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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5217_Библиотеки_им_академика_М_И_Перельмана.pdf
• Direct therapeutic agents
• Lead compounds for stronger analogs
• A pharmacophore that can be transformed into a drug through structural modifications
• Extracts as herbal medicines
• Pure phytochemicals
• A reference substance for the standardization of herbal extracts
Natural Compounds
Figure 2.1: The various therapeutic applications of natural compounds.
Terpenoids
Glycosides
Anthocyanins
Lignans
Saponins
Phenolics
Alkaloids
Tannins
Figure 2.2: Plant secondary metabolites.
Chapter 2 Methods of obtaining drugs from medicinal and aromatic plants 43
tors, they produce secondary metabolites, such as toxins, pigments, and aromatic
compounds. Phytochemical compounds exhibit a broad spectrum of polarities and
are found in highly complex matrices. These metabolites are diverse, complex in
structure, and abundant, including alkaloids, flavonoids, glycosides, terpenoids, lipids,
waxes, peptides, and phenolics (Figure 2.2) Secondary metabolites are also considered
bioactive substances, meaning they exhibit biological activity. Bioactive substances
can be defined as substances that have pharmacological or toxic effects on both humans and animals. These bioactive components are increasingly being studied by scientists with great interest for their potential in innovative treatments [5, 8–10].
Drug discovery from medicinal and aromatic plants offers several advantages over synthetic molecules. The most important of these is the diversity of compounds with much
more complex structures compared to synthetic molecules. Plants and other natural
sources perform chemical transformations using various enzymes. This enables highly
• Plant biodiversity
• Phytochemical diversity
•
Traditional use and knowledge accumulation
• Environmental adaptation and defense mechanisms
Figure 2.3: The factors that highlight the potential of plants for development as drugs.
44 İrem Yıldız Özbaş, Severina Pacifico, and Emre Özbaş
specific structural changes to occur at particular sites in a stereospecific manner, resulting in the formation of a complex molecule. Plant-derived molecules, many of which
remain undiscovered, largely provide the chemical diversity needed for new drug research. Through their chemical diversity, plants demonstrate a wide range of pharmacological effects [5, 11]. With their phytochemical diversity, traditional foundations, and
bioactivity of metabolites, medicinal and aromatic plants will continue to serve as sources of potential drug raw materials in every era. The key factors that make plants a
potential source for drug discovery are illustrated in Figure 2.3.
Libraries of natural compounds, which cover a wide chemical space, are significantly
richer than libraries of synthetic molecules. However, this also brings certain challenges. The rich phytochemical content of plants enhances their medicinal effects and
synergistic potential but complicates the identification of the component or components responsible for the effect. Determining the mechanism of action of the compounds is also challenging and quite time-consuming. In some cases, isolating individual components that exhibit synergistic effects can reduce the efficacy of the natural
compound. In these conditions, combination studies can be conducted by considering
the synergistic effects of therapeutic candidate components [9, 12].
To determine the chemical composition of bioactive components in plants and
evaluate their pharmacological properties, these compounds must first be isolated,
purified, and characterized from the plant. Drug discovery from natural products fundamentally involves the processes of screening, isolation, characterization, and optimization. The technical barriers encountered in each of these processes highlight the
challenges of discovering drugs from plants compared to synthetics. The structural
complexity of plant-derived products makes it challenging to determine structureactivity relationships and optimize chemical structures. In conclusion, obtaining new
drugs from natural compounds requires a variety of innovative approaches [9, 12].
With advancements in technology, new strategies have been developed for drug discovery from natural products and recent technical developments have significantly
overcome the obstacles faced in drug extraction from natural sources. Technologies
Chapter 2 Methods of obtaining drugs from medicinal and aromatic plants 45
such as several engineering methods, genome mining, advanced analytical tools, bioinformatics and artificial intelligence (AI), and increasing detection power and sensitivity in analytical methods have made it easier to research plants and plant-derived
products [5, 13].
This section aims to provide an overview of the stages involved in obtaining medicines from medicinal and aromatic plants, as well as the methods used at each stage.
This section will comprehensively address the methods and techniques used in source
plant selection, extraction, isolation, characterization, and optimization of active components with the application of advanced drug development approaches to plant-based
natural products. Additionally, recent trends and future prospects in plant-derived drug
development will also be discussed in this section.
2.2 An overview of the history of plant-based
medicines
The majority of the data on medicinal and aromatic plants that has reached us today
has been empirically obtained through trial and error, based entirely on observation.
This knowledge dates back approximately 5,000 years in India, China, and Egypt and at
least 2,500 years in Greece and Central Asia [14]. Although there was no documentation
in the beginning, word-of-mouth communication provided a simple way for community
members to share knowledge. Since writing and other recoding techniques made it possible for communities to preserve information about the therapeutic properties of
plants, many people have been treated with plant-based extracts documented in these
records [2]. The oldest written records of the clinical use of plants originate from India
and China. Over time, these clinical records accumulated and transformed into the
global pharmacopoeias of ancient civilizations, such as Egypt’s Ebers Papyrus, Greece’s
De Materia Medica, and China’s Shen Nong Ben Cao. These sources documented various
plants and formulations used as medicines. This ancient wisdom and legacy of experience have served as an inspiration for modern drug discoveries [15]. Therefore, plant
extracts and mixtures have been applied over the centuries to remedy various ailments,
leading to the development of medications for microbial organisms and cancer [16].
Initially, plants or plant parts were used in their raw form, but over time, tinctures,
poultices, powders, or teas derived from them began to be used in treatments. Since
these are often in the form of extracts containing multiple components as mixtures, information on which compounds are responsible for the healing effects is either very
limited or entirely absent [17]. However, as time progressed, the discovery of the therapeutic effects of plants sparked increased interest in research aimed at isolating the active compounds responsible for these effects. From the nineteenth century onwards,
with the advancements in chemistry, a period began in which active components were
isolated from plants. The discovery of drugs from plants and herbal products has accel-
46 İrem Yıldız Özbaş, Severina Pacifico, and Emre Özbaş
erated with the identification of bioactive compound groups and the detection of pharmacological activity of natural products through preclinical and clinical studies [18].
Scientists’ interest in researching medicinal plants led to the emergence of the first
drugs. The discovery of plant-based medicines created a revolution in medicine [9]. The
German pharmacist Friedrich Sertürner isolated the alkaloid morphine from the Papa-
ver somniferum L. plant in 1805. Morphine was the first active compound to be isolated
from a plant and marked a turning point in drug discovery from plants [19]. Isolation of
morphine is also the beginning of natural product chemistry. The isolation of morphine
was followed by the isolation of quinine in 1820, caffeine in 1821, nicotine in 1828, atropine in 1831, and digitalin in 1868 [13]. Aspirin, digoxin, pilocarpine, cocaine, codeine,
paclitaxel, tetracycline, artemisinin, doxorubicin, and cyclosporine are some of the
plant-derived active ingredients still used as medicines today [5, 9]. Some plant-derived
active compounds and their therapeutic uses are shown in the Table 2.1.
Following the isolation of natural products, studies to elucidate and characterize
their structures began. Structural determination studies of natural molecules accelerated in the 1940s with the introduction of physical tools by Robert Burns Woodward.
A new era in drug discovery from natural products has begun with the elucidation of
the structures of active compounds isolated from plants, allowing their chemical synthesis and enabling modifications to their structure to alter their efficacy and side effect profiles. Robert Burns Woodward pioneered the total synthesis of natural products by synthesizing bioactive compounds from natural sources, such as quinine,
cholesterol, cortisone, chlorophyll, and reserpine [13]. The period from the 1950s to
the 1960s was considered the Golden Age of drug discovery from natural products
[32]. Before the emergence of high-throughput screening (HTS) and the post-genomic
era, more than 80% of all drug active ingredients were either entirely natural products or derived from natural sources, including semisynthetic analogs. It has been
noted that these naturally sourced compounds and their by-products served as inspiration for the advancement of a majority of pharmaceutical compounds [6].
Today, the approach of isolating and evaluating individual components from
plants has shifted to examining and formulating potential therapeutic components by
utilizing libraries of natural compounds [9].
2.3 Methods for drug discovery and development
from plants
The production of drugs from medicinal and aromatic plants requires a multifaceted
and meticulous scientific research process. There are numerous stages involved in the
discovery of a bioactive component from a medicinal plant and its subsequent transition to clinical application as a drug. Different research methods are used in each of
these stages.
Ovarian and breast cancer [20]
Artemisinin Artemisia annua
Antimalarial
Chemotherapeutic
[21]
(continued)
Chapter 2 Methods of obtaining drugs from medicinal and aromatic plants 47
Table 2.1: Some plant-derived active compounds and their resources, chemical structures, and therapeutic uses.
Natural compound Plant Chemical structure Therapeutic use References
Paclitaxel Taxus brevifolia
Antihepatotoxic [22]
Morphine Papaver somniferum
Analgesic [19]
Quinine Cinchona officinalis
Antimalarial [23]
Caffeine Coffea arabica
Psychoactive [24]
48 İrem Yıldız Özbaş, Severina Pacifico, and Emre Özbaş
Table 2.1 (continued)
Natural compound Plant Chemical structure Therapeutic use References
Silymarin Silybum marinum
Psychoactive [25]
Vincristine Vinca rosea
Chemotherapeutic [26]
(continued)
Chapter 2 Methods of obtaining drugs from medicinal and aromatic plants 49
Nicotine Nicotiana tabacum
Analgesic
Anti-inflammatory
Antipyretic
[27]
Atropine Atropa belladona
Anticholinergic
Spasmolytic
[28]
Cocaine Erythroxylum coca
Anesthetic [29]
50 İrem Yıldız Özbaş, Severina Pacifico, and Emre Özbaş
Table 2.1 (continued)
Natural compound Plant Chemical structure Therapeutic use References
Aspirin Salix alba
Analgesic [30]
Colchicine Colchicum autumnale
Gout treatment [31]
Chapter 2 Methods of obtaining drugs from medicinal and aromatic plants 51
Codeine Papaver somniferum
Plant
selection
Collection
of plant
materials
Extraction
Isolation
and
purification
Structural
characterization
Bioassays
Clinical
trials
Optimization DRUG
Figure 2.4: The main processes in the production of drugs from plants.
52 İrem Yıldız Özbaş, Severina Pacifico, and Emre Özbaş
The process of drug development from plants begins with the selection and collection
of plant materials. The collected materials undergo extraction using appropriate
methods. The plant extracts are then divided into fractions to isolate bioactive compounds. The separation, quantification, and structural determination of the desired
components from the obtained extracts are performed using chromatographic and
spectroscopic techniques. Once the active compound is fully identified, structureactivity relationships are examined to optimize bioactivity, pharmacokinetics, and
other pharmacological parameters, enhancing its applicability as a drug. Analogs of
the lead compound can be synthesized to further the drug development process
through structural modifications, semisynthesis, or total synthesis routes [33]. The
evaluation of biological activity can be conducted by screening natural compound libraries prior to plant selection or through active extracts or isolated and purified
compounds obtained after plant selection. In some cases, bioactivity assessment is integrated into every stage of the process. Accordingly, various approaches exist in the
drug development process from plants.
In drug discovery from plants, there are two approaches: traditional and modern,
utilizing different methods. In traditional methods, extracts obtained from plants and
plant materials are subjected to various tests for bioactivity. Extracts that show activity are fractionated, and the active compound is isolated. Here, the extraction and isolation processes can be guided by bioactivity tests, or they may proceed independently of bioactivity, isolating components for subsequent bioactivity evaluation. In
modern methods, advanced robotic technologies such as HTS are used to rapidly test
hundreds of molecules found in natural compound libraries. Using this approach, a
lead compound required for drug development can be quickly identified, allowing
subsequent processes such as isolation, structural analyses and modifications, bioassays, and clinical trials to proceed efficiently. The drug discovery process from plants
can be divided into stages, including the selection and collection of plants or plant
materials, extraction, isolation, structural identification, bioassays, clinical studies,
and optimization (Figure 2.4) [34].
A comprehensive, cross-disciplinary approach that utilizes technological progress is
crucial for enhancing the drug development process from medicinal and aromatic
plants. In this process, the integration of bioinformatics, HTS technologies, genomics
and metabolomics, efficient extraction and suitable isolation procedures, and structural elucidation tools will make the process significantly more efficient. Various bioactivity assay methods are also employed to assess the pharmacological suitability of
phytochemical components [2, 7].