Phytochemical investigation of Indian Medicinal Plants in search of bioactive natural products

Abstract

The use of natural products as therapeutic interventions is as ancient as human civilization and for a long time, mineral, plant and animal products were the main sources of drugs. The value of natural products can be assessed using three criteria: (1) the rate of introduction of new chemical entities of wide structural diversity, including serving as templates for semi-synthetic and total synthetic modification, (2) the number of diseases treated or prevented by these substances and (3) their frequency of use in the treatment of disease. An analysis of the origin of the drugs developed between 1981 and 2002 showed that natural products or natural product derived drugs comprised 28% of all new chemical entities (NCEs) launched onto the market. In addition, 24% of these NCEs were synthetic or natural mimic compounds, based on the study of pharmacophores related to natural products. This combined percentage (52% of all NCEs) suggests that natural products are important sources for new drugs and are also good lead compounds suitable for further modification during drug development. The cumulative human endeavor and experience over a period of thousands of years developed into well organized indigenous systems of medicines viz, Ayurveda, Siddha and Unani besides folklore systems. These systems mainly rely on the usage of crude plant drugs against debility and disease. Ayurvedic system of medicine alone comprises about 2500 plant species. History narrates that extinct civilizations had also discovered the benefits of these medicinal plants. In fact, nearly 3000 years ago, the Mayans used fungi grown on roasted green corn to treat intestinal ailments. The Benedictine monks (800 A.D.), immulating the example of ancient Greeks, began to apply Papaver somniferum as an anesthetic and pain reliever. These plant based products, in general enhanced the quality of life and paved the way in unraveling the drug discovery approaches even though a better understanding of the complex chemical nature of bioactive compounds in these mixtures and mode of their functioning remains a mystery. Natural products have been the traditional pathfinder of 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 commonest 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. Another disease osteoporosis is said to be caused by disorder of balance between bone formation and resorption. One out of eight males and one out of three females in India suffers from osteoporosis, making India one of the largest affected countries in the world. Therefore, novel natural products have promising potential to prove their importance as therapeutic agents. 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 indigenous medicinal plants for various tropical diseases and other infectious and metabolic scourages and syntheses of biologically active natural product analogues using different synthetic methodologies. The main thrust is on the isolation and identification of a lead which through extensive biological studies could offer some promise on the clinical front. Under this programme, plants are collected from the different parts of the country and subjected to screening through a number of classic as well as modern biological tests. Exquisite bioinformatics tools are indispensably employed in arriving at an approach which could provide a rationale for targeted drug design and development. Plants showing significant activity are picked up for detailed chemical and pharmacological investigations for the identification of the active lead. 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 the Natural products with anti-osteoporotic activity with a brief overview. Chapter-2: Deals with the phytochemical and pharmacological studies of the leaves parts of Dodecadenia grandiflora. Isolation and characterization of nineteen compounds viz, flavonoid glycoside, phenyl-propanoid glycosides, dimers of phenyl-propanoid glycosides etc. are described. Among these compounds eight compounds are new{(6-O-(E)- Caffeoyl)-β-D-glucopyranosyloxyphenol, Catechol (4′-O-(E)-p-coumaroyl)-β-Dglucopyranoside, Catechol (6′-O-(E)-p-coumaroyl)-β-D-glucopyranoside, 6-O-(E)- Caffeoyl-1-O-ethyl-β-D-glucopyranoside, Catechol 2-O-β-D-glucopyranosyl-(12)-β-Dglucopyranoside, Dipyrocatechol-O-β-D-glucopyranoside ester of (2α, 2′′′α, 3α, 3′′′α)- 3,3′′′-bis(6,7-dihydroxyphenyl)-2,2′′′-cyclobutane dicarboxylic acid, 3-{7-Hydroxy-6-[4′′′- hydroxy-3′′′-(O-β-D-glucopyranosyl)-phenoxy]-phenyl} acrylic acid-1′-(2′′- hydroxyphenoxy)-β-D-glucopyranos-6′-yl ester, Dipyrocatechol-O-β-D-glucopyranoside ester of 8,2′-epoxy-7,4′,5′-trihydroxynapthalene-2,3-dicarboxylic acid}. These all new compounds are catechol derivatives. All the compounds were isolated for the first time from this plant. The anti-diabetic activity of the isolated compounds was evaluated. In which three compounds showed significant antihyperglycemic activity in streptozotocininduced (STZ) diabetic rats, which is comparable to the standard drug metformin. Chapter-3: Describes the phytochemical and pharmacological investigation of the leaves of Allophylus serratus. Isolation and characterization of seven compounds viz, flavones, flavone-glycosides etc. are described. The anti-osteoporotic activity of the isolated compounds was evaluated. Two of the seven compounds isolated from Allophylus serratus increased in vitro ALP activity with varying potency. Chapter-4: It comprises the chemical investigation of twigs of Ulmus wallichiana. Isolation and characterization of five compounds are described. Amongst these, one is a novel compound and rests are first time reported from this plant. The anti-osteoporotic activity of the isolated compounds and derivatization of the active principle is also described. Chapter-5: Encompasses the Chemical transformation of 16-dehydropregnenolone and their evaluation as anti-malarial agents.