International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 1, Issue 1, July-Sep. 2009 Review Article PLANTS IN TRADITIONAL MEDICINAL SYSTEM - FUTURE SOURCE OF NEW DRUGS SOUMYA PRAKASH ROUT 1 *, K. A. CHOUDARY2, D. M. KAR3, LOPAMUDRA DAS4, AVIJEET JAIN5 *Soumya Prakash Rout, 13-1-160/4/9, Plot No- 89, Snehapuri Colony, Motinagar, Hyderabad- 500 018, A. P., India Cont. No- +91-9912838639, E-mail - [email protected] 1 Dept. of Clinical Operations, AdPharma India Private Limited, Hyderabad, India-500033 2 Dept. of Pharmacology, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India 3 Dept. of Pharmacology, Dadhichi College of Pharmaceutical Sciences, Phulnakhara, Cuttack, Orissa, India 4 Clinical Research Associate, GVK Bio, Hyderabad, India-500018 5 Natural Product Research Laboratory, Dept of Pharmaceutical Sciences, Dr H S Gour Vishwavidyalaya, Sagar, MP, India ABSTRACT The approach to new drugs through natural products has proved to be the single most successful strategy for the discovery of new drugs, but in recent years its use has been deemphasized by many pharmaceutical companies in favor of approaches based on combinatorial chemistry and genomics, among others. Again with rapid industrialization of the planet and the loss of ethnic culture and customs, some of the information on ethnomedicine will no doubt disappear. An abundance of ethnomedical information on plant uses can be found in scientific literature but has not yet been compiled into a usable form. Collection of ethnomedical information especially in the developing countries remains primarily an academic endeavour of little interest to most industrial groups. This article reviews some of the past successes of the natural products approach and also explores some of the reasons why it has fallen out of favor among major pharmaceutical companies and the challenges in drug discovery from Natural Products especially Higher Plants. In this review we consider the past, present, and future value of employing information from plants used in traditional medical practices (ethnomedicine) for the discovery of new bioactive compounds. Keyword: Ethnomedicine, HTS, Bioprospecting, Prefractionation, Combinational chemistry INTRODUCTION western world documentation of use of Ayurveda is the most ancient health care Natural system and is practiced widely in India, purposes can be found as far back as 78 Srilanka and other countries1. Atharvveda A.D., when Dioscorides wrote “De (around 1200 BC), Charak Samhita and Materia Medica”, describing thousands Sushrut Samhita (100 - 500 BC) are the of medicinal main detailed included descriptions of many medicinal descriptions of over 700 herbs 2. In the plants that remain important in modern classics that given substances plants3. for medicinal This treatise 1 medicine, not because they continue to sector is focused on development of new be used as crude drug preparations, but innovative/indigenous plant based drugs because they serve as the source of through investigation of leads from the important pure chemicals that have traditional system of medicine5. The become mainstays of modern therapy. World Heath Organization has also The term “materia medica” which recognized the importance of traditional means “Medical Materials”3 is no longer medicine and has created strategies, utilized routinely in Western medicine, guidelines and standards for botanical the fact remains that the physicians of medicines. today continue to use many substances technologies need to be applied to the and products derived from natural sources, cultivation and processing of medicinal usually for the same therapeutic benefit as plants and the manufacture of herbal the crude drug. These single chemical medicines 6. entities, i.e., drugs, form the basis for Over the past decade, there has been a much of our ability to control disease. resurgence In recent times, there have been investigation of natural materials as a increased waves of interest in the field source of potential drug substance. This of Products review is not intended to be an Chemistry. This level of interest can be exhaustive review of natural product- attributed to several factors, including derived pharmaceuticals, but rather is unmet therapeutic needs, the remarkable aimed at highlighting the invaluable role diversity of both chemical structure and that natural products have played, and biological continue to play, in the drug discovery Research in Natural activities of naturally Proven of agro-industrial interest in occurring secondary metabolites, the process and its future perspectives. utility Background and issues of novel bioactive natural the products as biochemical probes, the Natural development of novel and sensitive important role throughout the world in techniques to detect biologically active treating and preventing human diseases. natural products, improved techniques to Natural product medicines have come isolate, from various source materials including purify, and structurally products have played an characterize these active constituents, terrestrial and advances in solving the demand for microorganisms, marine organisms, and 4 plants, terrestrial 7 supply of complex natural products . terrestrial vertebrates and invertebrates The R & D thrust in the pharmaceutical and its importance in modern medicine 2 has been discussed in different reviews drugs worldwide reveals the utility of and reports7-12. natural products as sources of novel The value of natural products in this structures, but not necessarily the final regard can be assessed from: (i) the rate drug entity, is still alive and well14. of introduction of new chemical entities The development of high throughput of wide structural diversity, including screens based on molecular targets had serving as templates for semisynthetic led to a demand for the generation of and total synthetic modification, (ii) the large libraries of compounds to satisfy number of diseases treated or prevented the enormous capacities of these screens by these substances, and (iii) their and frequency of use in the treatment of combinatorial libraries has continued, disease. with the emphasis now being on small, The large proportion of natural products focused (100 to ~ 3000) collections that in drug discovery has stemmed from the contain much of the “structural aspects” diverse structures and the intricate of natural products8. Various names carbon skeletons of natural products. have been Since from including “Diversity Oriented Syntheses”, natural sources have been elaborated preferably can be termed as “more within living systems, they are often natural product-like”, in terms of their perceived as showing more “drug- combinations likeness and biological friendliness than significant numbers of chiral centers totally synthetic molecules,”9 making within a single molecule15, or even them drug “natural product mimics” if they happen development11,13. Analysis of the sources to be direct competitive inhibitors of the of new and approved drugs during the natural substrate. It should also be period 1981 to 2002 reveals that natural pointed out that Lipinski’s fifth rule products play a highly significant role in effectively states that the first four rules the drug discovery and development do not apply to natural products or to process secondary good 12 metabolites candidates for the shift away given to of from large this process, heteroatoms and . Review of all approved any molecule that is recognized by an agents during the time frame of more active transport system when considering than 25 years from 01/1981 to 06/2006 “druggable chemical entities” 14. for all diseases worldwide and from Although combinatorial chemistry in 1950 (earliest so far identified) to one or more of its manifestations has 06/2006 for all approved antitumor been used as a discovery source for 3 approximately 70% of the period countries are turning to the use of 01/1981 to 06/2006, only one new traditional chemical entity (NCE) reported in the involve the use of herbal drugs and public domain as resulting from this remedies18 and according to the World method of chemical discovery and Health Organization (WHO), almost approved for drug use anywhere. This is 65% of the world’s population has the antitumor compound known as incorporated the value of plants as a sorafenib from Bayer, approved by the methodology of medicinal agents into FDA in 200514. Proudfoot also reported their primary modality of health care19. that 8 out of 29 small molecule drugs It is often noted that 25% of all drugs launched in 2000 were derived from prescribed today come from plants20, 21. Natural Products or hormones and This estimate suggests that plant-derived concluded that HTS did not have a drugs make up a significant segment of significant impact on the derivation of natural product– based pharmaceuticals. these drugs 16. Despite competition from Out of many families of secondary other drug discovery methods, Natural metabolites, or compounds on which the Products are still providing their fair growth of a plant is not dependent, share of new clinical candidates and nitrogen-containing drugs and there is rapidly evolving contributed the largest number of drugs recognition that a significant number of to the modern pharmacopoeia, ranging natural product drugs/leads are actually in produced by microbes and/or microbial (atropine) to analgesics (opium alkaloids) interactions with the “host from where it and from antiparasitics (quinine) to was isolated”, and therefore this area of anticholinesterases natural product research should be antineoplastics (vinblastine/vincristine) expanded significantly 14. 22 Importance of plants as a source of in new drugs terpenoids (including steroids) have The development of effects medicinal from systems alkaloids that have anticholinergics (galantamine) to . Although not as plentiful as alkaloids the modern pharmacopoeia, traditional made an equally important contribution medicinal systems incorporating plants to human health. They range from as means of therapy can be traced back Na+/K+ pump-inhibiting cardiac glycosides to the Middle Paleolithic age some from Digitalis spp.23, to antineoplastic 60,000 years ago as found from fossil paclitaxel24 to antimalarial artemisinin25, studies17. In recent times, developed to anti-inflammatory triptolide26, 27. It is 4 important to note that, the activity of based, some natural products has yet to be morphine, certified by extensive testing or clinical khellin, and khellin; c) to use agents as trials; pharmacologic tools, e.g., lysergic acid as multicomponent botanical (MCBTs). This therapeutics respectively, taxol, diethylamide, on galegine, podophyllotoxin, mescaline, yohimbine; overrepresentation of natural product– and d) to use the whole plant or part of it derived drugs begs the question of as a herbal remedy, e.g., cranberry, whether plant secondary metabolites and echinacea, related synthetic compounds perform biloba, St. John’s wort, saw palmetto. better randomly The number of higher plant species synthesized compounds. Despite the (angiosperms and gymnosperms) on this increasing use of medicinal plants and planet is estimated at 250,00028, with a their importance in drug discovery, their lower level at 215,00029, 30 and an upper future, seemingly, is being threatened by level as high as 500,00031, complacency their about 6% have been screened for conservation. Reserves of herbs and biologic activity, and a reported 15% stocks of medicinal plants in developing have been evaluated phytochemically33. countries are diminishing and in danger With high throughput screening methods of extinction as a result of growing becoming more advanced and available, industrialization. these numbers will change, but the The goals of using plants as sources of primary discriminator in evaluating one therapeutic agents are, plant species versus another is the matter a) to isolate bioactive compounds for of approach to finding leads. There are direct use as drugs, e.g., digoxin, some broad starting points to selecting digitoxin, morphine, reserpine, taxol, and obtaining plant material of potential vinblastine, vincristine; b) to produce therapeutic interest. However, the goals bioactive compounds of novel or known of such an endeavor are straightforward. structures for Plants have an advantage in this area semisynthesis to produce patentable based on their long-term use by humans entities of higher activity and/or lower (often hundreds or thousands of years). toxicity, One as drugs concerning as e.g., oxycodon than lead compounds metformin, other might expect garlic, any 32 ginkgo and only bioactive narcotic compounds obtained from such plants to teniposide, have low human toxicity. Obviously, verapamil, and amiodarone, which are some of these plants may be toxic within analgesics), (and nabilone, feverfew, taxotere, 5 nordihydroguaiaretic reporting system to document these which, besides being active orally in effects. It is unlikely, however, that db/db diabetic mice, also lowered acute toxic effects following the use of a cholesterol levels. plant in these cultures would not be Some examples of drugs from plants noticed, and the plant would then be that served as models for the next used cautiously or not at all. Chronic generation of drugs are exemplified as toxic effects would be less likely to follows: Khellin [from Ammi visnaga signal that the plant should not be used. (L.) Lamk] was used as a bronchodilator In of in the United States until it was shown secondary plant metabolites those results to produce nausea and vomiting after from plant evolution may be equal or prolonged use. In 1955 a group of superior to that found in synthetic chemists in England set about to combinatorial chemical libraries. synthesize khellin analogs as potential Approaches of drug discovery from bronchodilators with fewer side effects. higher plants This eventually led to the discovery of Shaman Pharmaceuticals in South San chromolyn (used as sodium chromoglycate), Francisco, California is supposed to be which stabilized cell membranes in the the first company in United States to lungs to prevent the allergeninduced investigate plants through ethnomedical release of the substance ultimately addition, 34 approach chemical diversity acid (ndga)43 a given endemic culture that has no and SP-303, an oligomeric causing bronchoconstriction in allergic proanthocyanidin35 found in the process, asthma patients44. Further studies led to was shown to be clinically efficacious the synthesis of amiodarone, an useful and is currently marketed as a dietary antiarrythmia agent44. Papaverine, useful supplement for diarrhea. In addition, a as a smooth muscle relaxant, provided major the basic structure for verapamil, effort was directed toward discovery of novel antidiabetic agents, drug which resulted in the discovery of Galegine was isolated as an active several compounds: antihyperglycemic agent from the plant cryptolepine36-38, maprouneacin39, 3 ,30- Galega officinalis L. used ethnomedically dihydroxylupen-20(29)-en-2-one40, for the treatment of diabetes. Galegine harunganin, patented vismin41, and used to treat a 44 hypertension . quinines provided the template for the synthesis SP18904 and SP18905 . The most of metformin and opened up interest in 42 interesting discovery was 6 the synthesis of other biguanidine-type A number of reviews relating to antidiabetic drugs44. approaches for selecting plants It is always difficult to assess the value candidates for drug discovery programs of any approach to the use of higher have been published46,47-60 and these plants to develop new drugs. Artuso has approaches can be briefly outlined as outlined the entire process: formulating follows, an • appropriate biologic strategy, extracts, obtaining screening those extracts, isolating active compounds, conducting preclinical tests • followed • Random selection followed by one Follow-up of biologic activity reports • New Drug Application, and beginning Follow-up of ethnomedical (traditional medicine) uses of plants commercial production. According to • his estimation the entire process would Challenges and opportunities 45 by or more biologic assays Investigational New Drug Application, performing clinical trials, submitting a selection chemical screening and chemical modification, submitting an Random as Use of databases take 10–20 years or more . As it is In spite of the success of different drug improbable that one could collect all the discovery programmes from plants in 250,000 higher plant species to screen the past 2–3 decades, future endeavours for one or more biologic activities, and face many challenges. Natural products because the number of bioassays that scientists and pharmaceutical industries one could screen these species for is will need to continuously improve the unlimited, the species most likely to quality and quantity of compounds that produce be enter the drug development phase to selected judiciously. In addition, the keep pace with other drug discovery biologic targets must represent the efforts. The approach of herbal drug activities that correlate best with the development is associated with several rationale for plant selection. It would problems. appear that selection of plants based on • useful activity should The advent of routine HTS has long-term human use (ethnomedical) in been one of the most important conjunction with appropriate biologic changes to the drug discovery assays the process61-63. Screening of one ethnomedical uses would be most hundred thousand samples in a that correlate with appropriate. 7 routine assay now 61-63, 66-71 compound libraries using 384-well formatting, a data This is because Natural Product handling system, and limited extracts contain complex mixtures robotics. This screening time can of be decreased further using higher compounds, some of which have density formats and advanced undesirable properties. An added robotics61,64,65. of mostly . uncharacterized Therefore, the complication is that interfering compounds or compounds may be present in extracts that can be screened for the each drug target is generally not compounds of interest, which the rate-limiting step. may mask the biological effect. The decision when to screen Compounds Natural extracts compounds also may be present compared to compound libraries in an extract, which can interfere is extremely important for the with the screen in a nonspecific successful integration of Natural manner72. Product Product hits into a lead discovery • more problematic than screening be completed in just over a week number • can • extract in addition or Traditionally, families crude to of extracts program. This is because no have been used for screening, but matter how quickly the active the compounds can be isolated and available from HTS has enabled their structures identified, there the possibility of economically will always be a lag time behind screening prefractionated extracts. the pure The prefractionation process can compounds whose structure and produce fractions that can range method of synthesis is known at from relatively crude fractions to the onset. In fact, screening of mixtures of only a few compounds. Natural Product extracts well The before a synthetic library would separation be preferable, but in practice this instruments has enabled some rarely, if ever, happens. companies to assemble large The screening of Natural Product libraries extract Products, which can then be evaluation libraries of is generally extra screening advent of sophisticated and of capacity pure analytical Natural 8 screened in a manner analogous to to pure compound libraries73-82. contain the same or similar The advantage of these libraries unidentified compounds that are is that no further purification is responsible for the biological generally activity. required, which like-extracts This that grouping of enables active compounds to be extracts with like dereplication evaluated on an equivalent basis profiles significantly reduces the to synthetic compound libraries. possibility of different chemists The disadvantages are that it is a independently time-consuming identifying process and missed using an isolation isolating the same and active component. minor active components may be • group • The bioassay guided strategy based solely on peak fractionation procedure used to collection. There identify significant cost is also involved a in bioactive natural products is often perceived as preparation and screening of the rate extra intensive. However, the rapid fractions generated by limiting and resource prefractionation. improvement of instrumentation Dereplication is the process of and identifying known compounds revolutionize other aspects of that are responsible for the drug discovery can also be used activity of an extract before to improve the speed of the bioassay-guided isolation started69, 83-86 isolation has . The dereplication process, which has been an ongoing concern Product chemistry in Natural since the robotics used and to structure elucidation of Natural Products. The advent technology of 87 new and probe higher magnetic fields has led to a beginning of antibiotic research, significant is used to eliminate, group, and/ acquisition time for NMR data, or prioritize extracts for further and the structure elucidation of study and can save considerable Natural Products can be achieved research time. The dereplication routinely on amounts less than 1 procedure also can be extended mg. 88 shortening in . Progress has also been 9 made in automated structure solving , Crude herbs/plants (various plant but parts and exudates) are mostly presently none can rival the formulated as tablet and capsule structure elucidation skills of an and to some extent as oral liquid experienced preparations. chemist. • 89-91 algorithms • Natural Product However, these These dosage forms are not successful due to programs can be a valuable tool problems to search for alternative structures absorption, therapeutic efficacy that fit the same NMR data. and poor compliance. The biggest obstacle to Natural Product chemistry continuous amounts is supply of in Tablet or capsule dosage form the requires powdering of crude large herbs and particle size affects the Product process of blending, compression of Natural • encountered required for further biological and evaluation. The identification of homogeneity a sustainable source of the achieve due to the handling of Natural Product needs to be large addressed if a semisynthesis or moisture content and inherent total synthesis is not available. nature of raw materials (crude This is not so much trouble if drug). there is a microbial source of the difficult to formulate in solid compound. dosage A systematic filling. bulk In is difficult quantities, Crude forms addition, extracts due to to high are their approach called OSMAC (one hygroscopic nature, poor solubility strain-many and stickiness. compounds) to increase the yield and diversity of compounds produced by microorganisms was proposed by Zeeck while and advances co-workers92, are being • As drug discovery from plants has traditionally been time- consuming, faster and better methodologies for plant collection, bioassay screening, achieved rapidly in the area of compound microbial compound development must be combinatorial 93 biosynthesis . isolation and employed 94. 10 • Innovative strategies to improve group like-extracts. Some other the process of plant collection new screening methods64 include are needed, especially with the the novel microarray compound legal issues screening (microARCS) technology, benefit-sharing which utilizes agarose matrixes and political surrounding • agreements95,96. to introduce a majority of the The design, determination and reagents throughout the assay101, implementation of appropriate, and on-line biochemical detection clinically high- coupled to mass spectrometry, throughput bioassays are difficult which already has been used for processes for all drug discovery the screening of natural products programmes96, extracts102. relevant, 97 . Although the design of high-throughput screening • • Challenges in bioassay screening assays can be challenging98, once remain an important issue in the a screening assay is in place, future of drug discovery from compound and extract libraries medicinal plants. The speed of can be tested for biological active compound isolation can be activity. The common problem increased faced of techniques like LCNMR and LC- extracts is solubility and the MS. Development of drugs from screening of extract libraries is lead compounds isolated from many times problematic, but new plants, faces unique challenges. techniques Natural products, in general, are during screening including pre- using hyphenated fractionation of extracts can alleviate typically some of these issues94, 100. quantities that are insufficient for To get appropriate compound lead optimization, lead development from and clinical trials. Thus, there is screeing of Natural isolated in small a a need to develop collaborations complementary orthogonal assay with synthetic and medicinal or assays to remove as many chemists false positive hits as possible. possibilities of its semi-synthesis Dereplication can then be used to or total synthesis103,104,105. One remove nuisance compounds or can also improve the natural Products is to design to explore the 11 products compound development development and is biochemical by creating natural probes libraries that products combine discovery of process. features of natural products with • the pharmacological and biochemical the • combinatorial chemistry. for Combining the strengths of the With the dwindling population of knowledge taxonomists and rare introduction systems such as ayurveda with the of youngsters in this field, it dramatic power of combinatorial might take another 20–30 years chemistry and HTS will help in the with the current pace to survey generation of structure–activity libraries. the complete flora of the country. • base Traditional of traditional knowledge and Now the question before us is, experiential database can provide could the new functional leads to reduce time, pharmaceutical potential of all money and toxicity – the three main the floristic components that we hurdles in drug development. These know? The answer is no. records are particularly valuable, we assess Future perspectives since effectively these medicines Despite several problems, one cannot have been tested for thousands of discount the past importance of plants as years on people106. sources of structurally novel drugs and it • Bioprospecting demands a number provides a great opportunity to the of requirements which should be co- scientists in the field of Natural Product coordinated, Chemistry, Pharmacognosy, Pharmacology, scientific Ethnobotany and other related fields of expertise in a wide range of human life science to come together and work endeavours, including international in the direction of getting new drugs fro laws and legal understanding, social Natural Sources, especially from Plants sciences, politics and anthropology. for betterment of mankind. • • Ayurveda such experts and as team along other of with traditional The importance of natural products systems of medicine, rich genetic in the future of drug discovery is resources clear: ethnomedical knowledge are key novel biologically active and associated natural products will continue to components serve as lead compounds for drug bioprospecting and value-addition for sustainable 12 processes. • extracts. Globally, there is a need to build is needed, which will be instrumental in libraries. The extract libraries offer converting the discovery into a various commercial product. reduction in cost and time for repeat Important in any bioprospecting is collection of plants and availability the drafting and signing of an of properly encoded and preserved agreement extracts or Memorandum of natural products advantages, in large extract such numbers as for Understanding that should cover biological screening in terms of issues on access to the genetic high-throughput resources obtaining hits within a short period. (biodiversity), property on related to • screenings and Innovation and creativity regarding discovery, on the sharing of benefits the molecular scaffolds will be as part of the process (short term), substantially and in the event of discovery and discovery of relatively simple, small commercialization of a product (long molecular weight bioactive natural term), as well as on the conservation products. Combinatorial approach of the biological resources for the with a nucleus that is already known future generations. to When ethnobotanical with exciting the biological activity will increase the likelihood or of utilized, candidate. additional enhanced possess ethnopharmacological approach is specific creating interesting Similarly, drug mixing of requirements that relate to prior genetic information encoding for informed consent, recognition of specific secondary metabolites may Indigenous Intellectual Property and produce “unnatural” natural products Indigenous with specific therapeutic activity 109. 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