Phytochemical investigation of Medicinal Plants and chemical transformation of bioactive compounds

Abstract

The human race & natural products are coexisting since ages and their co-evolution has led to the possibility of finding new drugs for various diseases from this perpetual source-the nature. It must be emphasized that any metabolite from any organism is taken as natural product. With the advent of novel techniques of isolation and structure elucidation, newer areas can be tapped for discover of new compounds. Today drug discovery is essentially a malenge of chemistry and biology. Herbal drug development is totally based on experimental biology and quality control analyses. The revolutionary developing in experimental biology has led to identification of natural product. Apart from their conventional role in drug discovery and development, natural products have contributed to identification of new compounds and mechanism of action. The drug discovery and development has to take full spectrum of traditional knowledge and conduct researches with both perspectives of discovering New Chemical Entities (NCEs) for plants mentioned in literature of traditional medicines and developing marketable formulations or preparations based on traditional medicines formulae to overcome the recession of NCEs and to provide affordable medicaments. Natural product drug discovery can be persued in to two ways: the classical technique is the isolation of pure compound from the source rising bioassay guided fractionation to identify potential leads as well as reverse pharmacology from traditional systems of medicines. However, nature works in a complex manner and single compound does not always suffice the bioactivity. There are several examples where it has been observed that the further purification of extracts has led to a decrease in bioactivity. This phenomenon can be explained by synergism amongst natural products where by a mixture of compounds is more active than single compound. Thus the development of standardized extracts is an important area for the reproducibility of the biological activity. The rapidly developing area of semi-synthetic modifications of existing natural products as well as Computer Aaided Drug Design (CADD) have aided further enrichment of this goldmine of drugs. Even with untold centuries of human experience behind us and a movement in to a modern era of chemistry and automation, it is still evident that natural-product based compounds have had an immense impact on the modern medicine. For instance, about 40% of prescription drugs directed towards different ailments are based on natural products. Furthermore, well over 60% of the new chemical products registered by the FDA as anticancer agents, antimigraine agents and antihypertensive agents are natural products or derivatives thereof in the time frame of 1981-2002. Natural products have been the traditional pathfinder compounds with an untold diversity of chemical structures unparalleled and unmatched even by the largest combinatorial libraries. There is a clarion calls for new antibiotics, chemotherapeutic agents and agrochemicals that are highly effective, cost-effective, possess low toxicity and have minimal side effects. These findings are driven by the development of resistance by infectious microorganisms to existing drugs and by menacing the presence of naturally resistant organisms. The ingress to the human population of new disease causing agents such as HIV, Ebola and SARS and disorders like diabetes and dyslipidemia requires the discovery and development of new drugs to combat them. Not only do diseases like AIDS require drugs that target them specifically, but new therapies are needed for treating ancillary infections which are a consequence of a weakened immune system. In addition more drugs are needed to efficiently treat parasitic protozoan and nematodal infections such as malaria, leishmaniasis, trypanosomiasis and filariasis. Among the most common metabolic disorder, diabetes pose a lethal threat to present-day sedentary human population and the concurrent disabilities afflicted with this disease. Survey reveals that it affects more than 100 million people worldwide (6% of the population) and in the next 10 years it may affect about five times the number than it does now. In India prevalence rate of diabetes is estimated to be 1-5 % and this number is expected to rise sharply owing to the sedentary life style and intake of calorie-rich diet of people. Therefore, novel natural products have promising potential to prove their importance as therapeutic agents. Widely-used antimalarial drug artimisinine from Artimisia anua and Quinine from Cinchona ledgeriana. Antitumor drug etoposide, taxol, and vincristine from Podophyllum peltatum, Taxux brevifolia and Catharanthus roseus respectively. Since the Central Drug Research Institute, Lucknow, has an avowed objective of drug discovery and development, it is running an integral programme of screening the biological active indigenous plants and syntheses of biologically active natural product analogues using different synthetic methodologies. Under this programme, plants are collected from the different parts of the country and subjected to screening through a number of biological tests and plants showing significant activity are taken up for detailed chemical and pharmacological investigations. Chemists are exploring the possibility of identifying the novel structures and synthesizing the structural analogues of identified biologically active compounds. Under the support of ongoing programme on drug discovery and development, phytochemical and pharmacological investigation of Indian medicinal plants and syntheses of biologically active natural products and various analogues of isolated bioactive molecules were taken up to accomplish the desired objective of the current studies. The present thesis encompasses the results and discussion of these studies and is divided into five chapters as summarized below: Chapter-1: This chapter presents a review on protoberberine alkaloids and their biological activity in natural products with a brief overview. Chapter-2: Deals with the phytochemical investigation of Isolation and characterization of twelve compounds viz, protoberberine alkaloids, lignin etc. are described. Among these compounds, a compound (3-hydroxy-2,9,11-trimethoxy-5,6-dihydro isoquino[3,2-a,g] isoquinolinylium) is new and eight compounds were isolated first time from this plant. The anti-leishmanial activity of the isolated compounds were evaluated, In which new compound showed significant in vitro antileishmanial activity against Leishmania donovani promastigotes and intracellular amastigotes, which was comparable to the standard drug miltefosine. Chapter-3: Describes the phytochemical investigation of the dry seed coats (fruits) of Pterospermum acerifolium. Isolation and characterization of ten compounds viz, sphingolipids, acyl phytosterole-glycosides, phytosterole etc. are described. Among these compounds, four compounds are new 2-hydroxy-tetracos-10-enoic acid (2,3-dihydroxy-1-hydroxymethyl-heptadecyl)-amide, sitosterol-3-O-6- heptacosanoyl- β-D-glucopyranoside, sitosterol-3-O-6- nonacos-28-enoyl-β-D-glucopyranoside and 2-hydroxy-tetracosa-10,23-dienoic acid (2,3,4-trihydroxy-1-hydroxymethyl-icosyl)-amide. Chapter-4: It comprises the phytochemical investigation of seeds of Impatiens niamniamensis. Isolation and characterization of three compounds are described. Amongst these, hypaphorine is a major compound and rests are reported first time from this plant. Hypaphorine is evaluated for antihyperglycemic activity for the first time. It showed significant activity in streptozotocin induced diabetic rats when compared to the reference drug metformin. Chapter-5: Encompasses the synthesis of isoxazoline compounds and their evaluation as anti-stress agents. A series of fourteen isoxazolines were synthesized and evaluated for anti-stress activity in acute stress (AS) model. AS resulted in significant elevation in adrenal hypertrophy, gastric ulceration, hyperglycemia, plasma CK activity and corticosterone levels. Thus, these compounds might have important therapeutic implications in neuropsychological conditions and biological activity profiles of these compounds are worthy for further investigation to developed anti-stress drug.