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Valdir Cechinel Filho Editor

Natural Products as
Source of Molecules
with Therapeutic
Potential
Research & Development, Challenges
and Perspectives
Natural Products as Source of Molecules
with Therapeutic Potential
Valdir Cechinel Filho
Editor

Natural Products as Source

of Molecules with
Therapeutic Potential
Research & Development, Challenges
and Perspectives
Editor
Valdir Cechinel Filho
University of Vale do Itajaí - UNIVALI
Itajaí, SC, Brazil

ISBN 978-3-030-00544-3    ISBN 978-3-030-00545-0 (eBook)

https://doi.org/10.1007/978-3-030-00545-0

Library of Congress Control Number: 2018962876

© Springer Nature Switzerland AG 2018

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
This book is dedicated to:
– My family (Valdir Cechinel*, Amélia
Copetti Cechinel*, Emílio Cecconi*, and
Bilmar Canarin Cecconi—* in
memoriam)
– My wife Lenita Cecconi Cechinel and my
daughters Camile C. Cechinel and
Milene C. Cechinel
– My scientific fathers, Franco Delle
Monache and Rosendo A. Yunes
for all the support, trust, and understanding.
Acknowledgments

I thank all the authors and co-authors for the relevant participation as well as all the
collaborators of the University of Vale do Itajaí (UNIVALI) and other partners.
Special thanks to my daughter Camile for her excellent technical support.

vii
Contents

 edicinal Plants and Phytomedicines ������������������������������������������������������������   1

M
Rivaldo Niero, Valdir Cechinel Filho, and Rosendo Augusto Yunes
 lant Products with Antifungal Activity: From Field
P
to Biotechnology Strategies ������������������������������������������������������������������������������ 35
Giovanna Simonetti, Alessio Valletta, Olga Kolesova,
and Gabriella Pasqua
 iquid Chromatography for Plant Metabolite Profiling
L
in the Field of Drug Discovery�������������������������������������������������������������������������� 73
Luiz Carlos Klein-Júnior, Johan Viaene, Amorn Slosse,
and Yvan Vander Heyden
 unctional Foods as Source of Bioactive Principles: Some
F
Marked Examples���������������������������������������������������������������������������������������������� 111
Adriana Campos, Elisa Brasili, Camile Cecconi Cechinel-Zanchett,
and Valdir Cechinel Filho
 he Role of Flavonoids as Modulators of Inflammation
T
and on Cell Signaling Pathways��������������������������������������������������������������������   159
Liliana V. Muschietti, Jerónimo L. Ulloa, and Flavia DC. Redko
 urrent Approaches to the Isolation and Structural Elucidation
C
of Active Compounds from Natural Products ������������������������������������������������ 209
Alice L. Perez
Syntheses of Asymmetrically Substituted Pyrans of Natural Origin������������ 233
Wiesław Szeja and Grzegorz Grynkiewicz
 atural Products as Sources of Anticancer Agents: Current
N
Approaches and Perspectives���������������������������������������������������������������������������� 309
Gordon M. Cragg and David J. Newman

ix
x Contents

 irtual Screening for the Discovery of Active Principles

V
from Natural Products�������������������������������������������������������������������������������������� 333
Benjamin Kirchweger and Judith M. Rollinger
 urrent Regulatory Environment of Herbal Medicinal Products
C
in the European Union�������������������������������������������������������������������������������������� 365
Werner Knöss
 evelopment and Use of Polymeric Nanoparticles
D
for the Encapsulation and Administration of Plant Extracts������������������������ 391
Ashik Mosaddik, Vijaya Ravinayagam, Silviya Elaanthikkal,
Hatem Fessi, Waisudin Badri, and Abdelhamid Elaissari
 MR Identification of Biologically Active Natural Products:
N
Strategies and Challenges���������������������������������������������������������������������������������� 465
Gloria Ivonne Hernández-Bolio and Luis Manuel Peña-Rodríguez
 erbal Medicine and Public Healthcare: Current
H
and Future Challenges�������������������������������������������������������������������������������������� 495
Dâmaris Silveira, Jose M. Prieto, Marcela M. Freitas,
and Andre L. D. A. Mazzari

Index�������������������������������������������������������������������������������������������������������������������� 517
About the Editor

Valdir Cechinel Filho holds a bachelor’s degree in

Organic Chemistry from the Federal University of Santa
Catarina (1987), a master’s degree from the Federal
University of Santa Catarina (1991), and a PhD from
the Federal University of Santa Catarina (1995). He was
Pro-rector and Vice-Rector of Postgraduate, Research,
Extension and Culture of the University of Vale do Itajaí
(UNIVALI) (2002–2018) and is currently a professor/
researcher of the Postgraduate Program (M/D) in
Pharmaceutical Sciences of UNIVALI. He conducts
research projects in collaboration with national and
international researchers. He is also the Coordinator of
the RIBIOFAR/CYTED/CNPq Network and RIBECANCER/CYTED/CNPq
Network. He has experience in the field of Organic Chemistry, focusing on the fol-
lowing topics: bioactive natural products, synthesis of molecules of biological inter-
est, and investigation of the relationship between chemical structure and biological
activity. He has more than 360 published articles, 50 books and book chapters, and
10 patents in his name. He has supervised around 50 dissertations and theses. He
serves as a Reviewer for more than 50 journals and as an Associate Editor of
Pharmaceutical Biology. In 2012, he was awarded first place in the Caspar Stemmer
Innovation Prize (FAPESC) for the Protagonist Innovation category. In 2013, he
was a Finalist for the Santander Student Guide Award (partnership with the private
sector) for his project developed in partnership with the pharmaceutical company
Eurofarma. In 2015, he was a Finalist for the Santander 2015 Award, for the cate-
gory Science and Innovation, with his project entitled “Search for new and effective
anticancer agents from the Brazilian biodiversity.” In 2017, he received the highest
commendation of Academic Merit of the Council of Rectors of Brazilian Universities

xi
xii About the Editor

(CRUB), supported by the CNPq, for his contribution to the Brazilian Higher
Education. In March 2018, he became President of the Foundation UNIVALI and
Rector of UNIVALI, with a mandate to head the Institution until 2022.
Medicinal Plants and Phytomedicines

Rivaldo Niero, Valdir Cechinel Filho, and Rosendo Augusto Yunes

Abbreviations

AIDS Acquired immune deficiency syndrome

ANVISA Agência Nacional de Vigilância Sanitária
BC Before Christ
BfArM Bundesinstitut für Arzneimittel und Medizinprodukte
BPH Benign prostatic hyperplasia
CNS Central nervous system
COX Cyclooxygenase
CPQBA Research Center for Chemical, Biological and Agricultural
CYP 450 Cytochrome P450
DNA Deoxyribonucleic acid
ED50 Effective dose that produces a therapeutic response in 50%
EMSA Electrophoretic mobility assay
ESI-MS Electrospray ionization mass spectrometry
FDA Food and Drug Administration
GABA Gamma-aminobutyric acid
HE Hydroalcoholic extract
HET-CAM-test Chorioallantoic membrane test
HPLC High-performance liquid chromatography
HPTLC High-performance thin-layer chromatography
IC50 Inhibitory concentration that produces a therapeutic response
in 50%
IL Interleukin
iNOS Nitric oxide synthase

R. Niero (*) · V. Cechinel Filho

Núcleo de Investigações Químico-Farmacêuticas (NIQFAR) e Programa de Mestrado em
Ciências Farmacêuticas, Universidade do Vale do Itajaí (UNIVALI), Itajaí, SC, Brazil
e-mail: niero@univali.br; cechinel@univali.br
R. A. Yunes
Departamento de Química, Universidade Federal de Santa Catarina (UFSC),
Florianópolis, SC, Brazil

© Springer Nature Switzerland AG 2018 1

V. Cechinel Filho (ed.), Natural Products as Source of Molecules with
Therapeutic Potential, https://doi.org/10.1007/978-3-030-00545-0_1
2 R. Niero et al.

LC-MS Liquid chromatography mass spectrometry

L-NOARG L-NG-nitro arginine
mRNA Messenger RNA
MRSA Methicillin-resistant Staphylococcus aureus
NF-kB Nuclear factor kappa B
NMR Nuclear magnetic resonance
PGE2 Prostaglandin2
SFE Supercritical fluid extraction
SGLT1 Sodium-glucose transport proteins
SRT Serenoa repens extract
TLC Thin-layer chromatography
TNFalpha Tumor necrosis factor alpha
WHO World Health Organization

1 Introduction

The use of plants for therapeutic purposes is one of the oldest practices of mankind.
The Egyptians recorded the analgesic use of opium, as well as the use of fungi with
antibiotic properties. Other civilizations, such as India and China, also left records
on the use of medicinal plants, with a collection of 700 species, and still play an
important role in traditional medicine (Barreiro and Bolzani 2009; Cechinel Filho
and Yunes 2016). Today, according to the World Health Organization (WHO),
approximately 80% of the world’s population uses plants to treat basic illnesses,
mostly in the form of extracts or their active ingredients (WHO 2018). The market-
ing of these phytomedicines has expanded considerably throughout the world, par-
ticularly in the European countries, such as Germany, France, Italy, the United
Kingdom, and Spain, and, more recently, the United States. Brazil has an important
role in this field, as it has the largest biodiversity in the world, with more than
35,000 catalogued species, of a total of between 350,000 and 550,000 plant species
identified worldwide (Dutra et al. 2016). Thus, expertise in the areas related to the
development of phytomedicines, including organic chemistry, preclinical pharma-
cology, clinical pharmacology, and pharmaceutical sciences, has increased in recent
years (Newman and Cragg 2016; Leonti and Verpoorte 2017).
Phytomedicines are defined as the use of a crude drug (dried herb), an essential
oil, an extract or fraction of it for medicinal properties, and quite often complex
mixture of compounds that generally occur in low (variable) concentrations. The
most commonly used phytomedicines are plant extracts obtained by the use of sol-
vents and by maceration or percolation of the dried plants (Pferschy-Wenzig and
Bauer 2015; Azwanida 2015). The extracts can be used as liquid preparations or in
powdered form. The solvents most commonly used for extraction are water and
alcohol. In some cases, fractions are used, which contain more concentrated levels
of the active principles, and are generally obtained by partition with solvents of
increasing polarity. However, due to the increasing popularity and expanding global
Medicinal Plants and Phytomedicines 3

market for phytotherapeutics, the safety of plant products has become a major
­public health concern. A lack of regulation and distribution channels (Internet sales)
may result in poor quality products and, consequently, adverse reactions. The most
common causes of adulteration are products with undeclared potent pharmaceutical
substances, substitution or misidentification with toxic plant species, incorrect
doses, and interactions with conventional medicines (Gurib-Fakim 2006).
The availability and quality of the raw materials are frequently problematic
because the active principles are often unknown, and standardization and stability,
though feasible, are not easy. Compared with modern medicine, herbal medicines
cost less, are more often used to treat chronic diseases, and appear to have less fre-
quent undesirable side effects. Thus, modern techniques have received attention in
recent years, and the number of publications produced annually in this field has
increased considerably. The most notable technique in this field is the hyphened
analytical technique, which has enabled a reliable fingerprint to be obtained (Patel
et al. 2010; Kulkarni et al. 2014). This has led to a growing class and a promising
market, as it generates revenue of $ 21.7 billion a year.

2 Quality Control of Phytomedicines

2.1 Quality and Efficacy of Plant Material

The use of plants with medicinal purposes involves the action of multiple com-
pounds generally in a very low concentration. Thus, its safety is known and accepted,
but not its effectiveness. A disadvantage of phytotherapy is that in most cases, there
is a lack of clearly defined, complete information on the composition of the extracts.
Furthermore, phytomedicines require a thorough, in-depth assessment of their phar-
macological qualities, which can now be done through the use of new biological
technologies. Consequently, the development of fast and effective analytical meth-
ods for fingerprinting plant extracts is of high interest. In this context, several stud-
ies have shown that ESI-MS and LC-MS methods are particularly effective for
characterizing plant extracts (Van Der Kooy et al. 2009).
Synergy between compounds is a basic principle of medicinal plants, which will
be discussed in this chapter. However, efforts are especially dedicated to studying
single molecules, rather than identifying synergies among different compounds.
From a scientific perspective, the extracts of medicinal plants as a whole constitute
the “active principles.” Thus, the measurement of one or more components as mark-
ers is necessary. Also, in the case of extracts in which an active constituent has been
determined, there is generally a group of substances that are active. It is therefore
necessary to obtain a “fingerprint” of the extract in which all the possible constitu-
ents can be characterized and/or identified. This is now possible through various
modern technological methods. Phytotherapy requires plant material with a stan-
dardized composition; however, natural material growing in the wild does not
4 R. Niero et al.

always have the same quality, due to different affecting factors such as climate, soil,
genetic constitution, etc. Therefore, it is more efficient to cultivate the plants, in
order to reduce variations in the constituents and to ensure controlled content of the
pharmaceutically relevant constituents (Wang et al. 2004).
To improve the accuracy and consistency of control of phytomedicine prepara-
tions, regulatory authorities worldwide are requesting research into new analytical
methods, for more rigorous standardization of phytomedicines. Significant differ-
ences have been observed in chamomile extracts by NMR-based metabolomics,
which combine high-resolution 1H-NMR spectroscopy with chemometric analysis,
showing that the origin, purity, and preparation methods contributed to these differ-
ences (Mattoli et al. 2006; Bansal et al. 2014; Kumar 2016).
Over the last 10 years, numerous cases of intoxication, leading in most cases to
end-stage renal failure, have been reported after consumption of weight loss diets
containing Chinese herbal preparations. These intoxications were associated with
species of the Aristolochia genus, such as A. fangchi, known to contain very neph-
rotoxic and carcinogenic metabolites called aristolochic acids (1 and 2, Fig. 1).
Several dietary supplements, teas, and phytomedicines used in weight loss diets
were analyzed. The presence of aristolochic acid I was confirmed by HPLC/
UV-DAD/MS analysis (Ioset et al. 2003). These products were immediately recalled
from the Swiss market.
Pesticides, which are mainly applied to crops to protect the plants, have been
found in medicinal plants, as well as in infusions, decoctions, tinctures, and essen-
tial oils (Zuin and Vilegas 2000). This important aspect of medicinal plants is
reviewed in a review article spanning more than 30 years. Other studies indicate the
incidence of toxigenic fungi and their mycotoxins in 152 Argentinean medicinal
and aromatic dried plants belonging to 56 species, which are used as raw material
for phytomedicines (Rizzo et al. 2004). Fortunately, over the years, the specific
pharmacognostical tools have changed dramatically, and most recently, DNA-based
techniques have become another element of our spectrum of scientific methods
(Heinrich and Anagnostou 2017).

Fig. 1 Major carcinogenic and nephrotoxic COOH

O
compounds from Aristolochia genus
NO2
O

(1) R=H; aristolochic acid I

(2) R=OMe; aristolochic acid II
Medicinal Plants and Phytomedicines 5

2.2 Production Methods

The nature of the solvents and the extraction and drying methods affects the compo-
sition of the extracts. For liquid phytomedicines, water and alcohol are the principal
solvents. Polar compounds are soluble in water, and nonpolar lipophilic compounds
are soluble in alcohol. However, when identical solvents are used, the extraction
methods can yield extracts with different pharmacological actions. Studies have
indicated, in the case of essential oils, that water steam distillation in acidic medium
can be more advantageous than the traditional method if the volatile terpene deriva-
tives present in the plants are in the form of glycosides or dimeric lactones (i.e.,
oregano, wormwood oils, siderites). Comparing the composition of essential oils
obtained by water steam distillation and supercritical fluid extraction (SFE), it was
found that SFE fractions are richer in ester constituents because the possibility of
hydrolysis is reduced and the oils are more valuable than the classic oils. However,
when the transformation processes are important (chamomile), the distillation
should be the appropriate method (Lemberkovics et al. 1998). A Korean researcher
has patented a method for the quantitative standardization of medicinal herbs by (i)
preparing the sample of medicinal herbs and measuring the weight of the sample,
(ii) roasting the sample by controlling the intensity of a fire, and (iii) classifying the
sample into three types: a low, medium, and strong flame (Choudhary and Sekhon
2011). However some authors have indicated problems in the standardization of
flavonoids in crude drugs and extracts from medicinal plants and in the application
of HPLC, HPTLC-densitometry, and spectrophotometry in standardization. This
fact demanded new and more efficient methods of analysis for controlling the qual-
ity of the extracts.

3 Medicinal Teas Today

Tea is the second most commonly consumed liquid on earth, after water. It has been
drunk socially and regularly since 3000 BC. Its medicinal effects date back almost
5000 years. Tea is an infusion obtained from dried leaves of different plants or roots,
herbs, spices, fruits, or flavors in hot water (Sharangi 2009). Scientific research
around the world has provided clear evidence of the health benefits associated with
drinking herbal tea. Today there are teas that prevent cholesterol, high blood pres-
sure, fatigue, diabetes, excess weight, and detoxification, among others (Barnes
2010; Khan and Mukhtar 2013). A related compound found in tea is theophylline
(3), a licensed medicine for the treatment of respiratory diseases such as asthma
(Fig. 2). Tea infusions can be prepared from individual plants or from plant mix-
tures. A basic distinction is made between:
–– Non-medicinal teas that are consumed for pleasure, such as black tea, flavored
teas, etc.
–– Medicinal teas
6 R. Niero et al.

Fig. 2 Major bioactive O

compound from medicinal teas
H 3C N
N

O N N
CH3
(3)

The indications for the use of medicinal teas are psychosomatic disorders, colds,
urinary problems, constipation and diarrhea, and gastrointestinal disorders, among
others (Schulz et al. 2001; Khan and Mukhtar 2013). There are no controlled clini-
cal studies on the efficacy of medicinal teas, and their medicinal values are based
largely on empirical evidence. In addition, the placebo effect must contribute to
their efficacy. Several studies describe the findings of these ethnomedicine research
efforts throughout the world over time (Khan and Mukhtar 2013; Boozari and
Hosseinzadeh 2017; Naveed et al. 2018).

4 Modern Phytotherapy

Studies have indicated that in order to investigate an extract, which is a complex

system, a reductionist method should be applied to determine each active compound
separately, but according to previous discussion above, such research must be car-
ried out with caution, as it will never quite explain the efficacy of the entire extract.
The saying that “the whole is more than the sum of all the individual parts” is appli-
cable to phytopharmaceuticals. After analyzing the progress introduced by the mod-
ern analytical method and in vitro and in vivo pharmacological assays with models
of biological molecular test, the phytotherapy was significantly improved.

4.1 New Scientific Screening

There has been a significant increase in news and important methods for biological
screening. Assays on Alzheimer’s disease have focused on agents that counteract
the loss of cholinergic activities. The Ellmann microplate assay and silica gel thin-­
layer chromatography were used to screen extracts from plants as possible new
sources of AchE inhibitors (activity in the NF-kB and the HET-CAM-test) (Salles
et al. 2003; Pohanka et al. 2011).
Peruvian medicinal plants were analyzed with respect to their antibacterial activ-
ity using a versatile microplate bioassay for rapid and sensitive determination of the
organic compounds (Langfield et al. 2004). Grifolin (4) and grifolic acid (5), which
are S. aureus and S. epidermidis growth inhibitors, were determined as the main
Medicinal Plants and Phytomedicines 7

Fig. 3 Main active OH

principles from Peruvian
medicinal plants

OH
R
(4) R=H; Grifolin
(5) R=COOH; Grifolic acid

active principles (Fig. 3). A recently developed method studied the correlation
between the chemical composition and bioactivity of herbal medicine and identified
the active components from the complex mixture. The advantage of this method
compared with bioassay-guided isolation was demonstrated by its application on a
typical herbal drug. Several modern methods of bioassay-guided fractionation have
been promising alternatives for valuable information on the biological effects of
complex materials with successful application in many fields (Weller 2012; Zhuo
et al. 2016; Ren et al. 2017).

4.2 Mechanism of Action

Drug resistance has been a major obstacle in cancer chemotherapy. Active princi-
ples from plants used in traditional Chinese medicine may act by different molecu-
lar targets from those of clinically used antitumor drugs, making them attractive
candidates for new therapeutics (Wu et al. 2011). Five hundred thirty-one natural
products were tested for correlation with the microarray-based mRNA expression of
six genes involved in nucleotide excision repair. The results showed no evidences
associated with the expression of these genes, suggesting that mRNA expression is
not related to resistance of the cell lines of these substances. In addition, other genes
were identified, but none of these appear to be involved in DNA repair (Konkimalla
et al. 2008).
Studies have been carried out using the electrophoretic mobility assay (EMSA)
as a suitable technique for the identification of plant extracts that alter the binding
between transcription factors and the specific DNA elements (Hellman and Fried
2007). These studies demonstrate that low concentrations of H. indicus, P. longifo-
lia, M. oleifera, and L. speciosa inhibit the interactions between nuclear factors and
target DNA elements, mimicking sequences recognized by the nuclear factor kappa
B (NF-kB). Extracts of P. foetida, C. sophera, and O. sanctum were unable to inhibit
NF-kB/DNA interactions. Extracts that inhibit both NF-kB binding activity and
tumor cell growth might be a source for antitumor compounds, while those that
inhibit NF-kB/DNA interactions with lower effects on cell grow could be of interest
in inflammatory diseases. More recently, the progress in new methodologies and
simulation of biomolecular processes to develop new drugs has been emphasized.
The contribution of recent techniques, such as a network of specific metabolisms,
8 R. Niero et al.

has helped to understand the complexity of the tumor as well as the mechanisms of
anticancer drugs (Olgen 2018). In addition, research findings shed light on the
potential novel applications and formulation of TCMs via regulation of autophagy,
which may be an important mechanism underlying the therapeutic effect of TCMs
in treating diseases. Autophagy dysregulation is implicated in the pathogenesis of
multiple diseases, such as aging, cancers, and diabetes, which may contribute to the
discovery of potential drug targets (Cui and Yu 2018).

4.3 Synergy

The term synergism means that the effect of two or more substances causes better
biological activity than the pure substances administered in a single dose (Wagner
and Ulrich-Merzenich 2009). In this context, this effect occurs by different chemi-
cal and biological means. There are many examples of mono- and multi-extract
combinations used presently, which exhibit synergistic efficiency based on multi-­
target mechanisms of action (Ma et al. 2009; Wagner 2011). Some phytotherapeu-
tics available on the market in different forms (extract or fraction) generally exhibit
synergism that has an important effect in improving the therapeutic potency.
However, a contrary effect can sometimes be observed, leading to a biological activ-
ity decrease, called antagonism.
Although only a few clinical studies have confirmed the existence of synergism,
preclinical studies have been extensively described, and large amounts of experi-
mental evidence can be found in the literature, exhibiting health benefits to humans,
improving consumer acceptance and economic value (Malongane et al. 2017).
To better illustrate the phenomenon of synergism, three examples are detailed:
1. Tabebuia avellanedae bark extract and β-lapachone (6) were combined to inves-
tigate the hematopoietic response of tumor-bearing mice (Fig. 4). Administration
of extract (30–500 mg/kg) and β-lapachone (1–5 mg/kg) in distinct combina-
tions caused a dose-dependent reversion of these effects. The best combination
was that of 120 mg/kg extract and 1 mg/kg β-lapachone, which prolonged the
life span of tumor-bearing mice, both producing the same rate of extension in the
duration of survival (Queiroz et al. 2008). Toxic effects were evidenced by the
higher doses of β-lapachone in normal and tumor-bearing mice. The studies by

Fig. 4 A bioactive compound that O

exhibits synergism with medicinal plants
O

(6)
Medicinal Plants and Phytomedicines 9

TLC and HPLC suggested that the antitumor action of extract and β-lapachone
also act synergistically with other factors, such as specific cytokines. More
recently, a study demonstrated that, in general, β-lapachone combined with beta
lactams antimicrobials, fluoroquinolones and carbapenems acts synergistically
inhibiting MRSA strains (Macedo et al. 2013).
2. Studies show that distinct plant extracts have caused synergistic effects against
human pathogenic microorganisms (Amenu 2014). Although the traditional anti-
biotics have exhibited effective therapeutic action in the treatment of infectious
diseases caused by fungi or bacteria, resistance to these drugs has re-emerged in
old diseases. The use of combined drugs or plant extracts with drugs has been
used as a strategy for decreasing this resistance, like the described use of
β-lactams associated with β-lactamase inhibitors. Synergy has been confirmed
between some components extracted from plants, such as flavonoids and essen-
tial oils, and synthetic antibiotics used to inhibit bacterial, fungal, and mycobac-
terial infections (Hemaiswarya et al. 2008; Cheesman et al. 2017). The potency
and/or mechanisms of action of some types of combination are very different
from that of drugs used pure, demonstrating the existence of synergism in these
cases.
3. A paper describes the antiplasmodial potential of 13 plant species (and combina-
tion of plants to determine a possible synergism) used in traditional folk medi-
cine in Kenya, for the treatment of malaria. Twenty-five percent of the tested
plants were highly active, and 46% exhibited moderate activity against the
malaria parasite (Gathirwa et al. 2011). Both synergism and antagonism were
demonstrated for combination of some studied extracts. Uvaria acuminata and
Premna chrysoclada presented the highest synergy, while the interaction between
Grewia plagiophylla and Combretum illairii caused a pronounced antagonistic
effect.

5 Some Selected Phytomedicines

Although the scientific results are not yet sufficient to establish the safety and effi-
cacy of most herbal products, some of them provide scientific evidence suggesting
that these are important medical therapies. However, it is still necessary to improve
some aspects related to these points and to regulate and standardize herbal products.
We have selected and shown some important aspects of herbal products among the
most commonly studied plants (Table 1), such as Ginkgo biloba (ginkgo), Serenoa
repens (saw palmetto), Valeriana officinalis (valerian), Hypericum perforatum (St.
John’s wort), Allium sativum (garlic), Piper methysticum (kava kava), and Glycine
max (soy). Some selected medicinal plants currently under used and studied in
Brazil are exemplified: Matricaria chamomilla, Maytenus ilicifolia, Ilex paraguar-
iensis, Phyllanthus niruri, and Cynara scolymus.
10 R. Niero et al.

Table 1 Biological activity and main classes of compounds from selected plants
Species Biological activity Active principles Ref.
Ginkgo biloba Anti-inflammatory, Terpenoids Chan et al. (2007), Van
antitumor, antiaging, CNS (ginkgolides), Beek and Montoro (2009)
disorders polyphenols and Zuo et al. (2017)
(biflavonoids),
organic acids,
carbohydrates
Serenoa repens Anti-infectious, anti-­ Fatty acids and Goldenberg et al. (2009),
inflammatory, spasmolytic, phytosterols Plosker and Brogden
antiandrogen, estrogenic (1996) and Saidi et al.
effect (2017)
Valeriana Analgesic, sedative, Alkaloids, Wichtl (2004a), Mennini
officinalis anticonvulsant sesquiterpenes, et al. (1993) and Savage
flavonoids, amides et al. (2018)
Hypericum Antidepressant, Anthrones, Butterweck and Schmidt
perforatum antibacterial phloroglucinol (2007), Marrelli et al.
derivatives, (2016) and Agapouda
flavonoids et al. (2017)
Allium sativum Cardiovascular action, Sulfur-containing Wichtl, (2004b),
antimicrobial, compounds Petrovska, Cekovska
antihypertensive, (2010) and Sharifi-Rad
antilipidemic, anticancer et al. (2016)
Piper Sedative, anxiolytic, Kavalactones Gary (1997), Sarris et al.
methysticum anti-stress, analgesic, local (2011) and Chua et al.
anesthetic, anticonvulsant, (2016)
neuroprotective
Glycine max Antidiabetic, anticancer Flavonoids, saponins Anupongsanugool et al.
antioxidant (2005) and Wang et al.
(2013)
Matricaria Anti-inflammatory, Flavonoids, McKay and Blumberg
chamomilla antimutagenic, anticancer, terpenoids (2006), Srivastava and
antispasmodic, anxiolytic Gupta (2015) and Miraj
and Alesaeidi (2016)
Maytenus Gastroprotective analgesic, Terpenoids, Carlini (1988), Mariot
ilicifolia contraceptive flavonoids and Barbieri (2007),
Niero et al. (2011) and
Tabach et al. (2017a, b)
Ilex Hypocholesterolemic, Flavonoids, Bracesco et al. (2011),
paraguariensis hepatoprotective, diuretic, triterpenoids, Luz et al. (2016) and
CNS stimulant alkaloids, caffeoyl Ronco et al. (2017)
derivatives
Cynara Antidiabetic, diuretic, Sesquiterpene Wegener and Fintelmann
scolymus hepatoprotective, lipid lactones, phenolic (1999), Noldin et al.
lowering, antispasmodic, acids, flavonoids (2003), Ben Salem et al.
hypocholesterolemic (2015) and Elsebai et al.
(2016)
Phyllanthus Analgesic, anti-hepatotoxic, Lignans, flavonoids, Calixto et al. (1998),
niruri anti-HIV, anti-hepatitis B, alkaloids, coumarins, Bagalkotkar et al. (2006)
antihypertensive saponins, tannins and Kaur et al. (2017)
Medicinal Plants and Phytomedicines 11

5.1 Ginkgo biloba (Ginkgo)

Ginkgo biloba is one of the world’s most important plants with recognized thera-
peutic potential. The World Health Organization indicates the medicinal uses sup-
ported by clinical data, which have been used for symptomatic treatment of mild to
moderate cerebrovascular insufficiency (dementia syndromes in primary degenera-
tive dementia, vascular dementia, and mixed forms of both) with the following
symptoms: memory deficit, concentration disturbances, depressive emotional con-
dition, dizziness, tinnitus, and headaches (Kleijnen and Knipschild 1992; Diamond
et al. 2000; Isah 2015). Ginkgo composition has several types of components,
mainly flavonoids and terpenoids. Bilobalide (7) and ginkgolides A (8) and B (9) are
the main bioactive substances (Fig. 5). The crude extracts from ginkgo and their
constituents have been investigated as scavenging free radicals, lowering oxidative
stress, reducing platelet aggregation, having anti-inflammatory properties, and oth-
ers (Chan et al. 2007; Van Beek and Montoro 2009). It is estimated that Ginkgo
biloba existed on earth for 200 million years, and it is considered as a “living fossil.”
Its natural habitats are in China, Japan, and Korea, and it was first introduced to
Europe in the eighteenth century (Heather and Smith 2004). Because of its thera-
peutic and economic interest, this plant has been cultivated on a large scale in sev-
eral countries, including France and the United States (Singh et al. 2008; Isah 2015).
Today, its standardized extract is available throughout the world, and it is one of the
most sold phytomedicines. A number of review articles concerning the different
aspects of G. biloba have been published, including recent papers focusing on its
chemical and biological aspects (Pedroso et al. 2011; Mohanta et al. 2014; Zuo et al.
2017).

5.2 Serenoa repens (Saw Palmetto)

Serenoa repens, commonly known as saw palmetto, is currently classified as

part of the genus Serenoa. It is known by a number of synonyms, including
Sabal serrulatum, under which name it still often appears in alternative

O O
H H H H
O O O HO O
O O O
O O O
O O
O O O
O OH
OH OH OH
O O OH
H OH
OH H H OH
(7)
(8) (9)

Fig. 5 Major bioactive compounds from Ginkgo biloba

12 R. Niero et al.

medicine (Wilt et al. 1998). It is endemic to the southeastern United States,

particularly along the Atlantic and Gulf Coastal plains, but also as far inland as
southern Arkansas. This small palm has dark red berries that contain volatile oil
consisting of 65% free fatty acids and 35% their ethyl esters. The berries also
contain phytosterols (β-sitosterol and derivatives), which are the main compo-
nents responsible for the activity in the treatment of benign prostatic hyperpla-
sia (BPH) (Plosker and Brogden 1996). This disease is a nonmalignant
enlargement of the prostate common in men and can lead to obstructive and
irritative lower urinary tract symptoms (Gordon and Shaughnessy 2003;
Tacklind et al. 2009). The synthetic drug finasteride (10), a 4-azasteroid (Fig. 6),
was designed considering the phytosterols. These molecules inhibit the
5-α-reductase, an enzyme that converts testosterone into 5-α-dihydrotestosterone,
which binds to androgen receptors in the prostate cells, stimulating their growth
and division. Its mechanism of action is unclear, but the effects are generally
attributed to a combination of the spasmolytic, antiandrogen, and anti-inflam-
matory activities of the extract (Goldenberg et al. 2009). Recently an investiga-
tion about the mechanism of 5α-reductase inhibition by extract through
computational methods has been performed. The results showed that sterols and
fatty acids can play a role in the inhibition of the enzyme, suggesting a competi-
tive mechanism (Governa et al. 2016). More recently, a study evaluated the
effects of Serenoa repens alcohol extract in patients with BPH symptoms. The
study was performed on 70 men aged 40–79 divided into 2 groups. Forty patients
were treated with Serenoa repens extract (SRT), and 30 were observed only. The
treated group showed statistically significant differences between patient con-
trols in all observed parameter. The mild improvements of the urine flow and
prostate size indicate the efficiency of this phytotherapeutics agent in patients
with BPH (Saidi et al. 2017).

Fig. 6 The structure of finasteride, a

synthetic drug for the treatment of BHP
O N H

H H
O N
H

(10)
Medicinal Plants and Phytomedicines 13

5.3 Valeriana officinalis (Valerian)

Valerian (Valeriana officinalis, Valerianaceae) is a hardy perennial flowering plant,

with heads of sweetly scented pink or white flowers. Valerian is a native plant of
Europe and parts of Asia and has been introduced to North America (Plushner 2000;
Hadley and Petry 2003). Several active principles were determined for valerian
(Fig. 7), including actinidine (11), valerianine (12), isovaleramide (13), valeric acid
(14), acevaltrate (15), isovaltrate (16), valtrate (17), acetoxyvalerenic acid (18),
valerenic acid (19), hesperidin (20), 6-methylapigenin (21), and linarin (22) (Wichtl
2004a). The historical use of valerian to treat diseases related to the CNS prompted
scientists to investigate the interaction of its components with the GABA neu-
rotransmitter receptor system (Mennini et al. 1993; Savage et al. 2018). However,
these studies remain inconclusive, and the action mechanism remains obscure.
Valerian is used in herbal medicine as a sedative and is currently used as a remedy
for insomnia. Studies have showed a significant reduction in anxious behavior when
valerian extract or valerenic acid is exposed, suggesting as a potential alternative to
the traditional anxiolytics (Murphy et al. 2010; Felgentreff et al. 2012; Leach and
Page 2015). However, the literature has demonstrated some conflicts with respect to
the medicinal properties in preclinical studies, indicating no significant differences
between valerian and placebo, either in healthy individuals or in individuals with
general sleep disturbances or insomnia (Taibi et al. 2007). A review evaluating the
therapeutic potential of 1000 plants concluded that only 9 plants, including valerian,
demonstrated considerable evidence of a therapeutic effect. On the other hand,
some adverse effects related to the use of valerian have been reported. Large doses
or chronic use may result in stomachache, apathy, and a feeling of mental dullness
or mild depression (Cravotto et al. 2010; Leach and Page 2015).

5.4 Hypericum perforatum (St. John’s Wort)

Hypericum perforatum is among the most commonly used and preferred herbal
drugs and is still the only herbal alternative to classic synthetic antidepressants for
the treatment of mild to moderate depression (Butterweck and Schmidt 2007). A
great number of preclinical and clinical studies have been conducted to verify the
effectiveness of the plant extract (Vacek et al. 2007). The literature data indicates
that several organic compounds contribute to the antidepressant efficacy of the plant
extract, particularly hypericin (23) and hyperforin (24), which are considered the
main active principles of this plant (Agapouda et al. 2017). Some flavone deriva-
tives, including the well-documented rutin (25), seem to contribute to the antide-
pressant efficacy (Fig. 8). On the other hand, despite the great number of studies
focusing on the clinical efficacy of this plant, only a few have been published con-
cerning its oral bioavailability and pharmacokinetic data. Besides the recognized
antidepressant potential of H. perforatum, other important biological actions are
14 R. Niero et al.

O O
N N
NH2 OH
(11) (12) (13) (14)

O
O O
O O O O
O O O O

O
O O O
O O
O H O
O O H O H O
O O O
(15)
(16)
(17)

O
H3CO OH
H
HO
H
HO
O
H 3C
OH
O OCH3
O
HO O O
HO O
HO
HO O OH

(19)
(18) OH O
(20)
OH
HO
HO
OH O
H 3C
HO O O OCH3
O
H 3C HO O O
HO
OH O OH

(21)
OH O
(22)

Fig. 7 Major active principles from Valeriana officinalis

Medicinal Plants and Phytomedicines 15

OH O OH
OH

HO O HO O
HO CH3 OH OH
HO CH3 HO
OH
O O
O O OH O O
H 3C
OH O OH HO O

(24) HO
(23) (25) OH

Fig. 8 Major active principles from Hypericum perforatum

Fig. 9 Main active O

principle from Allium S S
sativum S

(26)

attributed to its extracts and/or fractions and constituents (Marrelli et al. 2016). The
literature reports several review articles on the therapeutic properties and active
principles of this plant, such as those recently published and indicated in bibliogra-
phy (Sarris 2013; Wölfle et al. 2014; Agapouda et al. 2017).

5.5 Allium sativum (Garlic)

Allium sativum, popularly known as garlic, exhibits a great number of medicinal

properties (Petrovska and Cekovska 2010; Sharifi-Rad et al. 2016). The literature
reports that about 2000 active compounds are produced by this plant. Because of its
widespread medicinal and nutritional use, many different forms are currently avail-
able in the worldwide market, generally with variation of sulfuric compounds,
which are considered the main active components of this plant (Wichtl 2004b).
Ajoene (26) was identified as one of the main active principle of this plant (Fig. 9),
with several confirmed biological effects, including antithrombotic, antitumor, anti-
fungal, and antiparasitic properties (Adaki et al. 2014; Bayan et al. 2014; Sharifi-­
Rad et al. 2016; Foroutan-Rad et al. 2017). Dietary patterns in the Mediterranean,
characterized by high consumption of fruits and vegetables, especially garlic, are
believed to be beneficial, according to regional patterns of atherosclerotic disease
(El-Sabban and Abouazra 2008). Although preclinical studies have demonstrated
promising results for the treatment of several ailments, the evidence based on rigor-
ous clinical trials of garlic is not convincing. For hypercholesterolemia, the reported
effects are small and may not, therefore, be of clinical relevance. Few studies are
16 R. Niero et al.

available on its use for reducing blood pressure, and the reported effects are too
minor to be clinically meaningful (Pittler and Ernst 2007). For all other conditions,
there is not enough available data for clinical recommendations. Studies suggest
anticancerogenic effect of Allium and their associated organosulfur components
against several cancer types. However, there are several limitations, including dif-
ficulty to establish a dose-risk relationship, which suggest caution in the interpreta-
tion (Li et al. 2013; Guercio et al. 2014).

5.6 Piper methysticum

Piper methysticum, well-known as kava kava, is a native plant of the Pacific Islands
and has been used in ceremonies for thousands of years. Traditionally, a beverage
is prepared, which is drunk before the evening meal (Gary 1997). Indigenous meth-
ods of mastication of the kava root have given way to grinding or pounding the
plant substance, which is then mixed with water or coconut milk/water (Kava-kava
1998; Sarris et al. 2011). For the past few decades, kava has also gained popularity
due to its anxiolytic and sedative properties (Bilia et al. 2002). However, in recent
years, it has been involved in several cases of liver failure, which has led to its being
banned in several countries and prompted widespread discussion of its benefits and
risks as a social beverage and herbal remedy. This plant was well-tolerated and
considered devoid of major side effects up until 1998, when the first report about its
hepatotoxicity appeared (Teschke 2010). Causality of hepatotoxicity co-medicated
drugs was evident after the use of predominantly ethanol and acetonic extract of
kava in Germany, Switzerland, the United States, and Australia. Risk factors were
found in most patients and include daily overdose, prolonged therapy, and co-med-
ication with up to five other herbal remedies, dietary supplements, and synthetic
drugs. On November 2001, the German health authority Bundesinstitut für
Arzneimittel und Medizinprodukte (BfArM) published evidence that suggested an
association between kava consumption and liver damage in 24 cases. However in
2002, BfArM withdrew the marketing authorizations of all medicinal products con-
taining kava and kavain, including homeopathic products, which had to be recalled
immediately (Mills and Steinhoff 2003). The active constituents consist of a group
of lactones (about 18 compounds) of which kavain (27), yangonin (28), methysticin
(29), dihydrokavain (30), demethoxyyangonin (31), and dihydromethysticin (32)
account for about 95% of the lipid extract (Fig. 10) (Chua et al. 2016). It has been
demonstrated that several kavalactones, the assumed active principles of the
extracts, are potent inhibitors of several enzymes of the CYP 450 system (CYP1A2,
2C9, 2C19, 2D6, 3A4, and 4A9/11). This indicates that kava has high potential to
cause pharmacokinetic drug interactions with other herbal products or drugs, which
are metabolized by the CYP 450 enzymes (Anke and Ramzan 2004; Olsen et al.
2011; Chua et al. 2016).
Medicinal Plants and Phytomedicines 17

O O
O

O
O O O O
O O
O (28) O (29)
(27)

O O
O

O
O O O O
O O

(30) O
(31) (32)

Fig. 10 Major active constituents from Piper methysticum

HO O HO O

O OH O
OH OH
33 34

Fig. 11 Major active constituents from Glycine max

5.7 Glycine max (Soy)

For some 5000 years, the soybean was cultivated by the Chinese, but it was not until
the twentieth century that it was commercially cultivated in the United States,
achieving a rapid growth in production, with the development of the first cultivars
(Shurtleff and Akiko 2015). In Brazil, it was brought over by the earliest Japanese
immigrants in 1908, but its expansion occurred in the 1970s, through the interest of
oil industry and the expanding international market. Soya is a well-known source of
natural isoflavones, especially daidzein (33) and genistein (34) as the main active
principles (Fig. 11) (Anupongsanugool et al. 2005). Such compounds are phytoes-
trogen mimetics and are considered by some nutritionists and physicians to be use-
ful in cancer prevention while, in some cases, as carcinogenic and disruptive to the
endocrine system (Fitzpatrick 2003). Several investigations of the potential of soy
foods to reduce the risk of cancer, in particular breast cancer, have been reported
(Messina and Wood 2008; Fritz et al. 2013). Most interest in this relationship is due
to the fact that it is essentially a unique dietary source of isoflavones. This has led to
increasing popularity and the commercial availability of supplements. Some dis-
agreements concerning the therapeutic potential and toxic action have been evi-
denced, such as studies suggesting that isoflavones may stimulate the growth of
existing estrogen-sensitive breast tumors (Messina and Wood 2008; Wang et al.
18 R. Niero et al.

2013). In addition, a study conducted to evaluate and compare the influence of diets
containing genistein (34) and soy extract on the growth of estrogen-independent
human breast cancer cells demonstrated inhibition of tumor growth, presumably
resulting from the synergistic effect of various bioactive substances. Isoflavones
such as daidzein (33) and genistein (34) are found only in some plant families,
because most plants do not have an enzyme, the isoflavone synthase, which converts
a flavanone precursor into an isoflavone. In contradiction to well-known benefits of
isoflavones, genistein (34) acts as an oxidant (stimulating nitrate synthesis) as well
as blocking the formation of new blood vessels. Some studies have shown that
genistein (34) acts as an inhibitor of the activity of substances in the body that regu-
late cell division and cell survival (growth factors).

5.8 Matricaria chamomilla

Chamomile (Matricaria chamomilla) is a widely used medicinal plant dating back

to the times of ancient Egypt, Greece, and Rome, when it was used to treat fever,
heat stroke, and many other conditions. It is one of the most commonly used herbal
ingredients in teas or tisanes. Chamomile tea, obtained from the dried flower, has
been traditionally used for medicinal purposes due to its calming, carminative, and
spasmolytic properties (Srivastava and Gupta 2015; Miraj and Alesaeidi 2016). The
main constituents of the flowers include phenolic compounds such as apigenin (35),
quercetin (36), patuletin (37), luteolin (38), and their glycosides (Fig. 12). The prin-
cipal components of the essential oil from the flowers are the terpenoids α-bisabolol
(39) and their oxides (Singh et al. 2011). Evidence-based information regarding the
bioactivity of this herb has been published (McKay and Blumberg 2006). Chamomile

OH OH
OH OH OH
HO O HO O O
HO

OH O OH
OH O OH O OH O
(35) (36) (37)
OH
OH

HO O HO

OH O
(38) (39)

Fig. 12 Main active constituents from Matricaria chamomilla

Medicinal Plants and Phytomedicines 19

has moderate antioxidant and antimicrobial activities and significant in vitro anti-
platelet activity. Studies indicate potent anti-inflammatory action, some antimuta-
genic and cholesterol-lowering activities, and antispasmodic and anxiolytic effects.
However, studies on humans are limited, and there have been clinical trials that
examine the purported sedative properties of chamomile tea (McKay and Blumberg
2006). Adverse reactions to chamomile, consumed as a tisane or applied topically,
have been reported among individuals with allergies to other plants. In addition, the
anticancer properties of aqueous and methanol extracts were evaluated against vari-
ous human cancer cell lines. Exposure of chamomile extracts caused minimal
growth inhibitory responses in normal cells, whereas a significant decrease in cell
viability was observed in various human cancer cell lines (Srivastava and Gupta
2007).

5.9 Maytenus ilicifolia

The family Celastraceae comprises about 60 genera and 200 species distributed in
tropical and subtropical regions around the world (Carlini 1988; Mariot and Barbieri
2007). Maytenus ilicifolia Mart. ex. Reissek (Celastraceae), popularly known in
Brazil and other South American countries, including Paraguay and Argentina, as
“Espinheira Santa,” “Espinheira divina,” or “Cangorosa,” is commonly used to treat
stomach disorders and as a contraceptive (Niero et al. 2011). The therapeutic effects
of M. ilicifolia are manifested not only in the stomach, for combating dyspepsia and
gastrologer hyperchloric acidity, but also in the intestine, where it has analgesic
action. M. ilicifolia is a phytotherapic compound, sold in various markets and drug-
stores (dry extract standardized), which contains principally tannins in its composi-
tion. Various extracts have shown gastroprotective properties in experimental ulcer
models using rodents after oral and intraperitoneal administration (Tabach and
Oliveira 2003; Leite et al. 2010). However, the compound responsible for its antiul-
cerogenic action remains unknown. Studies have shown that after several purifica-
tion steps from tea, it consists of a polysaccharide arabinose, galactose, galacturonic
acid, 4-O-methylglucuronic acid, rhamnose, and glucose mixture (Cipriani et al.
2006). This compound significantly inhibited ethanol-induced gastric lesions in rats
with an ED50 of 9.3 mg/kg, suggesting that the arabinogalactan liberated from the
infusion has a protective anti-ulcer effect. Several studies on its chemical constitu-
tion, and quality control, have been performed by hyphenated analysis as LC-MS
and HPLC/ESI-MS and NMR. These techniques were useful for identifying the
isomers present in complex flavonoid mixtures and for better phytochemical char-
acterization (Cipriani et al. 2006; De Souza et al. 2008; Preto et al. 2013). The stud-
ies also demonstrated that the triterpenes friedelin (40) and friedelan-3-ol (41) are
the major bioactive components of this plant (Fig. 13). More recently, a study evalu-
ates their clinical and toxicological effects in order to establish its maximum safe
dose. All selected volunteers completed the study without significant changes in the
evaluated parameters (Tabach et al. 2017a, b).
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