INTRODUCTION:

The Plants, Marines, Animals, and Microbes which are the basic pathways that having complex or controversial chemical entities. Traditionally they have been used to cure, prevent or treat diseases. Unless and until, a scientific proof for such crude drugs, their will not be a systematic approach to come the product into a market. The identity, quality, purity, safety and efficacy of new drug or the chemical markers is the most essential to achieve its global market. The other important concept of drug discovery is to extract plants or to treat microbes or to initiate the proper treatment on animals, to create a new practical method for isolation of chemical entities from marine and other sources. Other objectives are to isolate chemical marker or target molecules by proper methods and characterization by different analytical methods. This will be the modern pathway of drug discovery. To design the confirmed isolated target molecule in various dosage form for internal administration or external application or as the case may be, this will be the modern pathway of drug discovery. Design and optimization chemical markers or active constituents are the systemic and scientific approach for the safety and efficacy of final product.

Thus the products will be maintained no waiting is considered to grow and development of traditional used plants, animals, and microbial sources. New approach to improve and accelerate the drug discovery and development process is accepted to take place mainly from innovation in drug target elucidation and lead structure discovery. Research is mainly based on the traditional uses of natural things and thus it will act as a powerful engine to promote the scientific ideas for new drug discovery and development. In the present study, we summarized on certain important plants, marines, animals and microbes, which have been used since from many years for medicinal purpose. The history of medicine includes many ludicrous therapies. Nevertheless, ancient wisdom has been the basis of modern medicine and will remain as one important source of future medicine and therapeutics. The future of natural product dug discovery will be more holistic, personalized and involve wise use of ancient and modern therapeutic skills in a complimentary manner so that maximum benefits can accrued to the patients and the community.¹ Natural product have come from various sources² including plants, microbes, animals and marines. The importance of natural product in modern medicine has been discussed in recent reviews and reports ^3-8. Drug development between 1981-2002 showed that a natural product comprises 25% of all New Chemical Entities (NCEs) launched on to the market. Combined percentage of NCEs indicates good lead compounds suitable for further modification during drug development. Secondary metabolites from natural origin have been elaborated within living system, they are pursued as showing drug likeness than totally synthetic molecules, making them good candidate for further drug development⁹. There is also new drug development from natural sources launched from 2000-2005 in clinical trials ¹⁰. Historical experiences with some Indigenous and non Indigenous plants as therapeutic tools have helped to introduced chemical entities in modern medicines. Plants with ethnopharmacological uses have been the primary sources of medicine for early drug discovery.

PLANT SOURCES:

Withania somniferum

It is also called as an Indian Ginseng. It is one of the chief crude materials in Chavanprash. The main constituents of Ashwagandha are steroidal lactones¹¹. Withanin is the main constituent. It also contents 2-acyl steryl glycosides. The steroidal lactones are called as withanolides. Withanolide D is the target molecule or chemical marker. Many research papers have been reported¹²on immunomodulatory activity, protective effect, antiproliferative, antioxidant¹³, adaptogenic¹⁴and antibacterial and cardioprotective¹⁵ action of Ashwagandha.

Aegle marmelos

It is also called as bael. It is one of the ingredient of `Dasamul`. According to Fluckiger Hanbury the dry pulp contains chiefly mucilage and probably pectin. Other constituents are sugar, tannin (tannic acid), volatile oil and bitter principle. The aqueous extracts of fruit of this plant showed¹⁶ hypoglycemic effect in streptozotocin diabetic rats. The methanol extract of leaves of this plant shows analgesic, antipyretic, anti-inflammatory activity, while ethanol extract possesses antifertility effect¹⁷. This plant was used to prevent cancer in Bangladesh as folk medicine and the same work is scientifically proved as anticancer potential¹⁸.

Bacopa monniera

Bacopa monniera is also called as `Mandukparni`. It has been reported that bacoside A and B as the target molecule or chemical markers enhances protein kinase activity. Hepatoprotective effect of bacoside A a major constituent of Bacopa monniera Linn have been reported. The hydroalcoholic extract of Brahmi shows adaptogenic effect¹⁹ and antioxidant activity²⁰. Brahmi plants have an important role in neuroprotection against aluminium induced oxidative stress in the hippocampus of rat brain. Traditionally the leaves of Brahmi were use for treating inflammation and now anti-inflammatory activity is reported. Bacoside I and II two pseudojujubogenin²¹and bacosaponin E and F: two jujubogenin bisdesmosides²² from Bacopa monniera as active markers have been reported for antidepressant activity in experimental models.

Asparagus racemosus

It is one of the main components of Chavanprash and Shatawari kalp. Shatawari roots were used as galactogouge, tonic, and diuretic. The Phytochemical investigations supports²³ isolation characterization of shatawarin I to IV as steroidal saponins. Shatawarin is the target molecules which are used in rheumatism, in nervine disorder and antioxytocic property. Current research support antitussive activity²⁴. Shatawari also has antioxidant²⁵ and gastroduodenal ulcer protective activity²⁶.

Azadirachta indica

The target molecule of Neem is azadirachtin. Traditionally Neem was used as antifeedant, spermicidal, antiviral, and insect repellant, antimicrobial. Recently a lot of work has been done on Neem. The activity²⁷of Neem proven recently, is to treat cholera and diarrhoea in India. It is also reported²⁸that Neem has cardioprotective effect. The methanol extract of Neem leaf has effect on stem cell reproduction. A clinical study showed²⁹ Neem leaf extract gel has antiplaque activity. A case study with aqueous Congo red solution of Neem shows that it is an effective biosorbent for dyes. Neem also possesses antioxidant³⁰, antimalarial³¹, molluscicidal³² activity.

Curcuma longa

The Indian saffron is also known as turmeric. The curcuma consist curcumin as a chemical marker. Recently study shows³³ that curcuma has the antidepressant effect in the forced swimming test involve 5-HT1 and 5-HT2 receptors. A study also proven that curcumin has chemoprevention of colon cancer. The in vitro study of fresh and dried rhizomes of turmeric has antioxidant property³⁴. The turmeric rhizome also showed³⁵ antiplatelet activity. The chemical marker curcumin enhances Apo2L/TRAIL which induced apoptosis in chemo resistant ovarian cancer cells³⁶.

MICROBIAL SOURCES:

The discovery of antibiotics is a versatile and valuable approach for treating patients. The world of natural products has been waiting more beneficial exploitation for several millennia. Several diseases have been created righted from the animal human survival. In ancient times, generally plants and minerals were used as medicines to treat diseases. After some period the discovery of antibiotics has came into existence. The success of penicillin³⁷in treating infection led to an expansion in the area of drug discovery from micro-organisms. Terrestrial micro-organisms are a plentiful source³⁸ of structurally diverse bioactive substances and have provided important contributions to the discovery of antibacterial agents including penicillin, cephalosporin, amino glycosides, tetracycline, and polyketides. Current therapeutic applications of metabolites from micro-organism have expanded into immunosuppressive agents (eg. cyclosporine and rapamycin), cholesterol lowering agents (eg. lovastatin and mevastatin), anthelmintic agent (eg. evermectin), and antidiabetic agent (eg. Acarabose), and anticancer agents (eg. Pentostatin, peplomycin, and epirubicin).

Micafungin Sodium (Mycamine, Fujisawa, 2005)

Micafungin, the active ingredient in Mycamine, inhibits the synthesis of 1, 3-β-D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells. Micafungin exhibited in-vitro activity³⁹ against C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. Standardized susceptibility testing methods for 1, 3- β -D-glucan synthesis inhibitors have not been established, and the results of susceptibility studies do not correlate with clinical outcome. Micafungin sodium has shown activity⁴⁰ in vivo, both mucosal and disseminated murine models of candidiasis. Micafungin sodium, administered to immunosuppressed mice in models of disseminated candidiasis prolonged survival and/or decreased the mycological burden.

Tigecycline (Tygacil, Wyeth, 2005)

Tigecycline is the most potent antimicrobial agent tested⁴¹ against S. pneumoniae, regardless of susceptibility to penicillin, inhibiting all isolates at concentrations of ≤0.12 μg/mL.

Telithromycin (Ketek, Aventis, 2004)

One report shows⁴² that there is an acute hepatitis attack probably associated with telithromycin administration, given to the patient having history of jaundice. Telithromycin, a ketolide antibiotic, is able to inhibit⁴³ in vitro secretion of inﬂammatory cytokines by LPS or Shiga toxin-stimulated human monocyte. The PROTEKT study has shown⁴⁴that the in vitro activity of telithromycin has remained at a high level since it was launched, irrespective of the genotype or phenotype of the relevant pathogens.

Miglustat (Zavesca, Actelion, 2003)

In vitro and in vivo studies⁴⁵ have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids. In clinical trials, miglustat improved liver and spleen volume, as well as hemoglobin concentration and platelet count. Enzyme replacement therapy using human placenta-derived alglucerase (Ceredase) has been available for type I Gaucher⁴⁶ disease since 1991.

Elsamitrucin (elsamicinA)

This compound binds to DNA but also inhibits activity of topoisomerase II, leading to an antitumor effect. A phase II study shows⁴⁷ that if elsamitrucin is given to the patient in the dose of 25mg/m² IV over 5 to 10 minutes weekly for 6 weeks there is no surgically incurable non small cell lung cancer activity.

The target molecules from above reviewed⁴⁸microbial flora are very effective which can lead to the animals and human free from several diseases. Antibiotic research on bioactive microbial product led to the discovery of agents beneficial of improving the human quality of life. Despite recent advices in utilizing chemically synthetic approaches to drug design and sophisticated structure activity analysis, their continuous to exist a great requirement in medicines for novel compound with unique action mechanisms.

MARINE SOURCES:

The oceans are a rich source of natural productis potential medicines significant discoveries have resulted primarily from screening of natural product. Recent development in combinatorial chemistry that can rapidly generate thousands of new chemical, the pharmaceutical industry still realize heavily on a staggering array of undiscovered possibilities from the natural environment. This could lead to the discovery of novel compounds. That will surely extend the boundaries of our chemical research efforts. Currently, promising compounds are being trapped from the world oceans. Many of these compounds are structurally complex which challenges modern organic chemist with unlimited approaches to mimic the synthetic versatility of nature. In future marine compounds are likely to yield entirely new classes of drug which would be a valuable contribution to our ability to treat human diseases. The first breakthroughs in the area were the arabinose nucleosides discovered from marine invertebates in 1950s, demonstrating for the first time that also sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. However, it took as long as 2004 until the first marine-derived drug was approved. The cone snail toxin ziconotide, also known as Prialt, was then approved by Food and Drug Administration (FDA, USA) to treat severe neuropathic pain. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain. One of the most promising classes of these agents is in pipeline. Among the first bioactive compounds from marine sources, spongouridine and spongothymidine from the Caribbean sponge (Cryptotheca crypta), were isolated⁴⁹ 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, 15 years later⁵⁰. Dolastatins and linear peptides isolated⁵¹ from the Indian Ocean sea hare Dollabela auricularia, demonstrate antineoplastic activity through inhibition of microtubule assembly. Dolastatin, soblidotin (a derivative of dolastatin 1), and synthadotin (an analog of dolastatin 1), is currently undergoing on clinical trials. A derivative of the Halichondria okadai constituent, halichondrin was found to inhibit tumor cell proliferation in association with the G2/M arrest and microtubule polymerization⁵².

HTI-286

The conformation of HTI-286 (I) in complex with the protein was determined from TRNOESY/ROESY experiments and is similar to the X-ray crystal structure conformation observed⁵³ for hemiasterlin methyl ester in the absence of protein.

Squalamine

One research stated⁵⁴that Squalamine is not a proton ionophore. The recent study showed⁵⁵ that a squalamine analogue has anti-trypanosomal and anti-leishmanial activities.

Source	Target molecule	Structure	Uses
Plant Source
W. somnifera	Withaferine A		Immunomodulatry, antioxidant, cardioprotective
A. marmelos	Marmelosine		Anticancer, antidirrhoeal, antifertility
B. monniera	Bacoside A and B		Hepatoprotective, antidepressant, anti-inflamatory.
A. racemosus	Shatavarin I		Antioxytocic, antitussive.
A. indica	Azadirachtin		Antiplaque, cardioprotective, antioxidant.
C. longa	Curcumin		Antioxident, anticancer
Microbial Source
Fungus- coleophoma empetri	Micafungin sodium		Antifungal, candidiasis.
S. aureofaciens	Tigecycline		Antimicrobial.
Saccharopoly-spora erythraea	Telithromycin		Antibacterial.
S. lavendulae	Miglustat		Goucher disease I
S. chartreusis	Elsamitrucin		Antiviral.
Marine Source
Hemiasterella minor	HTI-286		Antitumor.
Squalus acanthias	Squalamine		Antitrypanosomal, antileishmanial
Ecteinascidia turbinata	Ecteinascidin 743		Antitumor
N. spumigena	Nodularin
Animal source
Teprotide, found in snake venom.	Captopril		antihypertensive
Slaughtered meat animals such as porcine (pig) intestine or bovine lung	Heparin		anticoagulant
The Islets of Langerhans in the pancreas	Insulin		In diabetis mellitus.

Ecteinascidin 743

Trabectedin (also known as ecteinascidin 743 or by the brand name Yondelis) is an experimental anti-tumor drug⁵⁶ first isolated from aqueous ethanol extract of tunicates in 1969. This structure was not determined until 1984, and was first totally synthesized by Elias James Corey in 1996. Ecteinascidin 743 possesses potent cytotoxic activity⁵⁷

against a variety of tumor cell lines in vitro and against several rodent tumors and human tumor xenografts in vivo. One study has shows⁵⁸ that high-dose of dexamethasone protects against the hepatotoxicity of ET-743 in the female rat.

Nodularin

The study showed⁵⁹ Nodularin induces oxidative stress in the Baltic Sea brown alga Fucus vesiculosus (Phaeophyceae). One researches concluded⁶⁰ that Nodularin-induced genotoxicity following oxidative DNA damage and aneuploidy in HepG2 cells. Removal of nodularin is done from brackish water by the reverse osmosis or vacuum distillation⁶¹. Acute nodularin-induced (LD50=50 µg/kg rat) hepatotoxicity⁶² was monitored in vivo, using MRI techniques over a period of 3 hour.

ANIMAL SOURCES:

The discovery of product as medicines or biotechnology derived products from animal source has been rapidly increasing from last few years. The progress in animal cell technology over the last 20 years has been extremely rapid. The production of newer drug animal sources is a satellite component which affects the life of animal and human. Some of the typical, important and applicable examples derived from recombinant DNA technology⁶³ are blood factors, insulin, human growth hormones, GH inhibitors, tissue plasminogen activators, Interferons. Other examples are captopril, adrenaline, heparin, etc.

Captopril

A recent study showed⁶⁴ that combined administration of captopril with an antihypertensive Val–Tyr di-peptide to spontaneously hypertensive rats attenuates the blood pressure lowering effect. The latest study shows⁶⁵that captopril is capable of suppressing endotoxin-induced uveitis (EIU) in rats. Captopril can be addressed as a promising agent for the treatment of ocular inﬂammation. Pancreatic islet blood ﬂow is selectively enhanced by captopril. Captopril inhibits⁶⁶ the oxidative modification of apolipoprotein B-100 caused by myeloperoxydase in a comparative in vitro assay of angiotensin converting enzyme inhibitors.

Heparin

Heparin treatment in pregnancy⁶⁷ loss shows that in addition to direct effects of heparins on the coagulation cascade, heparin might protect pregnancies by reducing the binding of antiphospholipid antibodies, reducing inﬂammation, facilitating implantation and or inhibiting complement activation. Heparin acts as an antithrombotic agents⁶⁸ for acute Coronary syndromes in renal patients. Heparine also shows the non toxic anti cancer⁶⁹activity.

Mostly applicable and critical examples of natural origin with their sources, target medicinal molecules and uses are emphasized in Table No. 1.

CONCLUSION:

Many allopathic companies have been going to set a herbal and biotech units. Already each and every herbal industry has a R and D units. There is a great interest of researchers to orients a new drug development through investigation of led from the traditional system of medicine in addition many nutraceuticals are being consumed in unregulated market for pursue in health care an improvement of quality of life. Natural pharmaceutical, nutraceutical and cosmaceutical are of great important as a reservoir of chemical discovery. Aimed at a new drug discovery and are explored from antimicrobial cardiovascular system, immunosuppressive, and anticancer drugs. Through the guidelines of WHO and Indian system of medicines these is great chance for new researcher to find out a new target molecule or chemical marker having therapeutic activity. Globally, their have been efforts to monitored quality and regulate the growing business of herbal drug and traditional medicines. Drug discovery acts a heart to reach target molecule to consumers. Finally it is concluded that unless and until drug discovery and development, satisfactory human survival is impossible.

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Received on 27.09.2008 Modified on 12.10.2008

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