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12 Nanodelivery of Polyphenols as Nutraceuticals for Neurological Disorders
258
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260
Polyphenols: Food, Nutraceutical, and Nanotherapeutic Applications, First Edition. Edited by Mithun Rudrapal.
© 2024 John Wiley & Sons, Inc. Published 2024 by John Wiley & Sons, Inc.
13
Addressing Antimicrobial Resistance by Repurposing
Polyphenolic Phytochemicals with Novel Antibacterial Potential
Mithun Rudrapal
1,
*, Biswatrish Sarkar
2
, Prashanta Kumar Deb
2
, Atul R. Bendale
3
,
and Akhil Nagar
4
1
Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences,Vignan’s Foundation for Science,
Technology & Research, Guntur, India
2
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Ranchi, Jharkhand, India
3
Mahavir Institute of Pharmacy, Nashik, Maharashtra, India
4
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
*Corresponding author
13.1 Introduction
Infectious diseases caused by pathogenic microbes (bacteria, fungi, viruses, protozoa) are one of
the leading causes of morbidity and mortality across the globe. According to the World Health
Organization (WHO), it has been estimated that after 2050, 10 million people will die annually
because of microbial infections [1], which can be attributed to the increasing emergence of antimi-
crobial resistance (AMR) and multi-drug resistance (MDR) [2–4]. AMR and MDR are some of the
greatest challenges to global public health today. AMR is currently responsible for over 700,000
deaths annually worldwide. As AMR continues to increase, the effective treatment of drug-resist-
ant infectious diseases is a serious threat. In recent years, there have been several outbreaks of
deadly infectious diseases, including Ebola, Zika, swine flu (H1N1 influenza virus), antibiotic-
resistant bacterial infections, Candida auris infections, Plasmodium falciparum malaria, dengue,
and coronavirus diseases-2019 (COVID-19). AMR has emerged as one of the dominant public
health problems of the 21
st
century that threatens the effective prevention and treatment of a wide
range of infections caused by bacteria, viruses, fungi, and parasites. The emergence of AMR com-
bined with limited therapeutic efficacy and clinical usefulness of existing antimicrobial agents,
including antibacterial antibiotics, poses a significant challenge to public health [5]. These issues
urgently necessitate the discovery of novel and effective antimicrobial chemotherapeutics that
would fight against MDR pathogenic organisms. The medical need for novel antimicrobial drugs/
therapies globally is undeniable, and an effort to discover and develop novel antimicrobial drugs
is, therefore, urgent. However, modern drug discovery and development is a lengthy and arduous
process that inevitably struggles to deliver new therapies in a timely manner. The lengthy process
and high cost associated with research and development often culminates in high failure rates
because of safety and toxicity issues, among many other sources of attrition. Thus, strategies to
improve the efficiency of drug development are urgently needed to enable effective drugs to enter
the clinic. One creative strategy for the identification of novel antimicrobials that is gaining
momentum is drug repurposing [6, 7]. In recent years, interest in new approaches to drug research
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13.2 Antimicrobial Resistance (AMR) 261
and development, especially for antimicrobial drug discovery, has brought drug repurposing to the
forefront as a promising strategy. Faced with the threat of antimicrobial resistance, options for
treating infectious diseases are increasingly limited. Thus, drug repurposing is gaining traction as
a strategic approach in antimicrobial research with the potential to reduce costs and expedite
approval timelines. Drug repurposing efforts (in vitro and in vivo techniques) led to uncovering
novel antimicrobial agents to treat microbial infections [8]. Bioactive plant-based products or die-
tary phytochemicals/polyphenols are a potential approach for effective drug development against
infections caused by multi-drug resistant bacteria. Dietary plants are a rich source of polyphenolic
compounds, including flavonoids (e.g., catechins, epigallocatechin gallate (EGCG), quercetin, api-
genin, luteolin, genistein, etc.), which act as potential antioxidants (radical scavenging agents) in
counteracting various pathological conditions in infectious illnesses because of their antimicro-
bial, anti-inflammatory, and antioxidant properties.
13.2 Antimicrobial Resistance (AMR)
During the last few decades, the incidence of microbial infections has increased dramatically.
Continuous deployment of antimicrobial drugs in treating infectious diseases has led to the emer-
gence of resistance among various microorganisms (e.g., bacteria, fungi, viruses, and parasites).
Nearly all effective antimicrobial agents have created high levels of MDR with enhanced morbidity
and mortality; thus, they are referred to as “super bugs” [5, 8]. MDR is defined as insensitivity or
resistance of a microorganism to the administered antimicrobial medicines (which are structurally
unrelated and have different molecular targets) despite earlier sensitivity to the medicine. Although
the development of MDR is a natural phenomenon, the inappropriate use of antimicrobial drugs,
inadequate sanitary conditions, inappropriate food handling, and poor infection prevention and
control practices contribute to the emergence of and spread of MDR.
An extensive increase in the number of immunocompromised conditions, such as HIV infec-
tions, diabetic patients, chemotherapy for cancer treatments, individuals who have undergone
organ transplantation, and intensive care for pre-term newborns, makes the body an easy target for
hospital acquired (nosocomial) infectious diseases, thereby contributing to the further spread of
MDR [9–11]. According to the WHO, microorganisms (bacteria, fungi, viruses, and parasites) that
have developed resistance to antimicrobial drugs may lead to ineffective treatment, resulting in
persistence and spreading of infection. Some serious bacterial infections include Escherichia coli,
Pseudomonas, tuberculosis, pneumonia, methicillin-resistant Staphylococcus aureus (MRSA),
meningitis, gonorrhea, syphilis, Salmonella, and MDR-Acinetobacter infections. Studies indicate
very high rates of resistance in bacteria such as E. coli against cephalosporin and fluoroquinolones
antibiotics, Klebsiella pneumoniae against cephalosporin and carbapenems, S. aureus against
methicillin, Streptococcus pneumonia against penicillin, non-typhoidal Salmonella against fluoro-
quinolones, Shigella species against fluoroquinolones, Neisseria gonorrhoeae against cephalo-
sporin, and Mycobacterium tuberculosis against rifampicin, isoniazid, and fluoroquinolone, causing
common infections (such as urinary tract infections, pneumonia, and blood stream infections)
[12–14] (Table 13.1). Staphylococcal species, most notably S. epidermidis and S. aureus, cause
60%–70% of all infections, and numerous outbreaks of MRSA have been reported [15].
The list of WHO priority drug-resistant pathogens and their current antibiotics of choice for
treatment include carbapenem-resistant Acinetobacter baumannii (colistin, carbapenems, sulbac-
tam, rifampin, and tigecycline), carbapenem-resistant P. aeruginosa (ticarcillin-clavulanate, cef-
tazidime, aztreonam, imipenem, ciprofloxacin and colistin, vancomycin-resistant), Enterococcus
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13 Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential
262
faecium (streptogramin, linezolid, daptomycin, oritavancin, and tigecycline), methicillin-resistant
S. aureus (vancomycin, trimethoprim-sulfamethoxazole, clindamycin, linezolid, tetracyclines, and
daptomycin), fluoroquinolone-resistant campylobacter spp. (erythromycin, ciprofloxacin, and
fluoroquinolones), and clarithromycin-resistant Helicobacter pylori (amoxicillin, esomeprazole,
rabeprazole, omeprazole, metronidazole, levofloxacin, and clarithromycin) [14, 15].
Antibiotics have emerged as a firsthand strategy over the years to combat pathogenic organisms.
Over several decades, bacteria causing common or severe infections have developed resistance to
each new antibiotic coming to market. The WHO has long recognized the need for an improved
and coordinated global effort to contain AMR. The impact of antibiotic resistance in terms of mor-
tality and the public health cost is quite difficult to estimate, and there are few studies addressing
this issue. The US Center for Disease Control and Prevention (CDC) conservatively estimated that,
in the US, more than two million people every year are affected with antibiotic-resistant infections,
with about 23,000 dying because of the infection. The antibiotics seemed to induce different kinds
of stress in the bacterium and host, where the immune response towards oxidative stress (OS) is
one of the defense functions. Investigations indicate that several antibiotic functions to increase
OS. Thus, a bacterium may protect itself from both the host immune response and antibiotic ther-
apy by increasing its antioxidant capacities. Generally, there are three main modes of action for
antimicrobial drugs:
● By disruption of bacterial cell wall biosynthesis: Penicillin and other β-lactam antibiotics target
cell wall synthesis by inhibiting transpeptidation.
● By interfering with bacterial protein synthesis: Antibiotics, such as tetracycline, can accumulate in
the cytosol and bind to 30S ribosomal subunits to block key RNA interactions and thereby stop
the peptide chains formation.
● By blocking bacterial DNA replication and repair: Quinolones target DNA-topoisomerase com-
plexes to inhibit the cell division process of microbes.
Various mechanisms contribute to the development of MDR. The main mechanisms of resist-
ance include enzymatic inactivation, limiting uptake of a drug, modification of a drug target, inac-
tivation of a drug, and active efflux of a drug (Figure 13.1).
Table 13.1 Multi-drug resistant (MDR) bacteria and associated diseases.
Bacteria Diseases Caused By The Bacteria
Drugs Resistant To The
Bacteria
Escherichia coli
Urinary tract infections and blood stream
infections
Cephalosporins,
fluoroquinolones
Klebsiella pneumoniae Pneumonia and urinary tract infections Cephalosporins,
carbapenems
Staphylococcus aureus Wound and blood stream infections Methicillin
Streptococcus pneumoniae Pneumonia, meningitis, otitis Penicillin
Nontyphoidal Salmonella Food borne diarrhea, blood stream infections Fluoroquinolones
Shigella species Diarrhea (bacillary dysentery) Fluoroquinolones
Neisseria gonorrhoeae Gonorrhea Cephalosporins
Mycobacterium tuberculosis Tuberculosis Rifampicin, isoniazid,
fluoroquinolone
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13.3 Cellular Oxidative Stress (OS) and Microbial Infections 263
13.3 Cellular Oxidative Stress (OS) and Microbial Infections
13.3.1 Oxidative Stress (OS) and Infectious Diseases
Pathogenesis of diseases because of microbial invasion in the human body occurs because of
microbial toxins or various other mechanisms. Apart from virulence of pathogenic microorgan-
isms or microbial cytotoxins, increased reactive oxygen species (ROS) and reactive nitrogen spe-
cies (RNS) generated by activated immune cells create highly cytotoxic conditions (cytokine storm)
that directly damage target organs in the context of unbalanced inflammatory responses. Where
free radicals protect against invading microorganisms, they also cause tissue damage resulting in
further inflammation and exacerbation of the disease. Thus, a dual role of OS can be found in
human infectious diseases [16–18]. Expression of various enzymatic factors contributes to the gen-
eration of OS during the process of microbial invasions. Table 13.2 summarizes the role of a few
enzymes that serve as biomarkers for inflammation involving OS.
Microorganisms are often equipped with the production of antioxidant peptides themselves to
escape the action of ROS/RNS generated by immune cells. For example, Mycobacterium tuberculo-
sis, the causative organism of tuberculosis, releases mycothiol, and mycothiol-dependent reduc-
tase mycoredoxin-1 to survive within the macrophages [19]. Viral infections can severely impair
the oxidative homeostasis. During chronic viral hepatitis, OS has been found to cause liver fibrosis,
Enzymatic
Inactivation
of Drug
Decr
eased
Efflux
Efflux Pumps
Preventing Drug
Access to Targets
Bypassing of
the Target
Mutational
Alt
eration of Target
Pr
otein
Figure 13.1 Mechanisms of developing multi-drug resistance (MDR) in bacterial cells.
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13 Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential
264
cirrhosis, cancer, and metabolic dysfunction. The depletion of cellular antioxidant defenses, such
as ascorbic acid and GSH, an increase in malonaldehyde, along with the expression of catalase, are
causative factors behind OS [17]. HIV-induced OS contributes to the neurodegenerative complica-
tions observed in AIDS patients [18]. OS is commonly implicated in the case of acute respiratory
viral infections. Oxidative burst and hypoxemia have been recently associated with SARS-CoV-2/
COVID-19 infections. Despite the overwhelming evidence of the role of OS in microbial infection
and the associated diseases, the impact of most infectious agents on host redox systems is not
adequately investigated and requires separate attention [18].
13.3.2 Oxidative Stress-induced Microbial Infections
ROS plays a large role in immune cells by killing phagocytosed microorganisms or involving
immune and inflammatory signaling cascades. Inflammation is an integral part of immune defense
that is characterized by infiltration of cells, such as monocytes, macrophages, lymphocytes, neu-
trophils, and plasma cells, and the release of ROS by these cells leading to tissue injury. Neutrophils,
such as polymorphonuclear neutrophils, generate ROS by activating NADPH oxidase. Besides
causing direct OS to remove pathogens, ROS also stimulates inflammatory pathways and molecu-
lar signaling [20]. Figure 13.2 depicts the various ROS-induced cellular oxidative damages observed
in microbial/bacterial infections. Our understanding of inflammatory signaling indicates that an
array of pathways is activated with recognition of molecular patterns derived from pathogens and
oxidative damages. The immune receptors are equipped to sense pathogen-associated molecular
Table 13.2 Enzymes responsible for oxidative stress (OS) in microbial infections.
Sl.
No. Enzyme Origin Mechanism Of Action
1 Myeloperoxidase Activated
neutrophils
and within
lysosomes of
cells
● Has viricidal and bactericidal properties
● Converts hypochlorous acid from hydrogen peroxide and
chloride (H
2
O
2
+ Cl
−
→ ClO
−
+ H
2
O)
● Microorganisms captured within lysosomes are killed by
the action of hypochlorous acid along with lysozymes
2 NADPH oxidase Activated
neutrophils
● Catalyzes oxidation of NADPH with
concurrent reduction of oxygen to a superoxide
(
N
ADPH ONADPH O
+++
22
22
, ++
−
)
● Expressed during the inflammatory reaction to kill
captured pathogens
● Similar function as myeloperoxidase
3 Inducible nitric
oxide synthase
(iNOS)
Macrophages
and
leukocytes
● Catalyzes the formation of nitric oxide (NO) via oxidation
of L-arginine to N-hydroxy-L-arginine and subsequent
oxidation into L-citruline and NO
● Involved in several processes such as cellular
proliferation, apoptosis, and angiogenesis
● NO reacts with peroxynitrite in the presence of superoxide
● Peroxynitrite is essential in macrophages for the
destruction of pathogens
● Expression of iNOS and peroxynitrite is induced by
stress-activated protein kinases JNK/SAPK and p38MAP
kinase
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13.3 Cellular Oxidative Stress (OS) and Microbial Infections 265
patterns (PAMPs), pathogenic microbes or danger-associated molecular patterns (DAMPs), and
endogenous stress, triggering downstream signaling cascades. These multiprotein complexes,
which assemble upon sensing PAMPs or DAMPs (called inflammasomes), in turn initiate a caspase
signaling pathway that further leads to cell injury and death. Inflammasome-induced cell injury
and apoptosis contributes to the pathogenesis of Alzheimer’s and Parkinson’s diseases, as well as
neurodegenerative and metabolic disorders [20, 21].
Microorganisms can possess the ability to modulate the ROS formation in the host and thereby
increase the infectivity. By inducing or inhibiting oxygen radicals, pathogens reduce ROS-mediated
host responses to infection and facilitate colonization. The following are a few examples used by
the pathogens to evade the host redox defense system to cause persistent infections in human:
● Organisms such as Francisella tularensis, Anaplasma phagocytophilum, and Chlamydia tra-
chomatis modulate with assembly of NADPH oxidase (NOX2) by averting incorporation of
gp91phox, p22phox, and p47/p67phox (the key component of major cellular ROS-producing
enzyme) into phagosomes that engulf the microorganisms. This process also avoids activation of
the immune sensors, which may trigger the inflammatory cascade against pathogens [22–24].
● Microorganisms can also regulate the intercellular ROS levels. In neutrophils, microorganisms form
exopolysaccharide, which inhibits ROS production and directly scavenges free oxygen radicals.
● Entamoeba histolytica uses ROS molecules as a secondary signaling messenger to activate NOX2
and induce apoptosis and host cell death, and in turn helps the spread of pathogens [25].
● Several viruses mediate ROS accumulations within the host cells to stimulate the apoptotic sig-
nal and subsequent cell death, which promotes the spread of virions and persisting viral infec-
tion [26].
13.3.3 Oxidative Stress/Reactive Oxygen Species (OS/ROS) and Antimicrobial
Resistance (AMR)
Physiologically, ROS are generated spontaneously as a byproduct of the respiratory cycle the same
time ROS generation is usually supplemented by redox-cycling agents, disinfectants, and antibiot-
ics, which contributes to their antimicrobial bioactivity. Antibacterial agents (like disinfectants
Figure 13.2 Reactive oxygen species (ROS)/
oxidative stress (OS)-mediated cellular
damages in bacterial infections.
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13 Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential
266
and antiseptics), which cause oxidative damage to invading pathogens, is considered an effective
bactericidal agent [27]. Prokaryotes have developed their own inducible antioxidant defense net-
work against toxic effects of these ROS. There is a subtle mechanism to sense the ROS and activate
the expression of effectors that detoxify the ROS.
Irrespective of the targets and drug-target interactions, all antibacterials use a common mecha-
nism of inactivation to stimulate the production of lethal doses of hydroxyl radicals via the Fenton
reaction. Iron misregulation by the superoxide-mediated oxidation of iron–sulfur clusters gener-
ates hydroxyl radicals [28]. Investigations have proved that OS contributes to bactericidal antibi-
otic-mediated cell death such as in aminoglycoside antibiotics [29]. These studies indicate that OS
is involved in the antibiotic resistance within pathogens and the exposure of bacteria to antibiotics
may alter the antioxidant defense system and redox mechanisms in cells.
The frontline of drug resistance in bacteria is offered by a cell wall comprising a lipopolysaccha-
ride–phospholipid bilayer, which passively resists entry of antibiotics and other antibacterial drugs.
This can be illustrated by the susceptibility of gram-positive bacteria towards different antibiotics
because of their absence of outer membranes. Apart from this possible reduction in the affinity of
receptor sites, the substitution of alternative pathways, production of detoxifying enzymes, and acti-
vation of an efflux pump to inhibit cellular antibiotic uptake are different mechanisms that further
contributes to the drug resistance of bacteria. Similarly, genetic modification introduced by plasmid
conjugation, phage-based transduction, and horizontal gene transfer are principal mechanisms by
which bacteria induce resistance against different antibacterial agents [30].
13.3.4 ROS/OS Pathways and Therapeutic Interventions for Antimicrobial/
Antibacterial Agents
Current antimicrobial drugs are characterized on the basis of their ability to kill bacteria or inhibit
growth. The mechanism of action of these drugs ranges from inhibition of the cellular processes
essential for the biosynthesis of proteins, RNA, DNA, cell wall, and folic acid during the logarithmic
growth phase. However, pathogenic bacteria are continuously developing drug resistance mecha-
nisms against these antibacterial agents. Hence, in recent years, the focus has been exploring alter-
native biochemical pathways as a target space for the development of antibacterial classes [31].
Manipulating the metabolic flux, which is a hallmark of cancer metabolism, as a therapeutic
intervention could be adapted to the development of novel antibacterial agents. Oncogenic cells
uptake more glucose without changing mitochondrial oxidative phosphorylation, a phenomenon
known as aerobic glycolysis or the Warburg effect. Modulation of the oncogenic mammalian pyru-
vate kinase (PYK) isoform 2 (M2PYK) to the M1PYK isoform (expressed in healthy cells) leads to
the reversal of the Warburg effect and a reduction in tumor proliferation [31, 32]. In recent times,
similar induction of tricarboxylic acid (TCA) cycle flux has been revealed within enveloped viruses
(such as human cytomegalovirus), which has led to the development of novel antivirals like fatty
acid biosynthesis inhibitors [33]. Many classical antibacterial methods have been developed
against the backdrop of inhibition of the folate pathway in bacteria. Folate is an essential cofactor
and is an important precursor for the biosynthesis of purines, pyrimidines, and amino acids.
Antimicrobials, such as trimethoprim, selectively inhibit microbial dihydrofolate reductases
(DHFR) to deplete the cellular pool of precursors of DNA, RNA, and proteins, thereby impacting
bacteriostasis [34, 35]. Prontosil, the first synthetic antimicrobial agent, targets dihydropteroate
synthase (DHPS), another such folic acid biosynthetic pathway enzyme. A combination DHFR–
DHPS inhibitor was used as the first-line therapy in the prophylaxis and treatment of HIV-
associated secondary pneumonia caused by Pneumocystis carinii. Similarly, sulfanilamides act by
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13.4 Polyphenolic Phytochemicals as Antimicrobial Agents 267
competitive inhibition at the active site of dihydropteroate synthase. Para-amino salicylic acid
(PASA), the antituberculosis drug, also functions by inhibiting the folate pathway [31].
Augmenting the OS pathway and inducting ROS formation have emerged as potential antimi-
crobial targets recently. ROS have been involved in antibiotic-mediated lethality. For example,
bactericidal antibiotics can generate ROS in mammalian cells through mitochondrial dysfunction
[36]. A major class of antibiotics, such as β-lactams (e.g. ampicillin), quinolones (e.g. norfloxacin),
and aminoglycosides (e.g., kanamycin), can induce ROS generation that can inhibit the vital func-
tion of oxygen-respiring cells [28, 29]. To increase the antibiotic-mediated lethality, the TCA cycle
pathway can be targeted, which is a major source of OH
•
radicals. Antimicrobial agents enhance
the generation of O
2
•−
, which then is converted to H
2
O
2
by SOD, and finally OH
•
radicals are
formed. Unlike the other radicals, namely O
2
•−
and H
2
O
2
that are eradicated by SOD and catalase
and peroxidase, there is no enzyme to detoxify OH
•
. Thus, OH
•
exerts major cytotoxic effects by
damaging protein, lipid, and nucleic acid that also become the hallmark of bactericidal effects [37].
It has been further suggested that increasing the production of ROS may potentiate the antibacterial
activity of bactericidal antibiotics. Inhibiting target genes like succinate dehydrogenase by carboxin
increases the endogenous ROS formation and accumulation [36]. Similarly, if genes encoding antioxi-
dant defense systems are impaired in bacterial cells, then it could be easily targeted and killed by ROS-
generating antibacterials. Such genes as OxyR (confers resistance during increased H
2
O
2
conditions),
KatA (virulence factor in P. aeruginosa), and IscR (transcriptional regulator of an iron–sulfur assembly
and full activity of KatA and H
2
O
2
resistance) can be targeted to compromise the virulence of the patho-
gens. For example, avicin can chemically modulate OxyR in E. coli by avicinylation [38]. Pharmacophores
capable of ROS generations, but effective in non-bacterial systems, can also be repurposed as antibacte-
rial agents. Naphthoquinone derivatives, such as menadione, menaquinone, and alkannin, have shown
promise as antibacterial, antifungal, and antiprotozoal agents [36].
13.4 Polyphenolic Phytochemicals as Antimicrobial Agents
13.4.1 Dietary Polyphenolics and Flavonoids
Polyphenols are the major group of naturally occurring secondary metabolites that exist in the
plant kingdom. They are abundant in various plant parts, including fruits, the flowers and leaves
of herbs, and terrestrial plants. More than 8,000 phenolic compounds of diverse structural arrange-
ments have been reported from the plant kingdom [39]. Polyphenols are essentially biosynthesized
by plants for a defense mechanism against microbes, environmental stress, and other predators
[40]. These phytoconstituents are often found in plants as a conjugate with one or more sugar
moieties and are termed glycosides. Chemically, they contain one or more phenolic rings with
multiple hydroxyl groups on aromatic rings comprising many substitutions and structural diver-
sity [41]. Because of the presence of multiple hydroxyl groups, most of these classes of compounds
exhibit strong antioxidants and are well known as free radical scavengers. Polyphenols also exhibit
wide ranges of biological activities, such as antioxidant, hepatoprotective, antibacterial, antican-
cer, antidiabetic, and antihypertensive behaviors, depending on their structural features [42].
Chemically, polyphenols can be broadly divided into two major categories, flavonoids and non-fla-
vonoids, depending on the number and arrangement of different phenolic subunits and the linkage
of hydroxyl moieties to the phenolic skeleton [41]. The flavonoid class of compounds can be subdi-
vided into subclasses based on the degree of oxidation of the heterocyclic ring including flavones,
flavanones, isoflavones, flavonones, flavanols, flavonols, dihydroflavonols, flavandiols, chalcones,
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