Antibacterial activity of fla vonoids and their structu re ...
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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/328423406 Antibacterial activity of flavonoids and their structure–activity relationship: An update review Article in Phytotherapy Research · October 2018 DOI: 10.1002/ptr.6208 CITATIONS 24 READS 1,003 4 authors: Some of the authors of this publication are also working on these related projects: Study the effect of natural products on autoimmune diseases View project Antibacterial Activity of Silver Nanoparticle- Loaded Soft Contact Lens Materials: The Effect of Monomer Composition . View project Faegheh Farhadi Mashhad University of Medical Sciences 5 PUBLICATIONS 25 CITATIONS SEE PROFILE Bahman Khameneh Mashhad University of Medical Sciences 35 PUBLICATIONS 444 CITATIONS SEE PROFILE Mehrdad Iranshahi Mashhad University of Medical Sciences 234 PUBLICATIONS 5,009 CITATIONS SEE PROFILE Milad Iranshahi Mashhad University of Medical Sciences 35 PUBLICATIONS 582 CITATIONS SEE PROFILE All content following this page was uploaded by Faegheh Farhadi on 29 October 2018. The user has requested enhancement of the downloaded file.
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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/328423406
Antibacterial activity of flavonoids and their structure–activity relationship:
An update review
Article in Phytotherapy Research · October 2018
DOI: 10.1002/ptr.6208
CITATIONS
24READS
1,003
4 authors:
Some of the authors of this publication are also working on these related projects:
Study the effect of natural products on autoimmune diseases View project
Antibacterial Activity of Silver Nanoparticle- Loaded Soft Contact Lens Materials: The Effect of Monomer Composition . View project
Faegheh Farhadi
Mashhad University of Medical Sciences
5 PUBLICATIONS 25 CITATIONS
SEE PROFILE
Bahman Khameneh
Mashhad University of Medical Sciences
35 PUBLICATIONS 444 CITATIONS
SEE PROFILE
Mehrdad Iranshahi
Mashhad University of Medical Sciences
234 PUBLICATIONS 5,009 CITATIONS
SEE PROFILE
Milad Iranshahi
Mashhad University of Medical Sciences
35 PUBLICATIONS 582 CITATIONS
SEE PROFILE
All content following this page was uploaded by Faegheh Farhadi on 29 October 2018.
The user has requested enhancement of the downloaded file.
Received: 18 January 2018 Revised: 5 August 2018 Accepted: 12 September 2018
DOI: 10.1002/ptr.6208
R E V I EW
Antibacterial activity of flavonoids and their structure–activityrelationship: An update review
Faegheh Farhadi1 | Bahman Khameneh2 | Mehrdad Iranshahi3 | Milad Iranshahy1,3
1Department of Pharmacognosy, School of
Pharmacy, Mashhad University of Medical
Sciences, Mashhad, Iran
2Department of Pharmaceutical Control,
School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran
3Biotechnology Research Center,
Pharmaceutical Technology Institute,
Mashhad University of Medical Sciences,
Mashhad, Iran
Correspondence
Milad Iranshahy, Pharm. D., PhD, Department
of Pharmacognosy, School of Pharmacy,
Mashhad University of Medical Sciences,
Mashhad, Iran.
Email: [email protected]
Funding information
Mashhad University of Medical Sciences
Abbreviations: (FAB), fatty acid biosynthesis; (MO
Phytotherapy Research. 2018;1–28.
Based on World Health Organization reports, resistance of bacteria to well‐known
antibiotics is a major global health challenge now and in the future. Different strate-
gies have been proposed to tackle this problem including inhibition of multidrug resis-
tance pumps and biofilm formation in bacteria and development of new antibiotics
with novel mechanism of action. Flavonoids are a large class of natural compounds,
have been extensively studied for their antibacterial activity, and more than 150 arti-
cles have been published on this topic since 2005. Over the past decade, some prom-
ising results were obtained with the antibacterial activity of flavonoids. In some cases,
flavonoids (especially chalcones) showed up to sixfold stronger antibacterial activities
than standard drugs in the market. Some synthetic derivatives of flavonoids also
exhibited remarkable antibacterial activities with 20‐ to 80‐fold more potent activity
than the standard drug against multidrug‐resistant Gram‐negative and Gram‐positive
bacteria (including Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus
aureus). This review summarizes the ever changing information on antibacterial activ-
ity of flavonoids since 2005, with a special focus on the structure–activity relationship
and mechanisms of actions of this broad class of natural compounds.
KEYWORDS
antibacterial, biofilm, chalcones, flavonoids, multidrug resistance, natural compounds
1 | INTRODUCTION
Antibacterial resistance is the major global health challenge and
threats the public health. (Seleem, Pardi, & Murata, 2017). The anti-
bacterial resistance mechanisms can be divided into two categories:
(a) innate or intrinsic resistance and (b) acquired resistance. Intrinsic
resistance is mainly a feature of a particular bacterium and is based
on biological properties of bacteria. The second mechanism of resis-
tance is mainly due to the acquisition of resistance genes by other
pathogenic bacteria or chromosomal mutation and combination of
these two mechanisms. Regulatory genes controlling multidrug resis-
tance by expression of efflux pump and bacterial biofilm formation
also show important roles in antibacterial resistance (Frieri, Kumar, &
Boutin, 2016). Various strategies have been pursued to combat micro-
bial resistance. Employing new generations of antibiotics, combination
As), mechanisms of action
wileyonlinelibrary.com/
therapy via natural antibacterial substances and also using drug deliv-
ery systems are important approaches in this field. Over the past
decade, many classes of natural products intensively studied for this
purpose, especially against multidrug‐resistant Gram‐negative and
Gram‐positive bacteria (Barbieri et al., 2017; Hassanzadeh,
Rahimizadeh, Bazzaz, Emami, & Assili, 2001; Iranshahi, Fata, Emami,
Jalalzadeh Shahri, & Bazzaz, 2008; Iranshahi, Hassanzadeh‐Khayat,
Bazzaz, Sabeti, & Enayati, 2008; Salar Bashi, Bazzaz, Sahebkar,
Karimkhani, & Ahmadi, 2012). The results of these efforts were devel-
opment of new antibacterial agents, such as quinine (quinolones and
bedaquiline) and coumarin derivatives (novobiocin; Venugopala,
Rashmi, & Odhav, 2013).
Flavonoids are a large and structurally diverse group of natural
products obtained from nature, and some of them as ingredients of
propolis and honey were used in some traditional systems of medicine
for the treatment of infectious diseases. The basic structure of flavo-
noid compounds is diphenylpropane (C6–C3–C6) skeleton. The
© 2018 John Wiley & Sons, Ltd.journal/ptr 1
2 FARHADI ET AL.
various structure types of flavonoids differ in the degree of oxidation
of the C ring and in the substituents patterns in the A and/or B rings,
and these differences lead to the diversity of these compounds
(Kumar & Pandey, 2013). Some of the flavonoids (i.e., quercetin) with
a strong background of use in clinical trials are good candidates for
further clinical studies as antibiotics alone or in combination with
conventional antibiotics (Amin, Khurram, Khattak, & Khan, 2015).
In 2005, Cushnie et al. reviewed antibacterial properties of flavo-
noids. However, a large amount of information has been published since
then. In the present review, the antibacterial properties of flavonoid
compounds, which were studied in the last 12 years, have been
reviewed. The aim of the present review is the investigation of antibac-
terial properties of natural, semisynthetic, and synthetic flavonoids,
their structure–activity relationships andmechanisms of action (MOAs).
All relevant databases were searched for the terms “flavonoids”
and “antibacterial,” without limitation from 2005 till December 30,
2017. Information was collected via electronic search using Scopus,
Pubmed, Web of Science, and Science Direct.
2 | FLAVONOIDS
Flavonoids are a group of low‐molecular‐weight polyphenolic sub-
stances. Chemically, the core structure of flavonoids is based upon a
C6–C3–C6 skeleton in which the three‐carbon bridge is usually
cyclized with oxygen. These compounds are considered as chemotax-
onomic markers according to the biosynthesis pathway (combination
of phenylalanine with three malonyl‐CoA units to form a C‐15
chalcone), and they provide attractive color pigments such as yellow,
red, blue, and purple in plants. The chemical nature of flavonoids
depends on the degree of unsaturation and oxidation of the three‐car-
bon chain. Several subgroups of flavonoids have been found in higher
plants. Flavonols [most abundant flavonoids in foods, including quer-
cetin (48), kaempferol (55), and myricetin (46)], flavanones [found in
citrus fruits such as naringin (77)], flavones [e.g., luteolin (20) in celery],
and chalcones [licochalcone A (122), licochalcone E (123)] as well as
catechins in green and black teas, anthocyanin in strawberries and
other berries and isoflavonoids [with ring C in position 3 instead of
position 2], such as sophoraisoflavone A (94) found in legumes (Patra,
2012), are only few examples.
3 | ANTIBACTERIAL ACTIVITY OFFLAVONOIDS
3.1 | Flavones
Different studies evaluated the inhibitory effects of plant flavonoid‐
rich extracts and pure flavonoids against some pathogenic bacteria.
Various mechanisms have been proposed for the antibacterial activi-
ties of flavones. As a mechanism, flavones form a complex with the
cell wall components and consequently inhibit further adhesions and
the microbial growth as well. As an example, gancaonin Q (1; prenyl
flavone; Figure 1) and amentoflavone (2) isolated from Dorstenia spp.
showed activity against Bacillus cereus (Minimum Inhibitory Concen-
tration (MIC): 2.4 and 3 μg/ml, respectively) via the same mechanism
(Kuete et al., 2007; Mbaveng et al., 2008) and licoflavone C (19; from
Retama raetam flowers) was active against Escherichia coli via forma-
tion of complexes with extracellular and soluble proteins (MIC
7.81 μg/ml; Edziri et al., 2012).
Another proposed mechanism is inhibition of bacterial enzymes
(such as tyrosyl‐tRNA synthetase) that was mediated by artocarpin
(23) extracted from leaves of Artocarpus anisophyllus against B. cereus,
E. coli, and Pseudomonas putida (Jamil, 2014). Baicalein is an effective
bactericide and when combined with cefotaxime, the synergistic
effects were observed (Cai et al., 2016). The possible mode of action
of baicalein has been studied extensively. It was shown that this com-
pound is able to reduce the Pseudomonas aeruginosa‐induced secretion
of the inflammatory cytokines IL‐1β, IL‐6, IL‐8, and TNFα, which are
important for inflammatory injury after P. aeruginosa infection (Luo
et al., 2016). The results of Chen study indicated that baicalein at con-
centrations of 32 and 64 μg/ml was able to downregulate the quo-
rum‐sensing system regulators agrA, RNAIII, and sarA, and gene
expression of intercellular adhesin (ica) in Staphylococcus aureus bio-
film producer cells (Chen et al., 2016).
Other reports include gancaonin G (27) and semilicoisoflavone B
(28) from Glycyrrhiza uralensis toward vancomycin‐resistant Entero-
coccus bacteria with the MIC values of 32 and 64 μg/ml (Orabi,
Aoyama, Kuroda, & Hatano, 2014). Neocyclomorusin (33) and
neobavaisoflavone (34) among 19 natural products belonging to terpe-
noids, alkaloids, thiophenes, and phenolics from the methanolic
extract of Cameroon plants were active against Gram‐negative
bacteria (Klebsiella pneumonia and Enterobacter cloacae) with the MIC
value of 4–8 μg/ml (Mbaveng et al., 2015). Other biological activities
of flavones are summarized in Table 1.
Inhibition of the bacterial efflux pump and increase in the suscep-
tibility of existing antibiotics (by inducing depolarization of the cell
membrane) is another possible MOA, and artonin I (24) from Morus
mesozygia was effective against S. aureus by this mechanism (69–
89% inhibition; Farooq, Wahab, Fozing, Rahman, & Choudhary, 2014).
Potential antibacterial synergy of the desired compound in combi-
nation with well‐known antibiotics is measured by fractional inhibitory
concentration index (Khameneh, Diab, Ghazvini, & Fazly Bazzaz,
2016). In 2012, in vitro activity of flavones in combination with
vancomycin and oxacillin against vancomycin‐intermediate S. aureus
(multidrug‐resistant bacteria) was evaluated and results showed
synergism with fractional inhibitory concentration index values of
0.094 and 0.126, respectively (Bakar, Zin, & Basri, 2012). In addition,
diosmetin )25) and alpinumisoflavone (26) from Sophora moorcroftiana
in combination with ciprofloxacin and baicalin (37) in combination with
oxacillin, tetracycline, and ciprofloxacin exerted synergistic activity
against S. aureus by inhibition of the NorA efflux protein (Qiu, Meng,
Chen, Jin, & Jiang, 2016; Wang et al., 2014).
3.2 | Flavonols
Flavonols such as quercetin, myricetrin, morin, galangin, entadanin,
rutin, piliostigmol, and their derivatives are among the most important
class of flavonoids that show potent antibacterial activities. For exam-
ples, quercetin (48) and its derivatives showed a significant antibacte-
rial activity against some strains of bacteria, including S. aureus,
FIGURE 1 Chemical structures of flavone compounds
FARHADI ET AL. 3
methicillin‐resistant S. aureus (MRSA), and Staphylococcus epidermidis.
In vitro investigation of this compound against several oral microbes
showed that quercetin had potent activity against Porphyromonas
gingivalis with MIC value of 0.0125 μg/ml (Geoghegan, Wong, &
Rabie, 2010). In another study, the antibacterial activities of quercetin
against amoxicillin‐resistant S. epidermidis were assessed. The results
indicated that upon combination of quercetin and amoxicillin, the syn-
ergistic activity was observed and bacterial resistance to this tradi-
tional antibiotic was remarkably reversed (Siriwong, Teethaisong,
Thumanu, Dunkhunthod, & Eumkeb, 2016).
Morin (45) is well‐known to be effective against Gram‐positive
bacteria. Combination of this plant‐derived flavonol with conventional
β‐lactam antibiotics against MRSA showed that the susceptibility of
MRSA toward oxacillin was enhanced significantly (Mun et al., 2015).
Bioactive constituents from Croton menyharthii evaluated for their
inhibitory effects on selected bacteria. Among them, quercetin was
active against Bacillus subtilis whereas myricetrin‐3‐O‐rhamnoside (56)
was the most active compound against E. coli, K. pneumonia, and
S. aureus. These results validated the ethnomedicinal use of the plant
in folk medicine (Aderogba, Ndhlala, Rengasamy, & Van Staden, 2013).
Babajide, Babajide, Daramola, and Mabusela (2008) found that
piliostigmol (47) from Piliostigma reticulatum exhibited strong activity
against E. coli (MIC: 2.57 μg/ml), which was three times stronger than
amoxicillin. Recently, antibacterial study of lipophilic compounds
galangin (44) and galangin‐3‐methyl ether (72) against Gram‐positive
and Gram‐negative bacteria showed that compounds were active
against Gram‐positive bacteria with MIC values of 0.5–1 μg/μl
(Echeverría, Opazo, Mendoza, Urzúa, & Wilkens, 2017). In 2017, anti-
bacterial properties of eight compounds isolated from Entada abyssinica
(traditionally used against gastrointestinal bacterial infections caused by
Salmonella typhimurium) were assayed, and the results showed that
among them, compounds entadanin (73) and quercetin‐3‐O‐α‐l‐
FIGURE 1 Continued.
4 FARHADI ET AL.
rhamnoside (74) were active against S. typhimuriumwith the lowestMIC
values of 1.56 and 3.12 μg/ml, respectively (Dzoyem et al., 2017).
Galangin (44) is a well‐known antibacterial agent, and the plants con-
taining this flavonol were used traditionally in South African indigenes
to treat infections. This compound was effective against S. aureus
(Cushnie & Lamb, 2005a, 2005b), and in another study, galangin, quer-
cetin, and baicalein were able to reverse bacterial resistance to conven-
tional β‐lactam antibiotics against penicillin‐resistant S. aureus (Eumkeb,
Sakdarat, & Siriwong, 2010; Figure 2).
Many research groups investigated possible antibacterial MOA of
flavonols. It is well‐known that three types of β‐ketoacyl carrier pro-
tein synthases are predominant targets for the design of novel antibi-
otics. 3,6‐Dihydroxyflavone (50) exhibited antibacterial activity against
the multidrug‐resistant E. coli through inhibition of β‐ketoacyl acyl car-
rier protein synthase I (related to the elongation of unsaturated fatty
acids in bacterial fatty acid synthesis) and III with MIC value of
512 μg/ml (Lee, Lee, Jeong, & Kim, 2011). Kaempferol‐3‐rutinoside
(68), isolated from Sophora japonica flowers, was active against
Streptococcus mutans by inhibition of the action of sortase A that plays
a key role in the adhesion to and invasion of hosts by Gram‐positive
bacteria (Yang et al., 2015).
Some research groups studied the correlation between antimicro-
bial properties and liposome interaction activities of different flavo-
noids. The lipophilicity properties and the interaction of antibacterial
agents with the cell membrane attribute the success or failure of them
to access their target (Echeverría et al., 2017). Liposomal models were
used for investigation of antibacterial mechanism of four flavonoids
against E. coli. Among them, kaempferol (55) showed bacterial cell dis-
ruption by interaction with the polar head‐group of the model mem-
brane (He, Wu, Pan, & Xu, 2014). In a previous study, it was shown
that plants with high level of flavonoids can disrupt bacterial surface
and cellular leakages (Musa et al., 2011). It was inferred that the antibac-
terial mechanism of galangin is related to the alteration of topoisomer-
ase IV enzyme activity (Cushnie & Lamb, 2006). As mentioned above,
morin is effective against Gram‐positive bacteria. The possible mode
of action of the compound is related to the suppressing expression of
penicillin‐binding protein encoded by mecA (Mun et al., 2015).
Biofilm eradication is another antibacterial mechanism of flavo-
noids, for example, rutin (49) at concertation of 50 μg/ml reduced
biofilms of foodborne pathogens (E. coli and S. aureus; Al‐Shabib et al.,
2017) and inhibited biofilm formation of Streptococcus suis with 1/4
MIC value (78.1 μg/ml) without changing the structure of S. suis
(Wang et al., 2017). In another study, myricetin (46) inhibited biofilm
formation of S. aureus by MBIC50 values of 1 μg/ml (Lopes, dos Santos
Rodrigues, Magnani, de Souza, & de Siqueira‐Júnior, 2017).
Antifouling properties of purified quercetin (48) from marine
derived Streptomyces spp. against 18 biofouling bacteria confirmed
with MIC range between 1.6 and 25 μg/ml (Gopikrishnan,
Radhakrishnanauthor, Shanmugasundaramauthor, Pazhanimuruga-
nauthor, & Balagurunathanauthor, 2015). In another study, among
the nine flavonoids (from the leaves of Scutellaria oblonga), quercitin‐
3‐glucoside (65) could successfully kill S. aureus and reduction in
biofilms (90–95%) was observed (Rajendran et al., 2016). Other reports
of the antibacterial activity of flavonols are summarized in Table 2.
3.3 | Flavanones
Several studies have reported antibacterial activity of flavanones
(Table 3). For example, the result of in vitro investigation of prenylated
flavanones from Paulownia tomentosa fruits showed that compounds
3′,5‐O‐dimethyldiplacone (79), 3′,5‐di‐O‐methyl‐diplacone (80),
mimulone (81), and diplacone (82) had a strong antibacterial activity
TABLE
1Antibacterial
effect
offlavone
compo
unds
Compo
unds
Source
Bacteria
Metho
dActivity
Ref.
Gan
caoninQ
(1)
Dorstenia
angusticornis
Bacillus
subtilis
Liqu
iddilution
MIC:2.44μg
/ml
(Kueteet
al.,2007)
Amen
toflavone
(2)
Dorstenia
barteri
Bacillus
cereus
Bacillus
megaterium
Discdiffusion
MIC:3μg
/ml
(Mbaven
get
al.,2008)
ErysubinF(3)
Erythrinasubu
mbran
sTa
phylococcusau
reus
Discdiffusion
MIC:50μg
/ml
(Rukach
aisiriku
let
al.,2007)
Hev
eaflavone
(5)
Amen
toflavone
‐7″,4‴‐dim
ethy
l‐ethe
r(6)
Podo
carpusflavone
‐A(7)
Ouratea
multiflo
raStap
hylococcus
aureus
Bacillus
subtilis
Agarplatediffusion
ZI:10–1
2mm
(Carboneziet
al.,2007)
Cycloartocarpesin
(8)
Morus
mesozygia
Pseudo
mon
asaerugino
saLiqu
idmicrodilution
MIC:156μg
/ml
(Rukach
aisiriku
let
al.,2007)
Gen
istein
7‐O
‐gluco
side
(9)
Azadirachta
indica
Lactob
acillus
Microbroth
dilution
Inhibition:52–9
9.8%
(Kan
wal,H
ussain,
Siddiqui,&
Javaid,2
011)
5‐H
ydroxy
‐7‐m
etho
xy‐flavo
ne(10)
5,7‐D
ihyd
oxy
‐flavo
ne(11)
Popu
lusnigra/Po
pulusdeltoides
Ralston
iasolana
cearum
Pseudo
mon
aslachryman
sBroth
dilutionMTT
MIC:>300,2
5μg
/ml
(Zhonget
al.,2012)
5′‐Methy
l4′,5,7
trihyd
roxy
flavone
(12)
Bryop
hyllum
pinn
atum
Pseudo
mon
asaerugino
saFilter
pape
rdisc
diffusion
MIC:625μg
/ml
(Okw
u&
Nnam
di,2011)
5,7‐D
ihyd
roxy
‐4,6,8‐trimetho
xyflavone
(13)
5,6‐D
ihyd
roxy
‐4,7,8‐trimetho
xyflavone
(14)
Limno
phila
heteroph
ylla
Bacillus
subtilis
Broth
microdilution
MIC:300μg
/ml(Activity:
effect
onke
yen
zyme)
(Brahmachariet
al.,2011)
5,7‐D
ihyd
roxy
‐4′‐metho
xyisoflavan
one
(15),5,7,2′‐trihyd
roxy
‐4metho
xyisoflavan
one
(16),7,3′‐
dihy
droxy
‐4′‐metho
xyisoflavan
one
(17)
Astragalusad
surgens
Erwinia
carotovora
Stap
hylococcus
aureus
Microbroth
dilution
MIC
≥250μg
/ml
(Chen
etal.,2012)
5,4′‐Dihyd
roxy
‐7‐m
etho
xyflavone
(18)
Larrea
tridentata
Mycob
acterium
tuberculosis
Stap
hylococcus
aureus
Broth
dilutionMTT
MIC:250–5
00μg
/ml
(Favela‐Hernán
dez,G
arcía,
Garza‐G
onzález,Rivas‐
Galindo,&
Cam
acho‐
Corona,
2012)
Lico
flavone
C(19)
Retam
araetam
Escherichiacoli
Microdilutionbroth
MIC:7.5
μg/m
l(Edziriet
al.,2012)
Luteolin
(20)
Chrysin
(21)
Pure
Escherichiacoli
Microbroth
dilution
MIC:36.72an
d67.25μg
/ml
(Wuet
al.,2013)
Luteolin
(20)
Litchi
spp.
Stap
hylococcus
aureus
Escherichiacoli
Shigella
dysenteriae
Microdilutiontiter
MIC:14.6
μg/m
l(W
enet
al.,2014)
Luteolin
(20)
Diospyros
virginiana
Stap
hylococcus
aureus
Bacillus
cereus
Microdilution
MIC:1.5
±0.0003,μ
g/ml
MBC:2.5
±0.0003,μ
g/ml
(Rashed
,Ćirić,G
lamočlija,&
Soko
vić,
2014)
Psiad
iarabin(22)
Saud
iArabian
prop
olis
Mycob
acterium
marinum
Alamar
blue
MIC:61.9
μg/m
l(Alm
utairiet
al.,2014)
Atocarpin
(23)
Artocarpu
san
isop
hyllus
Pseudo
mon
aspu
tida
Discdiffusion
ZI:13.7
mm
MBC:450μg
/ml
(Jam
il,2014)
ArtoninI(24)
Morus
mesozygia
Stap
fStap
hylococcus
aureus
MicroplateAlamar
blue
Inhibition:%
69–8
9(Farooqet
al.,2014)
Diosm
etin
(25)
Alpinum
isoflavone
(26)
Soph
oramoo
rcroftiana
Stap
hylococcus
aureus
Broth
microdilution
MIC:8μg
/ml
(Wan
get
al.,2014)
Gan
caoninG
(27)
Semilico
isoflavone
B(28)
Glycyrrhiza
uralensis
Enterococcus
faecium
Liqu
iddilution
MIC:32μm
(Orabiet
al.,2014)
6‐M
etho
xy‐2‐[2(3‐hyd
roxy
‐4‐m
etho
xyph
enyl)ethyl]chromone
(29)
Aqu
ilariasinensis
Stap
hylococcus
aureus
Filter
pape
rdisk
agar
diffusion
ZI:9.10±0.06mm
(Liet
al.,2014)
(Continues)
FARHADI ET AL. 5
TABLE
1(Continue
d)
Compo
unds
Source
Bacteria
Metho
dActivity
Ref.
(Activity:
acetylch
olin
esterase
inhibition)
Techtoch
rysin(30)
Neg
letein
(31)
Scutellariaob
longa
Escherichiacoli
Enterococcus
faecalis
Bacillus
subtilis
Tim
e‐killcu
rves
MICs:
24–3
2μg
/ml(Activity:
biofilm
‐red
uced)
(Rajen
dranet
al.,2016)
CorylifolC(32)
Psoralea
corylifolia
Stap
hylococcus
aureus
Liqu
iddilution
MIC:16μg
/ml
(Cuiet
al.,2015)
Neo
cyclomorusin(33)
Neo
bavaisoflavone
(34)
Pure
Klebsiella
pneumon
iaEn
teroba
cter
cloa
cae
Colorimetric
MIC:4μg
/ml
(Mbaven
get
al.,2015)
5,6,7‐Trimetho
xyflavone
‐8‐O
‐b‐
D‐gluco
pyrano
side
(35)
6‐M
etho
xy‐baicalein
(36)
Oroxylum
indicum
Stap
hylococcus
aureus
Broth
microdilution
MIC/M
BC:320–1
28μg
/ml
(Fan
etal.,2015)
Baicalein
(37)
Scutellariaba
icalensis
Stap
hylococcus
aureus
Microdilution
MIC:64μg
/ml
(Qiu
etal.,2016)
Jaceosidin(38)
Artem
isia
californica
Escherichiacoli
Enzym
einhibition
MIC:10μg
/ml
(Allisonet
al.,2017)
5‐C
arbo
metho
xymethy
l‐4′,7
‐dihy
droxyflavone
(39)
Selaginella
moellend
orffii
Escherichiacoli
Agardilution
MIC:25μg
/ml
MBC:50μ g
/ml
(Zouet
al.,2016)
6 FARHADI ET AL.
against Gram‐positive bacteria including B. cereus, B. subtilis, Enterococ-
cus faecalis, Listeria monocytogenes, and S. aureuswith MIC values of 2–
4 μg/ml (Šmejkal et al., 2008). It has also been demonstrated that
abyssione‐V 4′‐O‐methyl ether (88) from the stem bark of Erythrina
caffra inhibit activity of E. coli with MIC value of 3.9 μg/ml
(Chukwujekwu, Van Heerden, & Van Staden, 2011). Katerere, Gray,
Nash, and Waigh (2012) reported excellent activity of pinocembrin
(87) isolated from Combretum apiculatum toward S. aureus with MIC of
12.5 μg/ml. In another study, this compound from the leaves of
Cryptocarya chinensis was potent against Mycobacterium tuberculosis
(MIC 3.5 μg/ml). Navrátilová et al. (2016) demonstrated that 3′‐O‐
methyldiplacol and mimulone have promising antibacterial activities
when used alone or in combination with conventional antibiotics
against MRSA (Figure 3).
In 2012, among three prenylated flavanones from the Mundulea
sericea, lupinifolin (90) has been reported to have significant antibacte-
rial activity against S. aureus with minimum inhibitory quantity value of
0.5 μg (Mazimba, Masesane, & Majinda, 2012). Synergism has been
demonstrated between various combination of flavanones and antibi-
otics. For example, Su‐Hyun et al. determined the antibacterial syner-
gism of sophoraflavanone B (94) with antibiotics including ampicillin,
oxacillin, and gentamicin against MRSA (Mun et al., 2013). Synergism
has also been reported between flavonoid and other antibacterial
agents. Sophoraflavanone has been reported as a phytochemical com-
pound with potent antibacterial activity (Tsuchiya & Iinuma, 2000).
SophoraflavanoneG (83; from Sophora flavescensn), for example, poten-
tiated the effect of ampicillin or oxacillin against MRSA infection (Cha,
Moon, Kim, Jung, & Lee, 2009). In addition, sophoraflavanone G (83)
showed significant antibiofilm formation against S. epidermidis, S. aureus,
and B. subtiliswithMIC values ranging from 3.1 to 12.5 μg/ml (Oh et al.,
2011;Wan, Luo, Ren, & Kong, 2015). Sophoraflavanone B showed anti-
microbial activity against MRSA (Mun et al., 2014).
Dzoyem, Hamamoto, Ngameni, Ngadjui, and Sekimizu (2013)
reported that 6, 8‐diprenyleriodictyol (95) from Dorstenia species
deactivated S. aureus via depolarization of membrane and inhibition of
DNA, RNA, and protein synthesis. This compound rapidly reduced the
bacterial cell density and caused lysis of S. aureus. In 2016, the
potential of C‐6‐geranylated flavonoids for the use in controlling
the growth of antibiotic‐resistant microorganisms were evaluated
against S. aureus. Out of them, mimulone (81), (geranylated flavonoids)
was more effective than the oxacillin (antibiotic standard) with MIC
values of 2/4.9 μg/ml (Navrátilová et al., 2016). The relationship
between lipophilicity and the structure of flavonoid analogues in growth
inhibition of Gram‐positive and Gram‐negative bacteria were evaluated
by flavones from Heliotropium filifolium. Compounds pinocembrin (87)
and 7‐O‐methyleriodictyol (99) were active with MIC values of 0.5–
4 μg/ml, and these results showed that the amphipathic properties
(lipophilic and hydrophilic moieties of flavones) were important for anti-
bacterial activity and selectivity, respectively (Echeverría et al., 2017).
3.4 | Flavane 3‐ols
One of themain group of flavonoids is flavane‐3‐ol compounds, and the
antibacterial activity of these compounds is well documented (Table 4).
In vitro investigation (Figure 4) showed strong antibacterial activity of
FIGURE 2 Chemical structures of flavonol compounds
FARHADI ET AL. 7
3′‐O‐methyldiplacol (100) against Gram‐positive bacteria including
B. subtilis, E. faecalis, L.monocytogenes, S. aureus, and S. epidermidiswith
MICs ranging from 2 to 4 μg/ml (Šmejkal et al., 2008). The MIC value of
quercetin 3‐O‐methyl ether (101) isolated from Cistus laurifolius flowers
was found to be 3.9 μg/ml against Helicobacter pylori (Ustün, Ozçelik,
Akyön, Abbasoglu, & Yesilada, 2006).Some researchers have reported
synergy between naturally occurring flavane‐3‐ols and antibiotic
agents. An, Zuo, Hao,Wang, and Li (2011) reported significant synergis-
tic effect between taxifolin‐7‐O‐α‐l‐rhamnopyranoside (102) and anti-
biotics including ceftazidime and levofloxacin against S. aureus with
FIC: 0.3–0.5. Navrátilová et al. (2016) evaluated the antibacterial activ-
ity of 3′‐O‐methyldiplacol (100) alone and in combination with oxacillin
against MRSA strain. Based on MIC/Minimum Bactericidal Concentra-
tion (MBC) result (4/4 and 2/4 μg/ml, alone, and combined, respec-
tively), this combination had a synergistic effect against MRSA and
this compound was more potent than the standard drug.
The activity of the 2‐(3,5‐dihydroxy‐4‐methoxy‐phenyl)‐3,5‐dihy-
droxy‐8,8‐dimethyl‐2,3‐dihydro‐8H‐pyrano[3,2]chromen‐4‐one (106)
isolated from Commiphora pedunculata has been investigated by agar
well diffusion and broth dilution methods against 10 microorganisms.
This compound exhibited good activity against six out of 10 tested
microorganisms, including two resistant strains (MRSA and vancomy-
cin resistant) with MIC/MBC values of (25/50) and (12.5/50), respec-
tively (Tajuddeen et al., 2016).
3.5 | Chalcones
Some researchers have reported significant increase in antibacterial
activity of chalcones in combination with other antibiotics. Example
of these includes THIPMC (115) extracted from the plants of the
genus Dorstenia (widely used in African and South American folk med-
icine for their pharmacological relevance) was active against tested
bacteria alone as well as in combination with ampicillin or gentamicin.
The MIC values (0.188 to 0.375 μg/ml) showed that the combined
effect of this compound is greater than their individual effect (Lee
et al., 2010). The investigation of bactericidal/bacteriolysis activities
of flavonoid compounds by time‐kill kinetic method exhibited that 4‐
hydroxyonchocarpin (118; Figure 5) plays a greater role in increasing
FIGURE 2 Continued.
8 FARHADI ET AL.
the antibacterial activity against S. aureuswithMIC values of 1–8 μg/ml
and had no toxicity effects 24 hr after injection (Dzoyem et al., 2013). In
2008, the antimicrobial activity of five flavonoids (from twigs of
Dorstenia barteri) was evaluated against Gram‐positive and
Gram‐negative bacteria by disc diffusion assay. The lowest MIC
value (0.3 μg/ml) of Gram‐positive bacteria was obtained only with
isobavachalcone (110), which was fourfold lower than the MIC value
(4.9 μg/ml) of the antibiotics (gentamicin; Mbaveng et al., 2008), and
in another study, this compound was potent against
methicillin‐resistant Staphylococcus strains (MIC: 8 μg/ml; Cui,
Taniguchi, Kuroda, & Hatano, 2015).
About 300 flavonoids have been isolated from licorice, and among
them, chalcones [licochalcone A (122) and licochalcone E (123)]
showed inhibitory activity of bacterial infection by decreasing expres-
sion of bacterial genes, inhibiting bacterial growth, and reducing the
production of bacterial toxin (Wang, Yang, Yuan, Liu, & Liu, 2015).
TABLE
2Antibacterial
effect
offlavono
lcompo
unds
Compo
unds
Source
Bactria
Metho
dActivity
Ref.
5,7‐D
ihyd
roxy
‐3,8‐dim
etho
xyflavone
(gna
phaliin
A)(40)
Achyroclinesatureioides
Stap
hylococcus
aureus
Broth
microdilution
MIC:128μg
/ml
(Caseroet
al.,2014)
Que
rcetin‐3‐O
‐α‐l‐arabino
pyrano
side
(41)
Psidium
guajava
Streptococcusmutan
sAgarwelldiffusion
MIC:400μg
/ml(Activity:
antiplaqueagen
tbyinhibiting
thegrowth
cell)
(Prabu,G
nan
aman
i,&
Sadulla,2
006)
Que
rcetin
3‐O
‐β‐D
‐rutinoside
(42)
Marrubium
glob
osum
Enteroba
cteraerogenes
Proteusvulgaris
Broth
dilution
MIC:320μg
/ml
(Rigan
oet
al.,2007)
3,4‐M
ethy
lene
dioxy
‐10‐m
etho
xy‐7‐
oxo
[2]ben
zopy
rano
[4,3‐
b]be
nzopy
ran(43)
Derrisindica
Mycob
acterium
tuberculosis
MicroplateAlamar
blue
MIC:6.25an
d200μg
/ml
(Koysomboon,V
anAlten
a,Kato,&
Chan
trap
romma,
2006)
Galan
gin(44)
Helichrysum
aureon
itens
Stap
hylococcus
aureus
Agardilution
MIC:500μg
/ml
(Cushnie,H
amilton,
Chap
man
,Taylor,&
Lamb,2
007)
Galan
gin(44)
Prope
lStap
hylococcus
aureus
Tim
e‐kill
MIC:50μg
/ml(Activity:
aggreg
ationofbacterial
cells)
(Cushnie
&Lamb,2
006)
Morin(45)
Psidium
guajava
Aerom
onas
salmon
icida
Microbroth
dilution
MIC:150–2
00μg
/ml
(Rattanachaiku
nsopon&
Phumkh
achorn,2007)
Myricetin
( 46)
Pure
Mycob
acterium
Microtiterplate
MIC:32μg
/ml
(Lechner,G
ibbons,&
Bucar,2008)
Piliostigmol(47)
Piliostigmareticulatum
Escherichiacoli
Microdilutiontiter
MIC:2.57μg
/ml
(Bab
ajideet
al.,2008)
Que
rcetin
(48)
Rutin
(49)
Pure
Escherichiacoli
Stap
hylococcus
aureus
Microbroth
dilution
MIC:33μg
/ml
(Activityblockingthech
arge
sofam
inoacidsin
theporins)
(Alvarez,D
ebattista,
&Pap
pan
o,2
008)
Que
rcetin
(48)
Pure
Porphyromon
asgingivalis
Broth
dilution
MIC:0.0125μg
/ml
(Geo
gheg
anet
al.,2010)
Que
rcetin
(48)
Pure
Stap
hylococcus
aureus
Activity:
50μM
(Hirai
etal.,2010)
Morin(45)
Pure
Escherichiacoli
IC50:0.7
μg/m
l(Activity
inhibitionofATPsynthase)
(Chinnam
etal.,2010)
3,6‐D
ihyd
roxyflavone
(50)
Pure
Escherichiacoli
Stap
hylococcus
aureus
Broth
microdilution
MIC:512μg
/ml(Activity:
inhibitionofβ‐ke
toacyl
acyl
carrierprotein
synthaseIII)
(Lee
etal.,2010)
Elatoside
A(51)
Elatoside
B(52)
Epim
edium
elatum
Pseudo
mon
asaerugino
saStap
hylococcus
aureus
Escherichiacoli
Salmon
ella
typh
i
Agardiffusion
ZI:11,1
6,1
9,2
0mm
(Tan
try,
Dar,Idris,
Akb
ar,&
Shaw
l,2012)
5,7‐D
ihyd
roxy
‐flavo
nol(53)
Popu
lusnigra×Po
pulusdeltoides
Ralston
iasolana
cearum
Modified
broth
dilutionMTT
MICs:
150μg
/ml
(Zhonget
al.,2012)
Kae
mkleb
siella
pneu
moniazpferol‐
7,8‐digluco
side
(54)
Farsetia
aegyptiaTu
rra
Klebsiella
pneumon
iae
Pap
erdisc
IZ:19mm
(Atta,
Hashem
,&Eman
,2013)
Kae
mpferol(55)
Pure
Escherichiacoli
MIC:25.00μg
/ml
(Wuet
al.,2013)
Que
rcetin‐3‐O
‐rutinoside
(42)
Calotropisprocera
Stap
hylococcus
aureus
Bacillus
subtilis
Agarwell‐diffusion
IZ:19.5
mm
MIC:80μg
/ml
(Nen
aah,2
013)
Myricetrin‐3‐O
‐rha
mno
side
(56)
Crotonmenyharthii
Bacillus
cereus
Microdilutionbioassay
MIC:30–2
50μg
/ml
(Aderogb
aet
al.,2013)
(Continues)
FARHADI ET AL. 9
TABLE
2(Continue
d)
Compo
unds
Source
Bactria
Metho
dActivity
Ref.
Que
rcetin
(48)
Escherichiacoli
Stap
hylococcus
aureus
Que
rcetin
(48)
Alnus
japo
nica
Stap
hylococcus
aureus
Microwellplate
(Activityinhibitionbiofilm
sform
ation>70%
at20μg
/ml)
(J.‐H.L
eeet
al.,2013)
Que
rcetin
(48)
Que
rcetin‐3‐O
‐arabino
side
(41)
Psidium
guajava
Pseudo
mon
asaerugino
saDiscdiffusion
Conc
entrate:
50an
d100μg
/ml
(Vasavi,Arun,&
Rek
ha,
2014)
Que
rcetin
(48)
Myricetin
(46)
Diospyrsvirginiana
Stap
hylococcus
aureus
Microdilution
MIC:50μg
/ml
(Rashed
etal.,2014)
Rutin
(49)
Litchi
chinensis
Stap
hylococcus
aureus
Escherichiacoli
Shigella
dysenteriae
Microdilutiontiter
MIC:62.5
μg/m
l(W
enet
al.,2014)
3‐C
inna
moyltribuloside
(57)
Heritiera
littoralis
Mycob
acterium
mad
agascariense
Mycob
acterium
indicus
pran
ii
Microtiterdilution
MIC:80–1
60μg
/ml
(Christopher,N
yandoro,
Chacha,
&de
Koning,
2014)
Kae
mpferol(55)
Pure
Escherichiacoli
Microdilutionin
broth
MIC
>10,000μg
/ml
(Heet
al.,2014)
Kae
mpferol(55)
Com
mipho
rapedu
nculata
Stap
hylococcus
aureus
MIC:6.25μg
/ml
(Tajuddee
n,S
aniSa
llau,
Muham
mad
Musa,
James
Hab
ila,&
Yah
aya,
2014)
Kae
mpferol(55)
Apo
cynu
mvenetum
Bacillus
thuringiensis
Pseudo
mon
asaerugino
saActive
(Konget
al.,2014)
3,4′,5
‐Trihy
droxy
‐3′,7
‐dimetho
xyflavone
(58)
Dod
onaa
angustifo
liaEscherichiacoli,Bacillus
pumilus
Agarwell‐diffusion
MIC
<31.25μg
/well
(Omosa
etal.,2014)
Kae
mpferol‐3‐O
‐(2″,3″,4″‐tri‐O‐
gallo
yl)‐a‐L‐rham
nopy
rano
side
(59)
Que
rcetin‐3‐O
‐(3″,4″‐di‐O
‐galloyl)‐a‐L‐
rham
nopy
rano
side
(60)
Calliand
ratergem
ina
Stap
hylococcus
aureus
Microdilution
MIC:256μg
/ml
(Chan
,Gray,
Igoli,
Lee,
&Goh,2
014)
Astragalin
(61)
Garciniapreussii
Stap
hylococcus
aureus
Broth
dilution
MIC:128μg
/ml
(Bilo
aMessiet
al.,2014)
Que
rcetin‐3‐O
‐β‐rha
mno
side
(62)
Ficusexasperata
Bacillus
subtilis
Agardiffusion
ZI:2–2
.5mm
(Taiwo&
Igben
eghu,2
014)
6‐H
ydroxyqu
ercetin7
‐O‐β‐
gluc
opy
rano
side
(63)
6‐H
ydroxy
quercetin7
‐O‐β‐(6‐
gallo
ylgluc
opy
rano
side
)(64)
Tagetesm
inuta
Micrococcusleteus
Agarwell‐diffusion
ZI:14.2
19mm
(Shah
zadi&
Shah
,2015)
Que
rcitin‐3‐gluco
side
(65)
Scutellariaob
longa
Stap
hylococcus
aureus
Tim
e‐killcu
rves
MIC:32μg
/ml
(Activity:
biofilm
‐red
uction)
(Rajen
dranet
al.,2016)
Rha
mne
tin‐3,3′‐di‐O
‐β‐D
‐gluc
opy
rano
side
(66)
Isorham
netin3‐O
‐b‐D
‐rutino
side
(67)
Diplotaxis.SP
P.Escherichiacoli
Stap
hylococcus
aureus
Diffusionagar
IZ:17.60±0.04,
13.00±0.01mm
(Salah
etal.,2015)
Kae
mpferol‐3‐rutinoside
(68)
Soph
orajapo
nica
Stap
hylococcus
aureus
MIC
>320.2
μg/m
l(Activity:
inhibitionthe
actionofsortaseA)
(Yan
get
al.,2015)
(Continues)
10 FARHADI ET AL.
TABLE
2(Continue
d)
Compo
unds
Source
Bactria
Metho
dActivity
Ref.
Que
rcetin
(48)
Pure
Stap
hylococcus
aureus
Antifoulingassay
MIC:1.62μg
/ml
(Gopikrishnan
etal.,2015)
Rutin
(49)
Pure
Escherichiacoli
Microbroth
dilution
MIC:25μg
/ml
(Activity:
inhibitionofbiofilm
)(Al‐Sh
abib
etal.,2017)
Que
rcetin‐3‐O
‐β‐D
‐gluco
pyrano
side
(69)
Maytenu
sbu
chan
anii
Stap
hylococcus
aureus
Broth
microdilution
MIC:16μg
/ml(Activity:
complexwithbacterial
cellwalls)
(Teb
ouet
al.,2017)
Isorham
netin3‐O
‐βD‐rutinoside
(70)
Artiplexo
side
(71)
Atriplexha
limus
L.Stap
hylococcus
saureus
Streptococcu
pyogenes
Enterococcus
feacalis
Escherichiacoli
Acinetoba
cter
baum
anii
Welld
iffusion
ZI:14–2
0mm
(El‐Aasr,Kab
bash,E
l‐Se
oud,
Al‐Mad
boly,&
Iked
a,2016)
Galan
gin‐3‐m
ethy
lethe
r(72)
Alpinia
calcarata
Stap
hylococcus
aureus
Microdilution
MIC:62.5
μg/m
l(Ran
dhaw
aet
al.,2016)
Entad
anin
(73)
Que
rcetin‐3‐O
‐α‐l‐rha
mno
side
(64)
Entada
abyssinica
Salmon
ella
typh
imurium
Liqu
iddilution
MIC:1.56μg
/ml
(Dzo
yem
etal.,2017)
Galan
gin(3,5,7‐trihy
droxyflavoe)
( 44)
3‐O
‐Methy
lgalan
gin(5,7‐D
ihyd
roxy
‐3metho
xyflavone
)(72)
Pure
Proteusmirab
ilis
Stap
hylococcus
aureus
Microdilution
MIC:0.25–0
.5μg
/ml
(Ech
everríaet
al.,2017)
Myricitrin(46),myricitrin(75)
Pure
Stap
hylococcus
aureus
Microdilutionin
broth
MBIC
50:1,3
2μg
/ml
(Lopes
etal.,2017)
Rutin
(49)
Pure
Streptococcussuis
MIC:78μg
/ml
(Wan
get
al.,2017)
FARHADI ET AL. 11
In addition, biofilm inhibition reported as an important activity of
chalcones, for example, in vitro investigation of antibiofilm activity
was evaluated by natural and synthetic chalcones against Haemophilus
influenza. Out of them, 3‐hydroxychalcone (120) exhibited approxi-
mately sixfold more activity than the reference drug, azithromycin
(MBIC50 16 μg/ml; Kunthalert, Baothong, Khetkam, Chokchaisiri, &
Suksamrarn, 2014). Rodríguez et al. found that 2′,4′,4‐trihydroxy‐
3,6′‐dimethoxychalchone (121) isolated from Piper delineatum
displayed a potent quorum sensing inhibitory activity in Vibrio harveyi
(bacterial model) by inhibitory effect on biofilm formation, without
inhibition of bacterial growth up to 16.5 μg/ml (Martín‐Rodríguez
et al., 2015). Recently, a new prenylated chalcone 4,4′,6′ trihydroxy‐
3‐methoxy‐3′‐pentene chalcone (124) has been extracted from
Elatostema parasiticum, which inhibited the growth of S. aureus and
B. subtilis with the MIC values of 7.8 and 1.95 μg/ml, respectively
(Mariani, Suganda, & Sukandar, 2016). Several antibacterial activities
of other chalcones compounds are summarized in Table 5.
4 | SYNTHETIC DERIVATIVES OFFLAVONOIDS
Developing novel, potent, and unique antibacterial drugs is important
to overcome bacterial resistance and increase effectiveness of thera-
pies. Many researchers reported that new derivatives of flavonoids
were more active than natural flavonoids against bacteria strains
(Table 6; Babii et al., 2016). For evaluation of the antibacterial activ-
ity of hybrids of chalcones and oxazolidinones, N‐{3‐[3‐fluoro‐4‐(3‐
pyridin‐2‐yl‐acryloyl)‐phenyl]‐2‐oxo‐oxazolidin‐5‐ylmethyl}‐acetamide
(126; containing both chalcone and oxazolidinone moieties) was syn-
thesized and showed potent activity toward S. aureus with MIC
values of 4–8 μg/ml (Selvakumar et al., 2007). More studies revealed
that the primary target of this agent is cytoplasmic membrane (Cushnie
et al., 2008). Konduru, Dey, Sajid, Owais, and Ahmed (2013) investi-
gated sulfone and bisulfone chalcone synthetic derivatives. Among
them, 1‐(4‐bromophenyl)‐3‐(3,4‐dimethoxyphenyl)‐3‐(phenylsulfonyl)
propane‐1‐one (130), 1‐(4‐bromophenyl)‐3‐(3,4,5‐trimethoxyphenyl)‐
3‐(phenylsulfonyl) propane‐1‐one (131), and 1‐phenyl‐3‐phenyl‐3‐
phenylsulfonylpropane‐1‐one (132) had good antibacterial activity
against S. typhimurium (MIC 1.95 μg/ml) in comparison with reference
drugs ampicillin and kanamycin (Figure 6).
Tran, Do, et al. (2012) investigated in vitro antibacterial activity of
synthetic chalcone analogues alone or in combination with nonbeta
lactam antibiotics (ciprofloxacin, chloramphenicol, erythromycin, van-
comycin, and doxycycline) toward S. aureus (MRSA). Ciprofloxacin in
combination with 4′‐bromo‐2‐hydroxychalcone (136), doxycycline
with 4‐hydroxychalcone (137), and doxycycline with 2′,2‐
dihydroxychalcone (138) were active against MRSA with MIC values
of 0.125–0.25 μg/ml via inhibition of efflux pump.
Biological evaluation for discovering urease inhibitors of synthetic
derivatives of flavonoids against H. pylori urease indicated that 4′,7,8‐
trihydroxy‐isoflavene (141) was the most active compound with IC50
0.85 mM, which was 20‐fold more potent than standard urease inhibi-
tor (acetohydroxamic acid; Xiao et al., 2013). Bozic, Milenkovic, Ivkovic,
and Cirkovic (2014) reported that among three newly synthesized
TABLE
3Antibacterial
effect
offlavan
one
compo
unds
Compo
unds
Source
Bacteria
Metho
dActivity
Ref.
7‐D
ihyd
roxy
‐2′‐metho
xy‐3′,4
′‐methy
lene
dioxyisoflavan
one
(76)
Urariapicta
Stap
hylococcus
aureus
Microdilutiontiter
MIC:12.5
μg/m
l(Rah
man
,Gibbons,&
Gray,
2007)
Naringe
nin(77)
Pure
Escherichiacoli
Bacillus
subtilis
Gen
erationtime:
25–3
9(Activity:
inhibition
ofnucleicacid
synthesis)
(Ulanowska,
Majch
rzyk
,Moskot,
Jakó
bkiew
icz‐Ban
ecka,&
Węg
rzyn
,2007)
5,7‐D
iben
zyloxyflavan
one
(78)
Helichrysum
gymno
comum
Stap
hylococcus
aureus
Quick
microplatemetho
dMIC
≤125μg
/ml
(Drewes
&vanVuuren,2
008)
3′‐O‐m
ethy
l‐5′‐hy
droxydiplacone
(79)
3′‐O‐m
ethy
l‐5′‐O‐m
ethy
ldiplaco
ne(80)
Mim
ulone
(81),Diplaco
ne(82)
Paulow
niatom
entosa
Enterococcus
faecalis
Bacillus
subtilis
Broth
microdilutionmetho
dMIC:2μg
/ml
(Šmejkalet
al.,2008)
Soph
oraflavan
one
G(83)
Soph
orafla
vescens
Stap
hylococcus
aureus
Broth
dilutionmetho
dMIC/M
BC:0.5/1
μg/m
l(Chaet
al.,2009)
5,7‐D
imetho
xyflavan
one
‐4′‐O‐b‐D
‐gluc
opy
rano
side
(84)
5,7,3′‐Trihy
droxy
‐flavano
‐ne‐40‐O
‐b‐
D‐gluco
pyrano
side
(85)
Naringe
nin‐7‐O
‐b‐D
‐gluco
pyrano
side
(86)
Retam
araetam
Escherichiacoli
Microdilutionbroth
metho
dsMIC:7.5
μg/m
l(O
rhan
,Özçelik,Ö
zgen
,&Ergun,2
010)
Soph
oraflavan
one
G(83)
Kurarinol(89)
Soph
orafla
vescens
Stap
hylococcus
aureus
Microtiterdilutionassay
MIC:7.12–7
.36μg
/ml
IC50:107.7
±6.6
μM(O
het
al.,2011)
Pinocembrin
(87)
Cryptocarya
chinensis
Mycob
acterium
tuberculosis
MIC:3.5
μg/m
l(Chou,C
hen
,Pen
g,Chen
g,&
Chen
,2011)
Aby
ssione
‐V4′‐O‐m
ethy
lethe
r(88)
Erythrinacaffra
Escherichiacoli
Stap
hylococcus
aureus
Microbroth
dilutionassay
MIC:3.9–6
2μg
/ml
(Chukw
ujekw
uet
al.,2011)
7‐H
ydroxyflavan
one
(91)
Zuccagniapu
nctata
Streptococcuspn
eumon
iae
Agarmacrodilutionmetho
dMIC:1,000μg
/ml
(Zam
piniet
al.,2012)
5,7‐D
ihyd
roxyflavan
one
(Pinocembrin)(87)
Com
bretum
hereroense
Stap
hylococcus
aureus
Microtiterdilutionassay
MIC:12.5
μg/m
l(Katerereet
al.,2012)
Lupinifolin
(90)
Mun
duleasericea
Stap
hylococcus
aureus
MIQ
:0.5
μg(M
azim
baet
al.,2012)
Och
naflavone
(92)
Och
naflavone
7‐O
‐methy
lethe
r(93)
Ochna
pretoriensis
P.aerugino
saS.
aureus
MIC
31.3,6
2.5
μg/m
l(M
akhafola,S
amuel,
Elgorashi,&
Eloff,2
012)
Soph
oraflavan
one
B(94)
Pure
Stap
hylococcus
aureus
Broth
microdilutionmetho
dMIC:31.5
μm(M
unet
al.,2013)
6‐8
Dipreny
leriodictyc
(95)
Pure
Stap
hylococcus
aureus
Microbroth
dilutionmetho
dMIC:0.5
μg/m
lActivity:
depolarizationof
mem
brane
(Dzo
yem
etal.,2013)
Soph
oraflavan
one
B(94)
Desmod
ium
caud
atum
Stap
hylococcus
aureus
Che
ckerbo
arddilutiontest
MIC:15.6
μg/m
l(M
unet
al.,2014)
4′,7
‐Di‐O‐m
ethy
lnaringe
nin(96)
Macaran
gatricho
carpa
Escherichiacoli
Shigella
dysenteriae
Broth
microdilution
MIC:62.4–1
24.9
μg/m
l(Fareza,
Syah
,Mujahidin,Juliawaty,
&Kurniasih,2
014)
Soph
oraflavone
G(83)
Soph
oraalop
ecuroides
Stap
hylococcus
epidermidis
Microdilutionmetho
dMIC:3.1
to12.5
μg/m
l(W
anet
al.,2015)
Liqu
iritigen
in(97)
Liqu
iritin
(98)
Pure
Escherichiacoli
IC50:198.6,3
37.8
μg/m
l(Konget
al.,2015)
Mim
ulone
(81)
Paulow
niatomentosa
Stap
hylococcus
aureus
Agardilutionmetho
dMIC:2/4
.9μg
/ml/μM
(Navrátilová
etal.,2016)
Pinocembrin
(87)
7‐O
‐Methy
leriodictyo
l(99)
Pure
Proteusmirab
ilis
Stap
hylococcus
aureus
Microdilutionmetho
dMIC:0.25–0
.5μg
/ml
(Ech
everríaet
al.,2017)
12 FARHADI ET AL.
FIGURE 3 Chemical structures of flavanone compounds
FARHADI ET AL. 13
chalcones with OH at positions 2, 3, and 4 of B ring of 1,3‐bis‐(2‐
hydroxy‐phenyl) (145; with hydroxy group in position 2) exhibited sig-
nificant effect on adherence and biofilm formation of MRSA strains. In
the synthetic fluoroquinolone‐flavonoid hybrids, naringenin‐ethyli-
dene‐ciprofloxacin (146; with cyclopropan on theN atom) was themost
active compound and showed eightfold to 88‐fold more potent activity
than the standard drug ciprofloxacin against E. coli, B. subtilis, and
S. aureus. These results suggested that covalently binding of this com-
pound with an efflux pump is a good strategy to overcome bacterial
resistance and increase the antibacterial activity of flavonoids (Xiao
et al., 2014). Asiri et al. investigated synthetic heterocyclic compounds
(pyrazolines and pyrimidines) for activity against two Gram‐positive
and two Gram‐negative bacteria by the disk diffusion assay, and among
them, thiosemicarbazide (147) was better antibacterial agent against
S. aureus, compared than the reference drug chloramphenicol (Khan,
Asiri, & Elroby, 2014). Evaluation of the antibacterial activity ofmodified
structures of olympicin A fromHypericum olympicum showed that (E)‐3‐
(2‐(allyloxy) phenyl)‐1‐(2,4,6‐trihydroxyphenyl)prop‐2‐en‐1‐one (148)
had a good activity against MRSA with MIC value of 0.39 μg/ml (Feng
et al., 2014). Between the synthetic tricyclic flavonoids, compounds
149 and150 (1,3‐dithioliumderivative) showed good activitywithMICs
of 0.25 and 1 μg/ml against S. aureus and E. coli, respectively (Bahrin,
Apostu, Birsa, & Stefan, 2014). In the other study, the antimicrobial
activity of synthesized flavones along with natural flavonoids was
assayed against Flavobacterium columnare by rapid bioassay. Compound
153 (a tricyclic flavonoid) containing S atoms on the heterocyclic ring
was found to have a stronger antibacterial effect at low concentrations
than other synthetic compounds against S. aureus and E. coli with MIC
values of 0.24 and 3.9 μg/ml, respectively (Babii et al., 2016). 2,3‐
Dibromo‐1,3‐diphenylpropan‐1‐one derivative (154) with two Br sub-
stitution at the positions α and β (the synthetic chalcone derivatives)
possessed antibacterial activity against S. aureus and E. faecalis with
MIC values of 6.25 and 12.5 μg/ml, respectively. This compound
showed similar activity to standard antibiotic nalidixic acid (MIC:
6.25 μg/ml; Alam, Rahman, & Lee, 2015).
The MIC value (8 μg/ml) of 27 chalcones and their pyrazoline and
hydrazone derivatives showed that (E)‐1‐(4‐hydroxyphenyl)‐3‐p‐
tolylprop‐2‐en‐1‐one (155) was active against E. faecalis (the equal
activity with gentamicin; Evranos‐Aksöz, Onurdağ, & Özgacar, 2015).
Fatty acid biosynthesis (FAB) is an attractive target for newantibac-
terial agents. Inhibitory effects of chrysin derivatives on FabH were
evaluated toward E. coli, P. aeruginosa, and S. aureus. Results showed
TABLE 4 Antibacterial effect of flavane 3‐ol compounds
Compounds Source Bacteria Method Activity Ref.
3′‐O‐methyldiplacol (100) Paulowniatomentosa
Bacillus CereusBacillus subtilisStaphylococcus
epidermidis
Broth microdilution MIC: 2 to4 μg/ml
(Šmejkal et al., 2008)
Conrauiflavonol (104) Ficus conraui Escherichia coli Rapid p‐iodonitrotetrazoliumviolet (INT)
MIC: 64 μg/ml (Kengap et al., 2011)
2‐(3,5‐Dihydroxy‐4‐methoxy‐phenyl)‐3,5‐dihydroxy‐8,8‐dimethyl‐2,3‐dihydro‐8H‐pyrano [3,2]chromen‐4‐one (106)
Commiphorapedunculata
Staphylococcus aureus Agar well diffusionand broth dilution
MIC/MBC:27 μg/ml
(Tajuddeen et al., 2014)
Quercetin 3‐O‐methylether (101)
Cistus laurifolius Helicobacter pylori Agar dilution MIC: 3.9 μg/ml (Ustün et al., 2006)
Ericoside (107) Erica mannii Escherichia coli Broth microdilution MIC: 64 μg/ml (Bitchagno et al., 2016)
3′‐O‐methyldiplacol (100) Paulowniatomentosa fruits
Staphylococcus aureus Agar dilution MIC: 2.4 μg/ml (Navrátilová et al., 2016)
Taxifolin‐7‐O‐α‐l‐rhamnopyranoside (102)
Hypericum japonicum Staphylococcus aureus Microdilution MIC: 32 μg/ml (An et al., 2011)
Lupinifolin (103) Mundulea sericea Staphylococcus aureusBacillus subtilisE. coli P. aeruginosa
MIQ: 0.5 μg (Mazimba et al., 2012)
Dihydrokaempferol (105) Commiphorapedunculata
EntrococciStaphylococcus aureus
MIC: 625 μg/ml (Tajuddeen et al., 2016)
14 FARHADI ET AL.
that compound 156 with heterocycle group at the C‐7 position was
active against S. aureus and E. coli with MIC values of 1.25 ± 0.01 and
1.15 ± 0.12 μg/ml, respectively (Li et al., 2017). Evaluation of the anti-
bacterial activity of structural analogues of xanthohumol (157) by
agar‐diffusion method revealed that chalconaringenin (158), with at
least one hydroxy group at C‐4 position, demonstrated good activity.
Replacing this substituent by a halogen atom, nitro group (NO2), ethoxy
group, or aliphatic group caused the loss of activity towards S. aureus
(Stompor & Żarowska, 2016). The synthetic compound (S)‐5‐hydroxy‐
4′‐hydroxy‐7‐(2‐morpholino‐2‐oxoethoxy)‐2,3‐dihydroflavone (160;
containing the flavanone core) displayed excellent activity against E. coli,
P. aeruginosa, and S. aureus (sixfold more potent than the marketed
antibiotic ciprofloxacin). The result showed that R4 (N‐containing het-
erocyclic compounds) were more active than alkyl or aromatic amino
containing analogues at the C‐7 side chain (Xiao et al., 2017)
5 | STRUCTURE–ACTIVITY RELATIONSHIP
The amphipathic features of flavonoids play an important role in the
antibacterial properties. In these compounds, hydrophilic and hydro-
phobic moieties must be present together (Echeverría et al., 2017).
The hydrophobic substituents such as prenyl groups, alkylamino chains,
alkyl chains, and nitrogen or oxygen containing heterocyclic moieties
FIGURE 4 Chemical structures of flavane 3‐ols compounds
FIGURE 5 Chemical structures of chalconecompounds
FARHADI ET AL. 15
usually enhance the antibacterial activity for all the flavonoids (Xie,
Yang, Tang, Chen, & Ren, 2015). The structure–activity relationships
have been found in the recent studies are summarized as follows. The
results showed that between different classes of flavonoids, mainly
chalcones, flavanes, and flavan‐3‐ol exhibit better results, respectively.
These findings are comparable to that of previous studies (Cushnie &
Lamb, 2011).
5.1 | Chalcones
According to the result of many types of researches, chalcones with a
lipophilic group such as isoprenoid and methoxy groups at positions
3′, 5′, and 2′ of ring A are the most potent inhibitors of MRSA strains
(Lee et al., 2010; Omosa et al., 2016). Based on the activity of
isobavachalcone (110; MIC: 30 μg/ml), Mbaveng et al. (2008) suggest
that A ring with prenyl group display good activity but cyclization or
addition of the prenyl group to another ring in addition to the ring
A (B ring) decrease the activity. Also, hydroxy group at 4′, 4, and 6
of A and B rings increase the activity (Figure 7). For example,
between compounds kuraridin (168) and THIPMC (115) with the
same structure, compound 168 with only one difference (with com-
pound 115) in position of OH on the B ring (2 and 4 instead of 4
and 6) showed high activity against MRSA strain (Lee et al., 2010;
Oh et al., 2011).
5.2 | Flavanes and flavanols
In many studies, flavanes with prenyl group at the A ring are the most
potent antibacterial compounds against S. aureus, and the number and
position of prenyl groups on this ring increase the activity (Figures 8
and 9). For example, Mazimba et al. (2012) proved that between com-
pounds lupinifolin (90) and 165 with almost similar structures, but dif-
ference at position 3 on the ring C, compound 90 inhibited the growth
of S. aureus and B. subtilis (minimum inhibitory quantity: 0.5 μg). Pres-
ence of the hydroxy group at different positions of A and B rings has
also been reported to improve antibacterial activity. Šmejkal et al.
(2008) reported that 3′‐O‐methydiplacol (100) with OH at positions
5, 3′, and 4′ on the A and B rings, respectively, geranyl group at C‐6
and OMe at C‐5′ showed good activity towered S. aureus with MIC
value of 4 μg/ml. Also, sophoraflavanone G (83) with isogeranyl at
C‐8 and OH at 3, 2′, and 4′ on the A and B rings was active against
S. aureus with MIC value of 7.3 μg/ml (Oh et al., 2011). Recently,
Bitchagno et al. (2015) found that the tetraflavonoids (166, 167)
without OH on the C ring were moderate activity against E. coli.
5.3 | Flavonols
In the ring A, many studies have confirmed that hydroxylation at posi-
tion 5 and 7 together are important on antibacterial activity of
TABLE
5Antibacterial
effect
ofch
alco
neco
mpo
unds
Compo
unds
Source
Bacteria
Metho
dActivity
Ref.
Ang
ustico
rnin
B(108)
BartericinA(109)
Dorstenia
angusticornis
Bacillus
cereus
Liqu
iddilution
MIC:0.61–1
.22μg
/ml
(Kueteet
al.,2007)
Isoba
vach
alco
ne(110)
Dorstenia
barteri
Stap
hylococcus
aureus
Bacillus
stearothermop
hilus
Discdiffusion
MIC:0.3
μg/m
l(M
baven
get
al.,2008)
2′‐Hyd
roxy
‐4′,6
′‐dibe
nzyloxych
alco
ne(111)
Helichrysum
gymno
comum
Stap
hylococcus
aureus
Microplate
MIC:63μg
/ml
(Drewes
&vanVuuren,2
008)
2,4‐D
ihyd
roxych
alco
ne(112)
2,3′‐Dihyd
roxych
alco
ne(113)
2,4′‐Dihyd
roxych
alco
n(114)
Pure
Slap
hylococcus
aureus
Turbidimetric‐kine
tic
MIC:25.3
μg/m
l(Alvarez
etal.,2008)
THIPMC(115)
Soph
orafla
vescensAit
Stap
hylococcus
aureus
resistan
tenterococci
Microdilutionbroth
MIC:0.188–0
.375μg
/ml
(Lee
etal.,2010)
4,2′,4
′‐Trihy
droxych
alco
ne(116)
Astragalusad
surgens
Escherichiacoli
Bacillus
cereus,
Stap
hylococcus
aureu
Microbroth
dilution
MIC:7.8–3
1.3
μg/m
l(Chen
etal.,2012)
Isoliq
uiritige
nin(117)
Pure
Porphyromon
asgingivalis,
Fusoba
cterium
nucleatum
Microdilution
MIC:5–2
5μg
/ml
(Feldman
,San
tos,&
Grenier,2011)
4‐H
ydroxyonc
hocarpin
(118)
Dorstenia
spp.
Stap
hylococcus
aureus
Tim
e‐killkine
tic
MIC:1–8
μg/m
l(D
zoye
met
al.,2013)
Macatrich
ocarpinsD
(119)
Macaran
gatricho
carpa
Enteroba
cter
aeroge
nes
Broth
microdilution
MIC:26.5
μM(Farezaet
al.,2014)
3‐H
ydroxych
alco
ne(120)
Pure
Haemop
hilusinflu
enzae
Broth
microdilution
MBIC
50:71.35Antibiofilm
(Kunthalertet
al.,2014)
Isoba
vach
alco
ne(110)
Artocarpu
san
isop
hyllus
Stap
hylococcus
aureus
Discdiffusion
ZI:9.8
±0.65mm
MBC:450μg
/ml
(Jam
il,2014)
Isoba
vach
alco
ne(110)
Psoralea
corylifolia
Stap
hylococcus
aureus
Liqu
iddilution
MIC:8μg
/ml
(Cuiet
al.,2015)
2′,4
′,4‐Trihy
droxy
‐3,6′‐
dimetho
xych
alch
one
(121)
Piperdelineatum
Enteroba
cter
aerogenes
MIC:500μg
/ml(Activity:
quorum
sensing
inhibition)
(Martín‐Rodrígu
ezet
al.,2015)
Lico
chalco
neA(122)
Lico
chalco
neE(123)
Licorice
Stap
hylococcus
aureus
Active
Activity:
1.Inhibitthebiofilm
form
ationan
dpreve
nt
yeast‐hyp
hal
tran
sition
2.Red
uce
theproduction
ofα‐toxin
(Wan
get
al.,2015)
4,4′,6
′‐Trihy
droxy
3metho
xy‐
3‐′pe
nten
ech
alco
ne(124)
Elatostemapa
rasiticum
Stap
hylococcsau
reus
Bacillus
subtilis
Microdilutionbroth
MIC:1.95–7
.8μg
/ml
(Marianiet
al.,2016)
Ardisiaqu
inone
(125)
Pure
Escherichiacoli
Colorimetric
MIC:125μg
/ml
(Activity:
combined
toefflux
pumpinhibitor
inthefigh
tagainst
MDRbacterial
infections)
(Omosa
etal.,2016)
16 FARHADI ET AL.
TABLE
6Antibacterial
effect
ofsynthe
ticco
mpo
unds
Compo
unds
Bacteria
Metho
dActivity
Ref.
N‐{3‐[3‐Fluoro‐4‐(3‐pyridin‐2‐yl‐acryloyl)‐ph
enyl]‐
2‐oxo
‐oxazo
lidin‐5‐ylm
ethy
l}‐acetam
ide(126)
Stap
hylococcus
aureus
—MIC:4–8
μg/m
l(Selvaku
mar
etal.,2007)
3‐O
‐octan
oyl‐(−)‐ep
icatechin(127)
Stap
hylococcus
aureus
Broth
microdilution
MIC:50μg
/ml
(Cushnie
etal.,2007)
4‐C
hloro‐flavano
ne(128)
Escherichiacoli
MIC:17μg
/ml
(Fowleret
al.,2011)
Thiosemicarba
zide
derivative
s(129)
Salmon
ella
typh
imurium,E
scherichia
coli
Discdiffusion
ZI:18.5,1
8.6
mm
(Asiri&
Khan
,2012)
1‐(4‐B
romoph
enyl)‐3‐(3,4‐dim
etho
xyph
enyl)‐3‐
(phe
nylsulfony
l)propa
ne‐1‐one
(130),1‐(4‐
bromoph
enyl)‐3‐(3,4,5‐trimetho
xyph
enyl)‐3‐
(phe
nylsulfony
l)propa
ne‐1‐one
(131),1‐phe
nyl‐
3‐phe
nyl‐3‐phe
nylsulfony
lpropa
ne‐1‐one
(132)
Salmon
ella
typh
imurium
Microwelldilution
MIC:1.95μg
/ml
(Konduru
etal.,2013)
1‐(Pyridine‐2‐yl)‐3‐(2‐hyd
roxyph
enyl)‐2‐prope
ne‐
1‐one
(133),1‐(furan‐2‐yl)‐3‐(3‐hyd
roxyph
enyl)‐
2‐prope
ne‐1‐one
(134),1‐(thioph
ene‐2‐yl)‐3‐
(2‐hyd
roxyph
enyl)‐2‐prope
ne‐1‐one
(135)
Stap
hylococcus
aureus
Microdilutionmetho
dMIC:32–6
4μg
/ml
(Tran,N
guye
n,e
tal.,2012)
4′‐Bromo‐2‐hyd
roxych
alco
ne(136),4‐
hydroxych
alco
ne(137),2′,2
‐dihy
droxych
alco
ne(138)
Stap
hylococcus
aureus
Discdiffusion
MIC:0.125–0
.25μg
/ml
(Tran,D
o,e
tal.,2012)
1‐(2′‐Hyd
roxy
‐6′‐metho
xy‐phe
nyl)‐3‐
(5‐dode
cyl‐2‐m
etho
xy‐phe
nyl)‐
prope
n‐1‐one
(139)
Stap
hylococcus
epidermidis
Escherichiacoli
Broth
dilutionmetho
dMIC:37–1
50μg
/ml
(Mallavadhan
i,Sa
hoo,
Kumar,&
Murty,
2014)
(E)‐6‐ferroceny
lvinyl‐chromen
‐4‐one
‐3‐
propionicacid
(140)
Stap
hylococcus
aureus
Liqu
idmicrodilution
MIC:32μg
/ml
(Kowalskiet
al.,2013)
4′,7
,8‐ Trihy
droxy
isoflaven
e(141)
Helicob
acterpylori
IC50:0.85mM
(Xiaoet
al.,2013)
4‐(6‐H
ydroxyspiro[1,2,3,3a,9a‐
pentah
ydrocyclope
nta[1,2b]ch
roman
e‐9,1′‐cyclope
ntan
e]‐3a‐yl)ben
zene
‐1,3‐diol(143)
Stap
hylococcus
aureus
MIC:20–4
0μg
/ml
(Man
ner,S
kogm
an,G
oeres,
Vuorela,&
Fallarero,2
013)
7‐O
‐butyl
naring
enin
(144)
Helicob
acterpylori
Discdiffusion
Inhibitory
effect:70.75±3.56(%
)(M
oonet
al.,2013)
7‐O
‐butyl
naring
enin
(144)
Stap
hylococcus
aureus
MIC:0.625μg
/ml
(K.A.L
eeet
al.,2013)
1,3‐B
is‐(2‐hyd
roxy
‐phe
nyl)‐prope
none
(145)
Stap
hylococcus
aureus
Biofilm
production6.25μg
/ml:2/1
5(Bozicet
al.,2014)
Naringe
nin‐ethyliden
e‐ciprofloxacin(146)
Bacillus
subtilis
Colorimetric,
MTT
MIC:0.062μg
/ml
(Xiaoet
al.,2014)
Thiosemicarba
zide
(147)
Stap
hylococcus
aureus
Diskdiffusion
MIC:16μg
/ml
(Asiri&
Khan
,2012)
(E)‐3‐(2‐(allyloxy)ph
enyl)‐1‐(2,4,6‐
trihyd
roxyph
enyl)prop‐2‐en‐1‐one
(148)
Stap
hylococcus
aureus
MIC:0.39μg
/ml
(Fen
get
al.,2014)
1,3
‐Dithioliu
mde
rivative
s(149,1
50)
Stap
hylococcus
aureus
Escherichiacoli
Diskdiffusion
MIC:0.25–1
μg/m
l(Bah
rinet
al.,2014)
Chrysin
(151)
5,7‐D
ihyd
roxy
‐4′‐metho
xyflavone
(152)
Flavob
acterium
columna
rMIC:0.3
μg/m
l(Tan
,Sch
rader,K
han
,&Rim
ando,2
015)
Tricyclic
flavono
idde
rivative
s(153)
Stap
hylococcus
aureus
Escherichiacoli
Microbroth
dilution
MIC:0.24an
d3.9
μg/m
l(Bab
iiet
al.,2016)
2,3‐D
ibromo‐1,3‐diphe
nylpropa
n‐1‐one
derivative
(154)
Stap
hylococcus
aureus
Enterococcus
faecalis
Filter
pape
rdisc
diffusion
MIC:6.25,1
2.5
μg/m
l(Alam
etal.,2015)
(Continues)
FARHADI ET AL. 17
TABLE
6(Continue
d)
Compo
unds
Bacteria
Metho
dActivity
Ref.
(E)‐1‐(4‐hyd
roxyph
enyl)‐3‐p‐tolylprop‐2‐en‐
1‐one
(155)
Enterococcus
faecalisStap
hylococcus
aureus
Broth
dilution
MIC:8.16μg
/ml
(Evran
os‐Aksözet
al.,2015)
Chrysin
derivative
s(156)
Stap
hylococcus
aureus
Escherichiacoli
MIC:1.25±0.01,1
.15±0.12μg
/ml
(Liet
al.,2017)
Xan
thohu
mol(157),Cha
lcona
ring
enin
(158)
Stap
hylococcus
aureus
Discdiffusion
ZI:6.84mm
(Stompor&
Żarowska,
2016)
(E)‐1‐(4‐bromoph
enyl)‐3‐(4‐iodo
phen
yl)prop‐
2‐en‐1‐one
(159)
Stap
hylococcus
aureus
Stap
hylococcus
epidermidis
Microwelldilution
MIC:250μg
/ml
(Zainuriet
al.,2017)
(S)‐5‐H
ydroxy
‐4′‐hy
droxy
‐7‐(2‐m
orpho
lino‐
2‐oxo
etho
xy)‐2,3
‐ dihyd
roflavone
(160)
Escherichiacoli
Pseudo
mon
asaerugino
saStap
hylococcus
aureus
MTTproliferation
MIC:11,2
9,5
9μg
/ml
(Xiaoet
al.,2017)
2‐(2‐H
ydroxyph
enyl)‐5‐m
ethy
l‐3‐(4‐(thioph
en‐
2‐yl)‐6‐(4‐m
ethy
l‐ph
enyl)‐py
rimidin‐2‐yl)
thiazo
lidin‐4‐one
(161),2‐(4‐fluoroph
enyl)‐
5‐m
ethy
l‐3‐(4‐(thioph
en‐2‐yl)‐6‐(4‐m
ethy
l‐ph
enyl)‐py
rimidin‐2‐yl)thiazolid
in‐4‐one
(162)
Escherichiacoli
Broth
dilutionmetho
dMIC:62.5–1
00μg
/ml
(Patel
&Patel,2
017)
18 FARHADI ET AL.
flavonols against S. aureus strains, (Figure 10), (Woźnicka et al., 2013).
In addition, hydroxylation on the B and C rings also increases the anti-
microbial activity of these compounds. For example, comparison of
compounds with the same structure showed that kaempferol (55) with
a hydroxy group at C‐4′ had less activity than galangin (44; without
OH at C‐4′) against S. aureus (Echeverría et al., 2017).
The number of glycosylic group instead of the hydroxy group at
position 3 also plays an important role on antibacterial activity. For
example, among the compounds extracted from Maytenus buchananii,
quercetin‐3‐O‐[α‐L‐rhamnopyranosyl‐(1 → 6)‐β‐D glucopyranoside]
(9) with a disaccharide group at the same position was the better
inhibitor of S. aureus growth than amentoflavone‐7″,4‴‐dimethyl‐
ether (6) with monosaccharide group (quercetin‐3‐O‐β‐D‐
glucopyranoside; Tebou et al., 2017). Substitution that decrease
activity is methoxylation at position 3. For example, piliostigmol (with
OMe and Me groups at position 6 and 7 of A ring and OH at
position 3) was more active against S. aureus than 6‐C‐
methylquercetin‐3,3′,7‐trimethyl ether (163; with OMe at the C‐3
position; Babajide et al., 2008).
5.4 | Flavones
As it was mentioned in many studies have been conducted on antibac-
terial activity of flavones (Hung et al., 2008; Novak et al., 2012; Xiao
et al., 2011), possessing at least one hydroxy group in the ring A (espe-
cially at C‐7) is vital for antibacterial activity, and in another position
such as C‐5 and C‐6 can increase the activity (Figure 11; Wu et al.,
2013). Also, substitution of OH with OMe at C‐7 decrease the activity.
For instance, between 5,7‐dihydroxy‐flavone (11) with two OH at
positions 5 and 7 and 5‐hydroxy‐7‐methoxy‐flavone (10) with OMe
at position 7 and OH at position 5, compound 11 was more potent
against Ralstonia solanacearum (MIC: 25 and 300 μg/ml; Zhong et al.,
2012). Presence of the prenyl (C5) group at position 6 without cycliza-
tion of this substituent with A ring has also been reported to improve
antibacterial activity. As an example, Kuete et al. (2009) showed that
the antibacterial activity of artocarpesine (164) toward E. coli was
much higher than cycloatocarpesin (8; MIC: 39, 156 μg/ml).
6 | MECHANISM OF ANTIBACTERIALACTIVITY
The proposed antibacterial mechanisms of flavonoids are mainly as
follows: nucleic acid synthesis inhibition, alteration in cytoplasmic
membrane function, energy metabolism inhibition, reduction in cell
attachment and biofilm formation, inhibition of the porin on the cell
membrane, changing of the membrane permeability, attenuation of
the pathogenicity (Cushnie & Lamb, 2005a, 2005b; Cushnie & Lamb,
2011; Xie et al., 2015), cytoplasmic membrane damage (possibly by
generating hydrogen peroxide [Cushnie & Lamb, 2005a, 2005b]) with
flavonols (Cushnie & Lamb, 2005a, 2005b), flavan‐3‐ol, and flavanol
compounds (Tamba et al., 2007). It was shown that combination of
ceftazidime and apigenin damages cytoplasmic membrane of ceftazi-
dime‐resistant Enterobacter cloacae and causes subsequent leakage of
intracellular components (Eumkeb & Chukrathok, 2013). Inhibition of
FIGURE 6 Chemical structures of synthetic derivatives of flavonoids
FARHADI ET AL. 19
nucleic acid synthesis (through inhibition of topoisomerase) and
dihydrofolate reductase by flavan‐3‐ols and isoflavones. Decreasing
the energy metabolism with flavonols, flavan‐3‐ols, and flavones clas-
ses (Chinnam et al., 2010; Gradišar, Pristovšek, Plaper, & Jerala,
2007; Wang, Wang, & Xie, 2010). Suppression of cell wall synthesis
(caused by D‐alanine–D‐alanine ligase inhibition; Wu et al., 2008).
Sophoraflavanone B caused cell wall weakening and consequently
membrane damage had occurred and intracellular constituents leaked
from the cell (Mun et al., 2014). Inhibition of cell membrane synthesis
(caused by inhibition of FabG, FabI, FabZ, Rv0636, or KAS III; Jeong
et al., 2009; Li, Zhang, Du, Sun, & Tian, 2006; Zhang et al., 2008). Inhi-
bition of enzymes such as dihydrofolate reductase (Navarro‐Martínez
et al., 2005), listeriolysin O (Ruddock et al., 2011; virulence factor
of the intracellular pathogen L. monocytogenes; Kohda, Yanagawa, &
Shimamura, 2008; Shi & Czuprynski, 2009), and urease (secretion
from H. pylori at the low pH of the stomach; Xiao et al., 2007). Inhi-
bition of sortase (the enzymes that catalyze the assembly of surface
proteins at Gram‐positive bacteria; Maresso & Schneewind, 2008).
Inhibition of the quorum‐sensing (cell‐to‐cell communication system
in biofilm formation) signal receptors TraR and RhlR (Zeng et al.,
2008). In the new research findings, additional evidence has been
presented in support of each of the mechanisms. The antimicrobial
potential of two bioflavonoids was evaluated by scanning electron
microscopy (Biva, Ndi, Griesser, & Semple, 2016) against B. subtilis,
S. aureus, E. coli, and S. typhimurium. The result showed the bactericidal
effect of 5,7‐dihydroxy‐4,6,8‐trimethoxyflavone (13; Figure 12)
against E. coli and S. aureus, whereas 5,6‐dihydroxy‐4,7,8‐
trimethoxyflavone (14) was found to effectively kill B. subtilis by cell
lysis (Brahmachari et al., 2011). When screening natural products for
inhibition of β‐ketoacyl acyl carrier protein synthase (Chitsazian‐Yazdi
et al., 2015), Lee et al. (2011) found that the 3,6‐dihydroxyflavone (50)
was very effective. This compound inhibition activity against a
β‐ketoacyl acyl carrier protein synthase of multidrug‐resistant E. coli.
It was shown that compound 50 selectively inhibited β‐ketoacyl acyl
carrier protein synthase III and I (important for fatty acid synthesis in
bacteria).
FIGURE 6 Continued.
20 FARHADI ET AL.
A synthetic flavanone, 4‐chloro‐flavanone (128) has been
reported to inhibit efflux pump and reduce the growth ability of E. coli
with MIC value of 70 μg/ml (Fowler, Shah, Panepinto, Jacobs, &
Koffas, 2011).
In the study of antibacterial activity (against Gram‐positive and
Gram‐negative bacteria) by radioactive precursors, Dzoyem et al.
(2013) showed that DNA, RNA, and protein synthesis inhibited by
FIGURE 7 Structure–activity relationship of chalcones
three flavonoids were isolated from Dorstenia species. Flavonoids
responsible for this activity were 6,8‐diprenyleriodictyol (95),
isobavachalcone (110), and 4‐hydroxyonchocarpin (118).
It was shown that baicalein could remarkably reverse the cipro-
floxacin resistance of MRSA possibly by NorA efflux pump inhibitory
effect. Additionally, the inhibition of MRSA pyruvate kinase could lead
to a deficiency of ATP (Chan et al., 2011). A research team (Wu et al.,
2013) reported the MOA of five flavonoids against E. coli. These com-
pounds were effective via rigidifying the liposomal membrane. The
authors suggested that the molecular hydrophobicity (C log P) and
charges on the C atom at position 3 may play a role in the intercalation
of liposomal model membranes (Wu et al., 2013). He et al. (2014)
screened antimicrobial mechanism of flavonoids [kaempferol (55),
hesperetin (170)] for inhibitory activity against E. coli through the cell
membranes and liposomal model. They found that interaction
between the polar head‐group of the model membrane and the hydro-
phobic regions may damage E. coli membrane. In the other study,
Wang et al. (2014) carried out research on genistein (171) and
FIGURE 8 Structure–activity relationship offlavans
FIGURE 9 Structure–activity relationship offlavanols
FARHADI ET AL. 21
diosmetin (25) from Sophora moorcroftiana against S. aureus by efflux
assay. The results showed that genistein inhibited NorA efflux protein
of S. aureus. In another study, the mode of action of genistein on dif-
ferent bacterial cells was investigated and the results showed that cell
morphology of bacteria changed. Additionally, significant inhibition of
global synthesis of DNA and RNA was observed immediately after
addition of this compound to a bacterial culture (Ulanowska, Tkaczyk,
Konopa, & Wȩgrzyn, 2006). Twenty‐one synthetic fluoroquinolone‐
flavonoid hybrids were evaluated against drug‐resistant microorgan-
isms (including E. coli, B. subtilis, and S. aureus) by DNA gyrase and
efflux pump. Two compounds (172 and 173) could inhibit DNA gyrase
and efflux pump (Xiao et al., 2014). Flavonostilbenes (83) exhibit anti-
bacterial and antibiofilm formation activities against S. epidermidis with
MIC values of 3.1 to 12.5 μg/ml (Wan et al., 2015). It has also been
demonstrated by Wan et al. that the chalcone compounds [such as
ardisiaquinone (125)] were active against MRSA strains by inhibition
of bacterial efflux pumps (Omosa et al., 2016). In the dose–response
assay, kaempferol (55) at 31.25 μg/ml concentration was found to
be better efflux pump inhibitor by inhibiting NorA pump in S. aureus
(Randhawa, Hundal, Ahirrao, Jachak, & Nandanwar, 2016). In the
study of 2015, the combination of morin (45), rutin (49), and quercetin
(48) could release the potassium from the cytoplasmic membrane of
FIGURE 10 Structure–activity relationship of flavonols
testing bacteria (Amin et al., 2015). Evaluation of the MOA of flavo-
noid compounds from Piper species [174 and 2′,4′,4‐trihydroxy‐3,6′‐
dimethoxychalchone (121)] against Vibrio harveyi exhibited a strong
dose‐dependent inhibition of biofilm formation without effect on bac-
terial growth up to 500 μM (Martín‐Rodríguez et al., 2015). In the
study of three flavonoids [techtochrysin (30), negletein (31), and
quercitin‐3‐glucoside (65)] against foodborne pathogens, 90–95%
reduction in biofilms was observed (Rajendran et al., 2016). Synthe-
sized tricyclic flavonoid (153) at low concentration caused not only
the inhibition of bacterial growth (MIC: 0.24 μg/ml) but also killing
bacterial cells via cell membrane integrity and cell agglutination (Babii
et al., 2016). For investigating the development of new antibiotics, one
promising strategy is inhibition of type 2 fatty acid synthase pathway
(FAS II; essential for the synthesis of fatty acids). Jaceosidin (38; from
Artemisia californica) was evaluated against E. coli, and this compound
indicated complete inhibition of FabI activity at the concentration of
100 μM (Allison et al., 2017). In 2017, the enzyme assays of 20 C‐7
modified flavonoids for inhibition tyrosyl‐tRNA synthetase in Gram‐
positive and Gram‐negative organism revealed that (S)‐5‐hydroxy‐
40‐hydroxy‐7‐(2‐morpholino‐2‐oxoethoxy)‐2,3‐dihydroflavone (160)
FIGURE 11 Structure–activity relationship of flavones
FIGURE 12 Chemical structures offlavonoids derivatives
22 FARHADI ET AL.
exhibited better activity against Gram‐negative organism with IC50
lower than 1 mM (Xiao et al., 2017).
7 | CONCLUSION
Since 2005, many studies have been conducted on antibacterial activ-
ity of different classes of flavonoids, and many others will be added to
this list in the future. The main focus of previous studies was on
assessment of antibacterial activity of isolated flavonoids on different
bacteria strains specially MRSA and E. coli. Chalcones in some cases
showed stronger activities than other classes and some of them like
3‐Hydroxychalcone (120) exhibited approximately sixfold more activ-
ity than the reference drug azithromycin on H. influenza. The results
were obtained from antibacterial activity of flavonoids of the genus
Dorstenia showed that considering traditional usage of plants can be
helpful for finding active antibacterial flavonoids. Isobavachalcone
(110) from twigs of Dorstenia barteri showed fourfold lower MIC value
than the conventional drug gentamicin.
In addition, synthetic derivatization of flavonoids showed sub-
stantial increase in antibacterial activity of flavonoids. A pyrazoline
derivative of flavonoids (129) with heterocyclic furan ring was found
to be more active than the reference drug chloramphenicol against
S. typhimurium and E. coli. Sulfone and bisulfone chalcone synthetic
derivatives are other examples of synthetic derivatives that showed
higher activity than reference drugs that have been used in the mar-
ket. These findings and many others show that synthetic derivatiza-
tion of flavonoids is a promising approach for finding new antibiotics
in the future studies.
However, the main gap in this research area is the lack of clin-
ical trials. Some of the flavonoids have been clinically tested for
other ailments and showed minimum adverse effects. For instance,
quercetin has been used in many clinical trials (not for antibacterial
activity) and passed phase 1 clinical trials successfully. Quercetin
showed remarkable synergistic activity in combination with refer-
ence drugs and can be safely used for further studies in the future.
Many other flavonoids can also be added to the list for future
clinical studies.
ACKNOWLEDGMENT
This study was partially supported by the Mashhad University of Med-
ical Sciences.
FARHADI ET AL. 23
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
ORCID
Mehrdad Iranshahi http://orcid.org/0000-0002-3018-5750
Milad Iranshahy http://orcid.org/0000-0002-5339-6294
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How to cite this article: Farhadi F, Khameneh B, Iranshahi M,
Iranshahy M. Antibacterial activity of flavonoids and their
structure–activity relationship: An update review. Phytotherapy
Research. 2018;1–28. https://doi.org/10.1002/ptr.6208
