Plants as sources of biomolecules for pharmaceutical drugs

Jiten Sharma *

Human evolution, during the course of time, has been related to continuous increases in primitive as well as advanced technological gains. Humans became capable of living in different environments, getting food and nutrients, and establish living conditions allowing the successful survival of their progenies. The characteristic human ability to observe, compare, analyse, and after careful evaluation, utilize natural resources constitutes basic milestones in the progress of human society.

Presently, science and technology are playing fundamental roles in the development of human society pushing it to newer frontiers and carry out careful re-investigations and re-evaluations of past anthropogenic activities. Plants have played basic roles for the existence of mankind and have been the sources for survival in the environment and for improvement of quality of life. It was discovered over the centuries that plants had specific properties which could be applied for benefits to human health.

Large variability of plant species located in different regions of the planet allowed the development of distinct cultures, use plants initially as traditional medicines, and later, as pharmaceutical drugs.

Recently, in developed countries, the use of plants as pharmaceutical drugs has moved from an empirical knowledge and application to more scientific uses. In many cases, it has been possible to isolate and characterize the active principles or bio-active molecules, evaluate the molecular mechanism(s) and synthesize the molecule(s) by chemical procedures in the laboratories. Such scientific approaches allow more precise investigations both at research and clinical levels, accurate dose of drug administration and use of the products.

At present, the world over, a large number of pharmaceutical drugs from plants are used, and recently, in view of growing human needs and as a consequence, wider marketing perspectives, extensive research activities have been started for discovering novel molecules useful for human health. Further, new perspectives have emerged from the use of plant molecules as anti-bacterials applied in agriculture thus opening possibilities for plant molecules as environmental pharmaceuticals.

Traditional medicine consists of different components such as botany, anthropology and religions, and had crucial roles in human history. Different cultures grew in different regions and gained knowledge of plants having unique pharmaceutical properties. The history of pharmacy was, for a long time, accomplished with the history of pharmacognosy which deals with drugs originating from plants or animals in all aspects, except under the physiological effect. Recent advances in biology, pharmacy, chemistry and medicine have resulted in the development of several pharmaceutical drugs directly from laboratories.

Discovery of novel molecules as pharmaceutical drugs relates to ethno-botany which studies interrelationships of primitive men and plants and ethno-pharmacognosy which provides the guide towards different sources and classes of compounds. The use of plants in traditional medicine systems of many cultures has been widely documented and these systems have given rise to important drugs still widely in use.

The complex process that leads from plants to pharmaceutical drug production can be observed in the development of aspirin. Development of pharmaceutical drug started when the Salix bark extract showed curative property for malarial fever. Such observations stimulated research activities, mainly of chemical nature and in several laboratories to identify the active principles and their possible production by chemical synthesis. Finally, acetylsalicylic pills went into industrial production and medicinal use. Since then, many acetylsalicylic derivatives have been made, tested and widely used around the world.

Another example of active principle standardised as pharmaceutical drug is Cinchona plant used in Peru by natives against malarial fever induced by Plasmodium falciparum. In the beginning of 19th Century, an alkaloid named quinine was isolated and chemically characterized, thus opening possibilities for development of pharmaceutical drugs. Thus, for several plants bio-active molecules were identified, chemically synthesised and used as pharmaceutical drugs in tune with their traditional uses. Consequently, the drug artemisinin extracted from Artemisia annua used in malarial treatment due to Plasmodium falciparum was discovered by Youyou Tu who got Nobel Prize in Medicine in 2015.

It has been estimated that only about 6% of plants has been investigated from a biological viewpoint and 15% in terms of their chemical components despite plants playing key roles in the system and representing a basic component of the human and animal diet. In addition, plants have wide uses in clothing, building, furniture and paper industries. Recently, biotechnological interventions have been carried out for using plants as molecule producers of industrial interest, for producing biofuels and biodegradable plastic to reduce plastic pollution. Plant tissue culture techniques have greatly contributed in this respect.

Although plants cannot move and have no complex organs as animals, depending on their cell structure and various biochemical and physiological processes similar to animal cells, they are eukaryotic organisms.

Plant cells also have peculiarities like the presence of cell wall, specialized organelles, such as plastids, large vacuoles in the cytoplasm and complex cellular metabolism producing, in addition to primary compounds like sugars, proteins, lipids and nucleic acids, a wide number of molecules termed as secondary metabolites. Sugar, protein, lipid and other molecules of plant origin have been the main components of human diet, and consequently, some species are specifically selected and widely cultured.

Among hundreds of thousands of plant species found in the planet, only a few have played direct fundamental roles in human progress. Recently, scientists have widened their interests to plants that in the past were of lower interest and their secondary metabolites seem to open new perspectives for human needs and requirements. That secondary metabolites result as specific components of specialised plant structures and organs have been already established.

They play different roles within plants such as defence against soil micro-organisms, plant viruses and herbivorous animals, and in the process of reproduction by producing flowering pigmentswhich possess strong anti-oxidant potentials (carotenoids, phenolics and flavonoids), fruits having particular fragrances (terpenoid and phenolic compounds) for attracting pollinators, and involving insects/animals as dispersal agents thereby increasing the possibility for enlarging the number of individuals.

In addition, secondary metabolites inhibit the growth of competitor plants and such compounds are often involved in key interactions between plants and their abiotic and biotic environments thus leading to evolutionary associations between particular groups of pests and plants. Secondary metabolites can be classified on the basis of their chemical structure, composition, solubility or the mechanism by which they are synthesized.

In chemical terms, these have been identified as phenolic and flavonoid compounds (8,000 compounds known) as terpenes and terpenoids (over 25,000 compounds) and alkaloids (around 12,000 types). The production of secondary metabolites is dependent on complex pathways derived from basic primary metabolites. The first step for secondary metabolite production involves the formation of specific enzymes which are involved in the transformation of primary metabolic products into secondary metabolites.

In the pathways for secondary metabolite production, processes of molecular oxidation occur. The oxidizing reactions are commonly catalysed by dioxygenases- enzymes which utilize oxygen and a-ketoglutarate. In addition to specific secondary metabolites, carbon dioxide and succinate are also released. Other steps of secondary metabolite biosynthesis require the methylation of potentially reactive carboxylic acid, amino and hydroxyl groups that can spontaneously interact and form products which are undesirable to the plant and then stored within the vacuoles. In many plants, the secondary metabolite contents are quite low although rich in the number of compounds. Depending upon requirement, large amount of molecules can be further obtained through chemical processes.

To evaluate the potential interest of plants and plant derivatives, different approaches can be used. The interest in novel plant molecules is dependent on many cross-linked aspects such as, availability of funds supporting the research activities, market interests, new industrial research plans, government policy decisions, newer pharmaceutical needs and specific scientific interest of researchers.

Once all or parts of such conditions are met, research activities can initiate.The first step consists of the selection of plants to be investigated which again depend on various aspects. In some cases, plants are selected on the basis known uses in traditional medicine. Further, religious rituals, believes and mortuary ceremonies also constitute precious reasons. These understandings represent the basic inspirations for advanced researches.

Depending upon facilities for carrying out crucial investigations, a large number of plants can be randomly tested. Once plants have been selected, research activities begin. Depending upon plants, the whole plant or specific parts such as roots, leaves, flowers or fruits are used as starting material to be processed for evaluating possible biological activities. In order to obtain molecules from the whole plant or specific parts, careful evaluations based on chemical analyses and biological tests are performed.

Chemical analyses are carried out to understand the chemical structure of the bio-active molecules. The first step consists of an extraction procedure for molecules collected without affecting their chemical structures. Molecular separation is then carried out by chromatographic techniques (TLC, CC, HPLC) and their chemical structures are investigated by methodologies such as FT-IR, GC-MS and NMR.

Sometimes, after identification of the chemical structures, molecules are synthesized, thus contributing to precise experiments for evaluating the biological activities. By in vitro tests carried out on specific cell lines which mimic human pathologies, it is possible to evaluate whether plant molecules have biological activities.

The data obtained can then beassessedfor potential perspectives of pharmaceuticals used against cancer or degenerative pathologies, anti-microbial activities and anti-viral pharmaceuticals, stimulation in human immune system, efficiency of vascular system and sperm movement contributing to contraceptive pharmaceuticals.

Common plants such as ginger (containing 6-gingerol, 6-shogaol and zingerone), garlic (allicin, alliin and 6-allylcysteine), turmeric (curcumin and related curcuminoids), bean (phaseolin), ginseng (ginsenosides and saponins), peppermint (menthol and rosmarinic acid), fennel (trans-anethole), rosemary (oleanolic acid), sage (safficinolide), etc. are widely used in Indian system of traditional medicine.

Plants like betel nut (containing arecoline and guvacine), tea (catechin, caffeine, and epicatechin gallate), bittergourd (momordicine and charantin),tulsi (eugenol, vicenin and orientin),amla (phyllantin and phyllantidine), etc. are used to treat human immunodeficiency virus. Even to cure the dreaded covid-19, several plants possessing anti-viral properties such as licorice (containing glycyrrhizin, liquiritigenin and glabridin), bayberry (myricetin and linolenic acid) and sweet sagewort (artemisinin) have been used.

The results of such in vitro investigations are dependent on the accuracies of the screening methods. In recent times, well-established screening methods and accurate protocols for biological tests are available.It is also possible to use virtual screening software to test libraries of compounds on panel of targets characterizing different pathologies. Molecules showing biological activities are further experimented in pre-clinical phases using laboratory animals, and if such tests confirm the results without toxic effects, further human experimentation can start.

The human experimental protocol(s) must be carried out and evaluated following precise guidelines established at the international level. It consists of different steps of investigation during which accurate biochemical studies are carried out to establish the drug, human target(s) and molecular mechanism(s) of action.

In addition, toxicological investigations are carried out to evaluate the dose and efficiency, the interaction with human cell and bodily defence system, human tolerance and degree of potential side effects. Such studies are carried out on large groups of human volunteers consisting of children, women and men in three phases. At the end of the whole process, from selection of plants to pharmaceutical products, it has been established that only one molecule among around 3000 good candidate molecules can function as potential pharmaceutical drug.Depending on the increased world population and the improvement of quality life, demand for new pharmaceuticals have increased exponentially, and as a consequence, pharmaceutical research activities have tremendously increased.

Further Reading:

Mahmood et al: Vaccines, 9, 2021,15-30.
Sytar et al: Molecules, 26,2021, 727-745.
Patel et al: Molecular & Cellular Biochemistry, 2021,
https://doi.org/10.1007/s11010-021-04084-7.