters, vascular
prosthetic grafts and heart valves. More than 70% of the bacterial species producing
such biofilms are likely to be resistant to at least one of the drugs commonly
used in anti-infectious therapy. In hospitals, there are also other examples
of Gram-positive (Enterococcus and Streptococcus) and Gram-negative
pathogens (Klebsiella, Escherichia, Enterobacter, Serratia,
Citrobacter, Salmonella and Pseudomonas); these hospital-inhabiting
microbes are called nosocomial bacteria. More than 60% of sepsis cases
in hospitals are caused by Gram-negative bacteria. Among them, Pseudomonas
aeruginosa accounts for almost 80% of these opportunistic infections. They
represent a serious problem in patients hospitalized with cancer, cystic fibrosis
and burns, causing death in 50% of cases. Other infections caused by Pseudomonas
species include endocarditis, pneumonia and infections of the urinary tract,
central nervous system, wounds, eyes, ears, skin and musculoskeletal system.
This bacterium is another example of a natural multidrug-resistant microorganism.
Although many strains are susceptible to Gentamicin, Tobramycin and Amikacin,
resistant forms have also developed. These multidrug- resistant bacteria make
hospitals dangerous places to be especially if you are sick but even if not.
CHEMICALLY SYNTHESIZED DRUGS ORIGINATING FROM NATURAL PRODUCTS
Drugs of natural origin have been classified as (1) original natural products
(2) products derived or chemically synthesized from natural products (3) synthetic
products based on natural product structures. Evidence of the importance of
natural products in the discovery of leads for the development of drugs for
the treatment of human diseases is provided by the fact that close to half of
the best selling pharmaceuticals in 1991 were either natural products or their
derivatives (Cragg et al., 1997). In this regard,
of the 25 top-selling drugs reported in 1997, 42% were natural products or their
derivatives and of these, 67% were antibiotics. Today, the structures of around
140 000 secondary metabolites have been elucidated. It is important to understand
that many chemically synthesized drugs owe their origin to natural sources.
Applications of chemically synthesized natural metabolites include the use of
a natural product derived from plant salicyclic acid derivatives present in
white willow, wintergreen and meadowsweet to relieve pain and suffering. Concoctions
of these plants were administered by Hippocrates back in the year 500 BC, and
even earlier in Egypt and Babylonia, for fever, pain and childbirth. Synthetic
salicylates were produced initially by Bayer in 1874, and later in 1897, Arthur
Eichengrun at Bayer discovered that an acetyl derivative (aspirin), reduced
acidity, bad taste and stomach irritation. These plant-based systems continue
to play an essential role in health care, and it has been estimated by the World
Health Organization (WHO) that approximately 80% of the worlds inhabitants
rely mainly on traditional medicines for their primary health care (Farnsworth
et al., 1985).
FREQUENCY OF DRUGS
Scrutiny of medical indications by source of compounds has demonstrated that
natural products and related drugs are used to treat 87% of all categorized
human diseases (48/55), including as antibacterial, anticancer, anticoagulant,
antiparasitic, and immunosuppressant agents, among others. There was no introduction
of any natural products or related drugs for 7 drug categories (anesthetic,
antianginal, anti histamine, anxiolytic, chelator and antidote, diuretic, and
hypnotic) during 1981 to 2002. In the case of antibacterial agents, natural
products have made significant contributions as either direct treatments or
templates for synthetic modification (Esmaeili and Moshiri,
2011). Of the 90 drugs of that type that became commercially available in
the United States or were approved worldwide from 1982 to 2002, ~79% can be
traced to a natural product origin (Newman et al.,
Frequency of use of natural products in the treatment and prevention of disease
can be measured by the number and economic value of prescriptions, from which
the extent of preference and/or effectiveness of drugs can be estimated indirectly.
According to a study by Grifo and colleagues, 884 of a representative 150 prescription
drugs in the United States fell into the category of natural products and related
drugs. They were prescribed predominantly as anti-allergy/pulmonary /respiratory
agents, analgesics, cardiovascular drugs, and for infectious diseases. Another
study found that natural products or related substances accounted for 40, 24,
and 26%, respectively, of the top 35 worldwide ethical drug sales from 2000-2002.
Of these natural product-based drugs, paclitaxel (ranked at 25 in 2000), a plant-derived
anticancer drug, had sales of $1.6 billion in 2000 (Oberlies
and Kroll, 2004).
DRUG DISCOVERY FROM TERRESTRIAL PLANTS
Terrestrial plants, especially higher plants, have a long history of use in
the treatment of human diseases. Several wellknown species, including licorice
(Glycyrrhiza glabra), myrrh (Commiphora species), and poppy capsule
latex (Papaver somniferum), were referred to by the first known written
record on clay tablets from Mesopotamia in 2600 BC, and these plants are still
in use today for the treatment of various diseases as ingredients of official
drugs or herbal preparations used in systems of traditional medicine. Furthermore,
morphine, codeine, noscapine (narcotine), and papaverine isolated from P.
somniferum were developed as single chemical drugs and are still clinically
used. Hemisuccinate carbenoxolone sodium, a semi-synthetic derivative of glycyrrhetic
acid found in licorice is prescribed for the treatment of gastric and duodenal
ulcers in various countries (Dewick, 2002). From terrestrial
plant-derived secondary metabolites, several new chemical entities are undergoing
clinical trials including four that are derivatives of known anticancer drugs
Such as camptothecin, paclitaxel, epipodophyllotoxin, and vinblastine (Butler,
DRUG DISCOVERY FROM TERRESTRIAL MICROORGANISMS
Until the development of penicillin in the early 1940s, most natural product-derived
drugs were obtained from terrestrial plants. The success of penicillin in treating
infection led to an expansion in the area of drug discovery from microorganisms.
Terrestrial microorganisms are a plentiful source of structurally diverse bioactive
substances, and have provided important contributions to the discovery of antibacterial
agents including penicillins, cephalosporins, aminoglycosides, tetracyclines,
and polyketides. Current therapeutic applications of metabolites from microorganisms
have expanded into immunosuppressive agents (eg., cyclosporins and rapamycin),
cholesterol-lowering agents (eg., lovastatin and mevastatin), antihelmintic
agents (eg, ivermectin), an antidiabetic agent (acarbose), and anti cancer agents
(eg., pentostatin, peplomycin, and epirubicin) (Sneader, 2005).
DRUG DISCOVERY FROM MARINE ORGANISMS
Unlike the long-standing historical medical uses of terrestrial plants, marine organisms have a shorter history of utilization in the treatment and prevention of human disease.
Among the first bioactive compounds from marine sources, spongouridine and
spongothymidine from the Caribbean sponge (Cryptotheca crypta), were
isolated serendipitously in the early 1950s. They were approved as an anticancer
drug (cytosine arabinoside, Ara-C) and an antiviral drug (adenine arabinoside,
Ara-A), respectively, years later. (Newman and Cragg, 2004a)
The secondary metabolites of marine organisms have been studied extensively
over the past 30 years, since a small number of academic chemists began to isolate
and elucidate novel compounds from marine sources in the 1970s. Drug discovery
research from marine organisms has been accelerating and now involves interdisciplinary
research including biochemistry, biology, ecology, organic chemistry, and pharmacology
(Capon, 2001) Recently, much attention has been given
to marine organisms due to their considerable biodiversity that has been found
in the widespread oceans that cover over 70% of the world. Structurally unique
secondary metabolites have been isolated and identified from marine organisms
and, consequently, a compound based on new chemical template has been developed
and launched in 2004, while numerous other candidates are in clinical trials
(Newman and Cragg, 2004b).
DRUG DISCOVERY FROM TERRESTRIAL VERTEBRATES AND INVERTEBRATES
During the course of research on human physiology and pathology, many biochemical
molecules have been discovered and their functions have been investigated. Since
these biochemical compounds are related to biological action in the human body,
an excess or deficiency of them has often caused pathological problems in humans
(San et al., 2010). Neurohormones (adrenaline,
levodopa, and histamine), peptide hormones (insulin and glucagons), sex hormones
(estrogens, progesterone, and testosterone), other hormones (hydrocortisone
and aldosterone), and prostaglandins (prostaglandin E 1 and E 2) are examples
of compounds used for the treatment of diseases related to their physiological
action. Besides human biochemicals and their analogs, other drugs in this category
have been discovered from various terrestrial vertebrates and invertebrates,
Including an inhibitor of Angiotensin Converting Enzyme (ACE) developed from
teprotide, which was isolated from the venom of Brazilian viper (Bothrops
jararaca) after the venom was found to cause a sudden andmassive drop in
blood pressure. Two drugs from vertebrates and invertebrates have been approved
from 2000 to the present.
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