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Antibacterial Activities of Flavonoids: Structure-Activity Relationship and

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132 Current Medicinal Chemistry, 2015, 22, 132-149

Antibacterial Activities of Flavonoids: Structure-Activity Relationship and

Mechanism
Yixi Xie1, Weijie Yang1, Fen Tang1, Xiaoqing Chen1,2,*,# and Licheng Ren3,*
1
College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, China;
2
Collaborative Innovation Center of Resource-conserving & Environment-friendly Society and Ecological
Civilization, Central South University, Changsha, 410083, China; 3Department of Burns and Reconstruc-
tive Surgery, Xiangya Hospital, Central south University, Changsha, 410008, China

Abstract: Flavonoids are well known as antibacterial agents against a wide range of pathogenic microor-
ganism. With increasing prevalence of untreatable infections induced by antibiotic resistance bacteria, fla-
vonoids have attracted much interest because of the potential to be substitutes for antibiotics. In this re-
view, the structure-relationship of flavonoids as antibacterial agents is summarized, and the recent advancements on the
antibacterial mechanisms of flavonoids are also discussed. It is concluded that hydroxyls at special sites on the aromatic
rings of flavonoids improve the activity. However, the methylation of the active hydroxyl groups generally decreases the
activity. Besides, the lipopholicity of the ring A is vital for the activity of chalcones. The hydrophobic substituents such as
prenyl groups, alkylamino chains, alkyl chains, and nitrogen or oxygen containing heterocyclic moieties usually enhance
the activity for all the flavonoids. The proposed antibacterial mechanisms of flavonoids are as follows: inhibition of nu-
cleic acid synthesis, inhibition of cytoplasmic membrane function, inhibition of energy metabolism, inhibition of the at-
tachment and biofilm formation, inhibition of the porin on the cell membrane, alteration of the membrane permeability,
and attenuation of the pathogenicity.
Keywords: Antibacterial activity, flavonoids, mechanism, structure-relationship.
#
Author’s Profile: Xiaoqing Chen is a professor at Central South University, China. She obtained a Ph.D. in applied chemistry
at Central South University in 2003. Her major areas of research expertise and interest are including asymmetric synthesis,
chiral separation, separation of natural products; analytical nanotechnology; polyphenols.

1. INTRODUCTION
The emergence of drug-resistant bacteria has become the
major cause of failure in the treatment of infectious diseases
[1, 2]. It has been recently reported that 23,000 Americans
die of an untreatable bacterial infection due to antibiotic re-
sistance each year, and 25,000 deaths for EU per year [3].
Epidemiologic studies have revealed the elevating morbidity
and mortality rates of infectious diseases due to antibiotics
resistance [4-6]. The inefficacy of currently available antibi-
otics urges the searching for new type antibacterial agents
against the drug-resistant bacteria. Since the pharmaceutical
development has historically relied on natural products to
provide biological active compounds, screening for natural
antibacterial agents have been broadly studied, and even
become new leads for antibacterial drug discovery [7-9].
Currently, a wide range of phytochemicals have proven to be
potential antibacterial agents including terpenoids, essential
oils, alkoloids, lectins, polypeptides, phenolics, and poly-
phenols [10, 11]. Among these compounds, phenolics and
polypenols have attracted many interests of researchers for
their wide existence, low toxicity, and high activity against
drug-resistant bacteria such as methicillin-resistant Staphylo-
coccus aureus (MRSA) [12, 13].
*Address correspondence to these authors at the College of Chemistry and
Chemical Engineering, Central South University, Changsha 410083, P R
China; Tel: +86 (731) 8830833; E-mail: xqchen@mail.csu.edu.cn and De-
partment of Burns and Reconstruction Surgery, Xiangya Hospital, Central
south University, Changsha, 410008, P R China; Tel: +86 (731) 85295888;
Fax: +86(731)533525; E-mail: renlicheng@sina.com
Flavonoids are the primary class of polypehols with C6-
C3-C6 skeleton. There have been over 8000 known flavon-
oid molecules until now [14]. Most of them have shown
multiple biological activities such as anti-oxidation, anti-
inflammation, anticancer and cardiovascular protection [15].
Flavonoids can be divided into several subclasses depending
on their oxidative status and substituents. The skeletons of
six common flavonoid subclasses with antibacterial activity
are shown in Fig. (1). The antibacterial activity of flavonoids
can be exerted in three ways: directly kill the bacteria, syner-
gistically activate the antibiotics, and attenuate the bacterial
pathogenicity [16]. It is worth mentioning that the flavonoids
have shown inhibitory activity against the efflux pump of
MRSA [17], and also restrained the synthesis of peptidogly-
can and ribosome in the cells of amoxicillin-resistant Es-
cherichia coli (AREC) [18]. They have also shown inhibi-
tory activity against different kinds of β-lactamases produced
by bacteria which are the key enzymes that disable the com-
mon antibiotics [19-21]. The mechanisms for flavonoids as
antibacterial agents have been discussed in more detail by
Cushnie et al. [16, 22].
The antibacterial activity of flavonoids depends on the
structures, namely on the substitutions on the aromatic rings.
With the plant extract with antibacterial activities increas-
ingly being found, more and more flavonoids have proven to
be antibacterial agents, especially the ones with hydrophobic
substituents such as prenyl groups [23-26]. Some studies
have focused on the structure prerequisites for antibacterial
activity of flavonoids, but no reviews have been systemati-
cally documented the developments on the antibacterial

1875-533X/15 $58.00+.00 © 2015 Bentham Science Publishers

Antibacterial Activities of Flavonoids
B
O O
O
A C
A *
R
B OH
O O
Flavone, R=H
Flavonol, R=OH Isoflavone, * as " "
Dihydroisoflavone, * as "
O
* O
R
O O
Flavanone, R=H
Chalcone, * as " "
Flavanonol, or
Dihydrochalcone, * as "
(Dihydroflavonol), R=OH
Fig. (1). Structure skeletons of the major subclasses of flavonoids.
flavoniods. Besides, the antibacterial mechanism of flavon-
oids has also been continuously testified and renewed. Here
in, based on the previous reviews and the recent literatures,
the structure-activity relationship and the advancements in
understanding the mechanisms of flavonoids as antibacterial
agents have been reviewed.
2. ANTIBACTERIAL ACTIVITIES OF FLAVONOIDS
2.1. Flavone
Flavones have been widely investigated on their antibac-
terial activity. Sohn et al. [27], isolated two di-prenylated
flavones kuwanon C and morusin from medicinal plants, and
evaluated their antimicrobial activities using the broth micro
dilution methods. The former showed strong activities
against both gram negative bacteria (E. coli, S. typhimurium)
and gram positive bacteria (S. epidermis, S. aureus), while
the latter only showed limited activities against gram posi-
tive bacteria. Yin and coworkers [28] also isolated a mono-
prenylated flavone named corylifol C from the seeds of
Psoralea corylifolia, and found it was not effective to inhibit
the growth of Staphylococcus aureus and S. epidermidis in
vitro. These results indicate the importance of the degree of
prenylation for the antibacterial activity. The substitutive
prenyl group sometimes reacts with the adjective hydroxyl
group to form a heterocycle of six members, which probably
decrease the activity. For example, morusin has a C-3 prenyl
group and another C-8 prenyl group which forms a ring-
substituent with the hydroxyl group at C-7 position, and it
showed lower activity than kuwanon C (seen Fig. 2) [27].
Due to the planar structure of flavonoid skeleton, the geranyl
group at C-3 position of C ring is apt to crosslink with the
hydroxyl group at C-3' position of C ring, a case in the point
is the prenylated flavone (PF) isolated from a hybid of Arto-
carpus plants which showed strong antibacterial activity
against A. baumannii with MIC value of 50 µg mL -1 [29]. In
addition to alkenyl substituted flavones, acyllated flavones
also have been evaluated on their antibacterial activities.
Babu and coworkers investigated the antibacterial activities
of 7-O-acyl derivatives of Oroxylin A and found the intro-
duction of acyl group at the C-7 position of Oroxylin A sig-
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 133
O
CH
O
Flavan-3-ols (catechin) Aorune
"
O
O
OH
O O
OH
R O
" Proanthocyanidin Bioflavonoid
nificantly enhanced the antibacterial activity [30]. When the
acyl groups contained long chain alkyls or phenyls (Fig. 2),
the Oroxylin A derivatives even showed stronger antibacte-
rial activities than the other derivatives. More over, nitrogen-
containing flavone analogs have been increasingly prepared
and studied on their antibacterial potentials. Babu et al. [31],
synthesized a series of chrysin derivatives in which chrysin
ring system linked to the alkyl amines by different spacers at
C-7 position, and evaluated their antibacterial activities. All
the derivatives showed higher antibacterial effects than chry-
sin,and the ones with morpholine or N,N-dimethyl amine
substituents even inhibited the growth of the tested gram
positive bacteria with the same minimum inhibitory concen-
trations (MIC) as streptomycin. Similar results were obtained
in study by Zhu’s group which showed the compounds with
N-heterocyclic moieties at C-7 position of chrysin had a
much higher activity than other species [32]. Zhu’s group
also found that morpholine, benzylamine and their derivative
subsituents were favorable for the antibacterial activities of a
series of luteolin analogs [33]. Another study by Liu and
coworkers demonstrated that the modifications of apigenin at
8-C position by nitrogen-containing cyclic or aliphatic chain
substituents enhanced the antibacterial activities [34]. Nota-
ble among these apigenin analogs was the one with mor-
pholine substituent which had potent antibacterial activities
similar to those of tetracycline against gram-positive strains
S. aureus and B. subtilis.
2.2. Flavanone
Unlike flavone, flavanone has the saturated C3-C4 bond
of C ring which makes the nuclear skeleton of flavanone
non-planar (Fig. 3). Flavanones such as nobiletin, tangeretin
and liquiritigenin have been reported as the responsible ac-
tive agents for the antibacterial activity of some medicinal
plants [35-37]. The subsitutents significantly influence the
antibacterial activity of flavanones. Celiz et al., found the
attachment of a saturated aliphatic chain with 10-12 carbon
atoms to the sugar attached to the A ring of narigenin greatly
increased the anti-listerial and anti-staphylococcal activity
[38]. The mono or poly methoxylation of flavanone,
134 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.

OH
HO OH
OH OH OCH3
HO
O O
HO O HO H3CO O
OH O
O
OH O
O OH O
OH O

Corylifol C
Kuwanon C Morusin PF
OH
CH2R
ROCO O HO O R O N
( )n O

H3CO
N,N-Dimethyl amine
OH O OH O
OH O
R=Morpholinyl; R=-N(C2H5)2
R=-NH-C2H5 R=:
1. R=Ph H CN N N O N

2. R=-(3,4,5-trimethoxy)phenyl 3
R: N
3.R=(CH2)16CH3
NH
N-methyl piperazinyl Piperidinyl Morpholinyl
Pyrryl Cyclohexane amine
7-O-acyl derivatives of Oroxylin
R1 Apigenin analogs 7-O-alkylamino derivatives of chrysin
R4
Fig. (2). Chemical structures of hydrocarbonyl substituted flavones.
O
*
COOR
6'
3' C:
6 R2 A: B: OH
HO
HO
prenyl isoprenyl geranyl OH
HO O O
R
Antibacterial Activities of Flavonoids Current Medicinal Chemistry, 2015, Vol. 22, No. 1 135
3
D: E:

OH O
R5 O
lavandulyl lavandulyl in the limonene form
alkyl prunin esters:R=(CH2) 1-16CH3
F:
farnesyl

Glabranine : R1=R2=R3=H,R5=OH, * = OCH3

8-Prenylnaringenin : R1=R3=H,
R2=R5=OH RO
a : R1=R2=R5=OH, R3=B, R4=A, * = HO OH OH
b : R1=OCH3, R2=R5=OH, R3=B, R4=A, * =
O
c : R1=OCH3, R2=R5=OH, R3=B, R4=A O O
Leachianone G : R1=R2=R5=OH,R3=H,R4=B OH O
Kushenol R: R1=OH, R2=R3=R5=H,R4=D,*
=
Sophoraflavanone G :R1=R2=R5=OH,R3=H,R4=C
Kenusanone D :R1=R5=OH,R3=H,R2=OCH3,R4=A
R=CH3 or
Exiguaflavanone D:R1=R5=OH,R3=H,R2=OCH3,R4=D,6=A OH O
propolin I:R1=R3=R4=H, R5=R2=3'=OH,6=F -CH2(CH2)1~14CH3

Fig. (3). Structures of antibacterial flavanones.

however, hardly increased the antibacterial activity [39].

Manner et al., reported that 8-prenylnaringenin and another agents. Tsuchiya et al., investigated the activity of a series of
geranyl and lavandulyl flavanones against MRSA and found
8-prenylflavanone glabranine were highly active in inhibit-
all these flavanones were active anti-MRSA agents. Besides,
ing the formation of S. aureus biofilms [40]. The flavanones
sophoraflavanone G with 6-lavandulyl group showed much
substituted by prenyl groups at 6-C or 8-C positions both
higher activity than leachianone G with 6-prenyl group, indi-
showed activity against S. aureus [41]. The prenylflavanones
cating lavandulyl group was a more efficient moiety for en-
even showed great activity against the biotic-resistant bacte-
hancing antibacterial activity. In addition, exiguaflavanone D
ria, for ex., three prenyl substituted flavanones (Fig. 3, a,b,c)
with two subsitutents at 6-C and 8-C positions exhibited
isolated from the roots of Dalea scandens all exhibited sig-
higher activity than kenusanone D with only single 6-C sub-
nificant activity against both methicillin-susceptible and me-
situent [43]. As sum in Table 2B, the geranyl and lavandulyl
thicillin-resistant S. aureus [42]. Table 3 summarized the
antibacterial activities of prenyl flavanones reported in litera- substituents were mostly appeared at C-6 and C-8 positions
of A ring, and also at 3'-C position of B ring in some cases.
tures. Besides of prenylflavanones, both geranyl and lavan-
For example, kenusanone A with and myrsininone B were
dulyl flavanones have also proven to be active antibacterial
respectively substituted by geranyl group and lavandulyl
136 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.

group, which both showed potent antibacterial activities [43,

44]. More over,the substitutive group sometimes reacts
with the adjective hydroxyl group to form a heterocycle of
six member, for example, lupinifolin has a C-8 prenyl group
and another C-6 prenyl group which forms a ring-subsituent
with the hydroxyl group at C-7 position [45]. Similar hetero-
cyclic structures also appear in the C-6 geranyl groups
of both mimulone C nad mimulone D which had moderate
ac- tivity against S. aureus and some MRSA strains [46].
In addition to alkenyl substituted flavones, alkylated fla-
vones also have been evaluated on their antibacterial activi-
ties. Zhang and coworkers investigated the antibacterial ac-
tivities of 7-alkoxyhesperetin derivatives and found the anti-
bacterial effects increased with the elongating hydrocarbon
chains substituted for H at C-7 position of hesperetin [47].
When substituted by alkyls with 8-12 carbon atoms, the hes-
peritin derivatives even showed stronger antibacterial activi-
ties against gram-positive bacteria (B. subtilis and S. aureus)
than the positive control streptomycin sulfate in vitro.
2.3. Flavonol and Dihydroflavonol
Compared with flavone, flavonol has an additional hy-
droxyl group at C-3 position, and when the C3-C4 double
bound is saturated, it turns into dihydroflavonol. Flavonols
have been reported to be active agents against both gram-
negative and gram-positive microorganisms, but the fla-
vonols with only hydroxyl or methoxyl substitutions gener-
ally show activity that is rather weaker than common antibi-
otics [48-50]. For example, kaempferol showed activity
against S. aureus and E. coli, and the MIC values was re-
spectively 63 and 16 µg mL -1, while those values of gen-
tamicin (antibiotic) was only 0.2 and 0.8 µg mL-1, corre-
spondingly [51]. However, hydrocarbonyl substitutions have
significantly enhanced the antibacterial activity of flavanols
and dihydroflavonols. Prenyl group is the most common
subsitutent for flavonol derivates. As tested by Sohn et al.,
the 6,5'-diprenyl substituted flavanol papyriflavonol A ex-
hibited the most potent antibacterial activity among the 18
prenylated flavonoids isolated from several medicinal plants,
and another dihydroflavanol kenusanone C with 6-geranyl
and 8-prenyl substitutions also showed potent activity [27].
In addition, 3'-O-methyldiplacol with 6-geranyl group has
shown low MIC values of 2~4 µg mL-1 against six gram-
positive bacteria [52], which has been verified by another
study that showed the MIC values of 4~8 µg mL -1 for the
same dihydroflavonol against S. aureus and other four
MRSA strains [46]. Lavandulyl group is another prenyl
group which has appeared in kushenol X with MIC values of
10 µg mL-1 against both S. aureus and B. subtilis [53]. The
prenyl group sometimes reacts with the adjacent hydroxyl
group to form a heterocyclic substituent which seems to be
favorable configuration for antibacterial activity. This was
supported by the result that lanneaflavonol and dihydrolan-
neaflavonol both showed great activity against S. aureus with
MIC values (about 2.0 µg mL-1) close to ampicillin (about
1.5 µg mL-1) [54]. More over, Sasaki et al. investigated sev-
eral prenylated dihydroflavanols on their anti MRSA activi-
ties, it was found that MRSA strains were sensitive to most
of the dihydroflavanols, and some flavonols with heterocyc-
lic substitutions on ring A even showed higher activity than
oxacillin [55]. According to the data summed in Table 3, the
dihydroflavanols generally exhibits better activity than
flavanols, and the compounds with double prenyl substitu-
ents are more active than the corresponding single substi-
tuted ones. The structures of the referred compounds are
shown in (Fig. 4).
2.4. Flavanols
Flavanols have been reported to exhibit several health
beneficial effects by acting as antioxidant, anticancer, cardio-
preventive, neuro-protective, antimicrobial, and anti-viral
agents [56]. Catechin (flavan-3ol) and its derivates are the
mostly studied monomeric falvanols with broad biological
activity [57]. Catechins are plentiful in tea leaves and have
been regarded as the ingredients responsible for the antimi-
crobial activity of tea extracts [58, 59]. The antimicrobial

Flavanols đã được cho rằng là có một số tác dụng có lợi cho sức khỏe
bằng cách hoạt động như chất chống oxy hóa, chống ung thư, phòng
ngừa tim mạch, bảo vệ thần kinh, kháng khuẩn và chống vi-rút [56].
Catechin (flavan-3-ol) và các dẫn xuất của nó là các flavanol đơn phân
chủ yếu được nghiên cứu với hoạt tính sinh học rộng [57]. Catechin
được tìm thấy nhiều trong lá trà và được coi là thành phần chính đóng
vai trò kháng khuẩn của chiết xuất trà [58, 59]. Chất kháng khuẩn

*Flavanol: là một nhóm hợp chất gồm nhiều nhóm nhỏ khác nhau như:
flavan-3-ol, flavan-4-ol, flavan-3,4-diol. Nhưng do nhóm hợp chất
flavan-3-ol thường xuất hiện trong tự nhiên nhiều hơn cả nên thông
thường khi nói đến flavanol người ta thường nghĩ vè flavan-3-ol. Nổi
bật nhất trong các flavan-3-ol là catechin và các đồng phân của nó.
Antibacterial Activities of Flavonoids Current Medicinal Chemistry, 2015, Vol. 22, No. 1 137

OH
HO OH

HO OH
HO O
O O OCH3
HO O
OR1
O OH
O OH
OH O OR2
OH O
OH O OH
A:R =R =a
1 2

Papyriflavonol A B:R1=a, R2= c

Stenopalustroside- Lanneaflavonol
C:R1=a, R2= b
OH
D:R1=b, R2= a

HO OR4
R2
H H O OCH3
HO O a: HO C C C
O O
R3 H O OH
R1 OH
b: HO C C C
OH O OH
H
c:
138 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.
Kenusanone C:R1= geranyl, R2= prenyl, H3CO
OH O
H O
R3=OH,R4=CH3
Kushenol X :R1=R3=R4=H,R2= lavandulyl HO C C C Dihydrolanneaflavonol
H
Fig. (4). Antibacterial flavonols and dihydroflavonols.
Antibacterial Activities of Flavonoids
Các hoạt động kháng khuẩn của những loại trà khác nhau và
những polyphenol của chúng (flavanol) đã được Bansal cùng
đồng nghiệp (trong bài báo của ông) giới thiệu gần đây. ].
Bài viết đã kết luận rằng hầu hết các catechin và theaflavin đều
được chứng minh có khả năng chống lại các vi khuẩn gây bệnh
phổ biến như S. aureus, MRSA, E. coli và H. Pylori. Việc thêm
vào một chuỗi bên hydrophobic alkyl có thể làm tăng hoạt tính
kháng vi khuẩn của EGCG (Epigallocatechin gallate) do tăng
cường khả năng thẩm thấu qua màng tế bào.
Tuy nhiên có một dẫn xuất của catechin được phân lập từ
Loropetalum chinense, có tên là loropetaliside A với một
nhóm thay thế 1-(3,4-dihydroxyphenyl) 3-methoxy-3-oxopropyl
ở vị trí C-8, không thể hiện hoạt tính chống lại các vi khuẩn
được kiểm tra. Điều này ngụ ý rằng, trong thí nghiệm,
loropetaliside A không có khả năng ức chế sự phát triển của các
vi khuẩn được thử nghiệm.
Trong một nghiên cứu gần đây [62], đã quan sát thấy hiệu ứng
ức chế tăng trưởng một phần giữa catechin và axit gallic đối với
H. pylori. Trong một nghiên cứu khác của Betts và đồng nghiệp
[63], cũng quan sát thấy sự tương tác cộng hưởng đáng kể giữa
theaflavin và epicatechin đối với các chủng lọc lâm sàng của S.
maltophilia và A. baumannii.
activities of different types of tea and their polyphenols have
been recently reviewed by Bansal et al. [60]. It was con-
cluded that most of catechins and theaflavins showed anti-
bacterial activity against the common pathogenic bacteria
such as S. aureus, MRSA, E. coli, and H. pylori. It was also
suggested that the additional hydrophobic alkyl side chain
enhanced the antibacterial activity of EGCG because of in-
creased membrane-permeability. However, a catechin de-
rivate isolated from Loropetalum chinense, named loropetal-
iside A with a 1-(3,4-dihydroxyphenyl) 3-methoxy-3-
oxopropyl substitutent at C-8 position showed no activity
against the tested bacteria [61]. Besides, a partially additive
growth inhibitory effect between catechin and gallic acid
against H. pylori was observed in the recent study [62]. The
significant synergy between theaflavin and epicatechin
against clinical isolates of S. maltophilia and A. baumannii
was also observed in another study by Betts and coworkers
[63].
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 139
Proanthocyanidins are oligomers and polymers of flavans
that are abundantly existed in the grape seed and berry fruits
[64-66]. They have been reported to be effective antibacterial
agents against both sensitive and multi-drug resistant strains
[67, 68]. Proanthoxyanidins are divided into two types ac-
cording to the linkage between the flavans: type A refers to
those where constituent flavanyl moieties are linked via only
one bond, while type B posses an second ether linkage to C
(2) of the terminal flavanyl unit (Fig. 5). Karioti et al. iso-
Proanthocyanidins là những oligomer và polymer của flavans,
tồn tại phong phú trong hạt nho và các loại quả mọng [64-66].
Chúng đã được công bố là các chất kháng vi khuẩn hiệu quả đối
với cả các chủng nhạy cảm và chống lại kháng sinh đa kháng
[67, 68].
Proanthocyanidins được chia thành hai loại tùy theo mối liên
kết giữa các flavans:
- Loại A ám chỉ những loại mà các đơn vị flavanyl thành
phần được liên kết thông qua chỉ một liên kết
- Loại B sở hữu một liên kết thứ hai qua C (2) của đơn vị
flavanyl cuối cùng (Hình 5).
Karioti và cộng sự đã phân lập một loại proanthocyanidin loại A
((+)-Epigallocatechin-(2β→O→7,4β→8)-(+)-catechin, EPA)
cùng với một số proanthocyanidins loại B như procyanidin B3
(PB3) và epicgallocatechin-(4β-8)-catechin (PEC) từ lá cây
Quercus ilex, và đã chứng minh rằng EPA là một chất kháng vi
khuẩn hiệu quả đối với cả vi khuẩn gram âm và gram dương với
giá trị MIC từ 0,08 đến 0,17 µmol mL-1 và giá trị MBC từ 0,17
đến 0,17 µmol mL-1. PB3 và PEC cũng đều có hoạt tính kháng
vi khuẩn mặc dù yếu hơn EPA [69].
Ngoài ra, đã được báo cáo rằng procyanidin B2 có hoạt động
trung bình chống lại B. cereus với giá trị MIC là 39,1 µg mL-1,
mặc dù hoạt động chống lại các vi khuẩn gây bệnh khác là khá
hạn chế [70].
Hoạt động kháng vi khuẩn hạn chế như vậy cũng đã được quan
sát đối với procyanidin A2 đối với B. subtilis [71]. So sánh với
các dimers, các trimmers flavans có vẻ có hoạt động kháng vi
khuẩn cao hơn một chút, và các flavanols oligomeric thường có
hoạt động cao hơn so với các flavanols đơn [71, 72]. Hoạt động
kháng vi khuẩn của flavanols được thay thế hydrocarbonyl chưa
được nghiên cứu đầy đủ, nhưng sự acyl hoá vòng tròn trên các
vòng A của catechin và procyanidin B2 đã được báo cáo là
giảm hoạt động của chúng đối với S. aureus [73]. Nói chung,
hoạt động kháng vi khuẩn của procyanidins polymer chỉ có mức
vừa phải so với các loại kháng sinh, nhưng ưu điểm thực sự của
chúng trong việc chống lại vi khuẩn có thể nằm ở việc chúng ức
chế β-lactamase để giảm sự ổn định của màng tế bào vi khuẩn
và do đó giảm giá trị MIC của các kháng sinh đối với vi khuẩn
kháng thuốc như MRSA [74]
 140 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.
A2 against B. subtilis [71]. Compared with dimmers, the flavans
lated a type A proanthocyanidin ( (+)-Epigallocatechin- trimmers seem to have a little higher antibacterial activity,
(2β→O→7,4β→8)-(+)-catechin, EPA) along with some type and the oligomeric flavanols generally showed higher
B proanthocyanidins such as procyanidin B3 (PB3) and activity than the monomeric ones [71, 72]. The
epicgallocatechin-(4β-8)-catechin (PEC) from Quercus ilex antibacterial activlity of hydrocarbonyl substituted flavanols
leaves, and demonstrated that EPA was an effective antibac- has not been fully stud- ied, but the annular acylations on the A
terial agent against both gram-negative and positive bacteria rings of catechin and procyanidin B2 have been reported to
with the MIC values of 0.08~0.17 µmol mL -1 and MBC val- decrease their activity against S. aureus [73]. In general, the
ues of 0.17~0.17µ mol mL-1, PB3 and PEC both showed antibacterial activity of polymeric procyanidins are only
antibacterial activities though weaker than EPA [69]. In moderate compared with the antibiotics, but their real
ad- dition, it has been reported that procyanidin B2 merits for anti-bacteria may lie in that they suppress β-
showed moderate activity against B. cereus with MIC lactamase to decrease the stability of bacterial cell membrane
value of 39.1 µg mL-1,although the activity against other and consequently low the MIC of antibiotics for drug-
panthogenic bacteria was quite limited [70]. Such limited resistant bacteria such as MRSA [74].
antibacterial activity has also been observed for procyanidin

OH
OH R1
OH O
OH OH
HO OH
O
HO O 2 O 2 HO O
R1 R1 OH
OH
4 O 4 O R2
OH OH HO
7 7 R3 OH
OH OH OH
8 8
(+)-Catechin(C): R1=R2=H, R3=OH A:gallate
O OH O OH
(+)-Catechin-3-gallate(CG): R1=R2=H,R3=A
HO HO OH
(-)-Epicatechin(EC): R1=R3=H, R2=OH
* (-)-Epicatechin-3-gallate(ECG): R1=R3=H, R2=A
OH OH
HO HO (-)-Epigallocatechin(EGC): R1=R2=OH, R3=H
O OH (-)-Epigallocatechin-3-gallate(EGCG): R1=OH, R3=H,R2=A
EPA: R1=OH,* = (+)-Gallocatechin(GC): R1=R3=OH, R2=H
HO
ProcyanidinA2: * = (+)-Gallocatechin-3-gallate(GCG): R1=OH, R2=H,R3=A
ProcyanidinA1:* = OH OH
HO
OR2 OH
Cinnamtannin B-1 Theaflavins:
OH OH OH T F1: R1=R2=H
HO O
OH T F2A: R1=H,R2=galloyl
OH OH
2
OH T F2B: R1=galloyl,R2=H
HO O
R1 HO
8
O HO O
TF3: R1=R2=galloyl
4 HO R5 OH
7 2
O A 3
7 OH
OH 4 OR1
O R3
OH 8 R2 R4 O
OH
OH R1 OH
O O HO
OH
HO
ProcyanidinB1: R1=(b-8)-(+)-catechin, R2=R3=R5=H,R4=OH
ProcyanidinB2: R1=(b-8)-(-)-epicatechin, R2=R3=R5=H,R4=OH 7-O 8
OH OH
HO ProcyanidinB3: R1=H,R2=(a-8)-(+)-catechin,R3 =OH,R4=R5=H Annular acyl
ProcyanidinB4: R1=H,R2=(a-8)-(-)-epicatechin,R3 =OH,R4=R5=H
Flavanol trimer:ixoratannin A-2 Epicgallocatechin-(4b-8)-catechin: R1=(b-8)-(-)-epicatechin, R2=R3=H,R4=R5=OH
Epicatechin-(4b-8)-gallocatechin: R1=(b-8)-(+)-gallocatechin, R2=R3=H,R4=R5=OH
Fig. (5). Structures of antibacterial flavanols.
Antibacterial Activities of Flavonoids
2.5. Chalcone
Chalcones, extensively existed in edible plants, are usu-
ally regarded as the open-chain flavonoids, in which the two
aromatic rings are linked by a three-carbon a,β-unsaturated
carbonyl system [75]. They have exhibited various biological
activities and been demonstrated to be the compounds re-
sponsible for the antibacterial effects of some medicinal
plants [76-78]. Nowakowska has summed the anti-infective
activity of synthetic and naturally occurring chalcones, and
discussed the structure requirements of effective antibacterial
chalcones. It has been suggested that hydroxyl groups espe-
cially the one at 4' position are likely to induce and enhance
the activity, while the methoxyl group tends to reduce or
eliminate the activity, and that the lipophilicity of ring A
substituents plays important role in modulating the activity
[79]. In the more recent review by Sahu, the necessary of
hydroxyl group at 4 position and the importance of lipophilic
substituents such as prenyl and hexyl groups in the molecular
structure were inferred, and the presentation of electron-
attracting groups was also regarded as the positive factor for
antibacterial activity [80]. Based on the above two reviews,
the newest literatures were discussed here to make an update.
At first, it has been demonstrated that 2',4'-
dihydroxychalcone isolated from Muntingia calabura L.
leaves showed antibacterial activity against methicillin-
sensitive S. aureus (MSSA) and MRSA with MIC values of
50 and 100 mg mL-1, respectively [77]. The result may tes-
tify the important role of hydroxyl group at 4' position.
However, in another study by Tran and coworkers, a total of
30 chalcone analogues was synthesized and screened for
their in vitro antibacterial activity against MSSA and MRSA,
and only 4 chalcones showed activity [81]. Analyzing the
structure-activity relationships of the chalcons, it is interest-
ing to see that chalcones with hydroxyl group at 2 or 4 posi-
tions at ring B show antibacterial activity, while the 2'-
hydroxyl group at ring A actually is not necessary for the
5 OH
4
B B
HO 5' 3 HO
b 2
A 2
a a
3'
OH O OH
2',4'-dihydroxychalcone
HO OH
Ar Ar
O O
Ar: 2-Furyl
Ar O O Ar
O O
Ar: 4-Chlorophenyl
Active bischalcone derivatives
Fig. (6). Structures of antibacterial chalcones.
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 141
activity. Nevertheless, the methoxylation still shows to
eliminate the activity. Besides, with 4' and 4 dihydroxyl
groups and a substituent of cinnamoyl ester derivate,
gemichalcone A has been found to be inactive for the activ-
ity agaisnt both A. baumannii and E. coli[29]. In addition to
the alterations on the substitution pattern of the aromatic
rings, some heterocyclic chalcone analogues were synthe-
sized to evaluate their antibacterial activity against MSSA
and MRSA. According to the results, it is indicated that re-
placement of aromatic ring B by heterocyclic ring containing
nitrogen, oxygen, or sulfur atoms dose not significantly en-
hance the antibacterial activity [82]. More over, some
bischalcone derivatives have also been synthesized and in-
vestigated on their activity against E. coli, P. aeruginosa,
and C. albicans. The structure-activity relationship revealed
that the compounds having free hydroxyls were more active
than those of the compounds having methoxy groups, and
the presence of electron withdrawing groups like chloro in-
creased the activity [83]. For dihydrochalcones, it has been
suggested before that reduction of the double bond exposed
negative effect on the activity [84]. The recent studies have
showed that both the C-benzylated dihydrochalcone and the
dihydrochalcone dimer were found to be inactive for antibac-
terial activity against M. tuberculosis [23]. The structures of
the referred antibacterial chalcones are shown in Fig. (6).
2.6. Aurone
Aurones are naturally existed in plants and responsible
for the bright yellow color of some important ornamental
flowers [85]. Besides the roles as pigments, aurones exhibit
various health beneficial characters such as antiviral, anti-
fungal, anticancer and antidiabetic activities [86, 87].
Aurones have two types of configurations (Z/E) due to the
double bond geometry (Fig. 7). Ferreira et al. isolated a hep-
tasubstituted (E)-aurone glucoside (HAG) from Gomphrena
agrestis and found it was active against 5 strains among 22
OCH3
B
b HO R1
A b
A
R a
R2
O O
OH O
R= O
HO
OCH3 R1=OH
R2=
Gemichalcone A OH
C-benzylated dihydrochalcone
O OH
N B
R1=OCH3
R R2=
O
HO OH
O
H3CO
S
Heterocyclic chalcone analogues Dihydrochalcone dimer
142 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.

R1 R2

R2 HO H
R3
O
O
R4
R3 R1
H
OH O
O R5
Z E
1. R1= R2= R3= OCH3
HAG: R2= R5=OH, R2= R3=OCH3,
2. R1= R3= H, R2= R =gulcopranosyl Dunaurone: R = R =H, R =
4 1 2 3
N(CH3)2 R5=OH, R4=rutinosyl Dunaurone alycone: R1=
3. R1= H, R2=R3= OH
R2=H, R3= R5=R4=OH
Fig. (7). Structures of antibacterial aurones.

tested bacteria [88]. Erazo et al., isolated dunaurone and its

aglycone (E-aurones) from Dunalia spinosa Dammer and
found both of them were weak antibactrail agents [89]. In
addition, Venkateswarlu et al. prepared a series of Z and E
aurones and evaluated their antimicrobial activity using agar-
cup plate diffusion method [87]. As they found, Z-aurones
exhibited potent activity against gram-positive organisms,
whereas the corresponding E-isomers exhibit no activity
even with high dosage, indicating the importance of Z-
configuration for the antibacterial activity of aurones. More
over, the aurone with dimethylamine group at the 4' position
showed weaker activity than those with hydroxyl or
methoxyl groups.
2.7. Isoflavanoids
Isoflavonoids are structurally characterized by a 3-
phenylchromen-4-one backbone where the phenolic B ring is
attached to the 3-C of ring C (Fig. 8). According to the struc-
tural pattern of ring C, they are classified into several sub-
classes such as isoflavone, isoflavanone, isoflavan, and
pterocarpan. Isoflavonoids are abundantly existed in pea
family plants and enter into human diet through soymilk and
soybean derivative foods. They are biological active com-
pounds such as phytoestrogens, inflammation inhibitors, and
antibacterial agents [90-93]. The structure prerequisites of
isoflavones as antibacterial agents have been discussed in a
mini review by Mukne et al., it has been concluded that the
presentation of prenyl groups, hydroxyl groups, and aryl
subsituions is very important for the activity, while methoxy-
lation of the hydroxyl group and cyclization between hy-
droxyl and prenyl group tend to decrease the activity [94].
For example, lupalbigenin substituted by 6,3'-diprenyls has
been demonstrated to be the most potent antibacterial agents
against S. aureus (MIC, 4 µg mL-1) and MRSA SK1 (MIC, 4
µg mL-1) . Among the 17 isoflavone derivatives isolated
from Derris scandens Benth [95]. In addition, 6,8-
diprenylation of genestein gives it strong activity against the
oral gram-positive bacterium S. mutans with a MIC value of
4 µg mL-1, while gancaonin G derived from genestein with
6-prenylation and methylation of 7-OH only shows moderate
activity against S. mutans (MIC,128 µg mL-1) [96]. More
over, cyclization between 4'-OCH3 and 5' prenyl group dra-
matically decreases the activity of erylatissin A against S.
aureus and B. subtilis, of which the minimum inhibitory
dosage enhances from 0.1 µg to 1 µg in a test using TLC
bioautographic technique [97].
Compared with isoflavones, isoflavanones have shown
moderate antibacterial activity, for example, platy-
isoflavanone A(S) isolated from Platycelphium voense has
exhibited activity against M. tuberculosis with MIC of 23.7
mmol L-1 in the microplate alamar blue assay [98]. Besides,
glabridin, an isoflavan, has showed potent activity against

R3 HO O HO O HO O
R1O O OH OH
OH OH
A C OH
R4
R2 OH O
B OH O OH O
OCH 3 OCH3
OH O OCH3
OH

Genistein derivates:
Lupalbigenin:R1=R3=H, R2=R4=prenyl
Gancaonin G:R1=CH3, R2=prenyl, R3=R4=H
6,8-diprenylgenistein:R1=R4=H, R2=R3=prenyl Erylatissin A Erythrabissin-1 Erystagallin A
HO O
HO O HO O
OCH3
OH HO O
O
OH O OH
O OH O
OCH3
O
OH

Erylatissin B Platyisofavanone A Eryvarins J Erythrabyssin II

Fig. (8). Antibacterial isoflavonoids and pterocarpans.

Antibacterial Activities of Flavonoids Current Medicinal Chemistry, 2015, Vol. 22, No. 1 143

Gram-positive strains such as S. aureus and S. epidermidis

(MIC: 3.9~7.5 µg mL-1), but weak activity against gram-
negative strains such as S. typhi and E. coli (MIC: 125~250
µg mL-1) [99].
Pterocarpan is regarded as derivates of isoflavonoids
formed by coupling the B ring to the 4-one position of
isoflavanons. The prenylated pterocarpans have shown anti-
bacterial activity, and it is noteworthy that the double preny-
lations are more favorable for the activity. For example,
erythrabissin-I with single prenyl group shows potent activ-
ity against MRSA strains (MIC, 6.25~12.5 µg mL-1), and
the double prenylated erystagallin A shows greater activity
than erythrabissin-I (MIC, 0.78~3.13µg mL-1) [100]. Be-
sides, erythrabyssin II with two prenyl groups at separate
rings has shown effective activity against MRSA strains
(MIC, 0.78~1.56µg mL-1), while eryvarin J with two prenyl
groups both at the A ring has been demonstrated to be inac-
tive to MRSA [100, 101].
2.8. Bioflavonoids
Bioflavonoid, as the name suggests, refers to the flavon-
oid consisting of two monomeric subunits. The linkage sites
of the flavonoid subunits are either on the backbone or on the
subsituents of flavonoid units (Fig. 9). Bioflavonoids are
widely distributed in plant derived foods and beverages and
have been regarded as health beneficial ingredients [102,
103]. Mbukwa et al., investigated the antibacterial activity of
5,7,3',5'',7'',4'''-hexahydroxy (4'-O-3''')-biflavone using the
bioautographic agar overlay assay [104]. It was demon-
strated that the bioflavone was less sensitive to gram-positive
and gram-negative bacterial strains compared with its
subunit luteolin. In addition, being a lavandulyl substituted
flavanone, remangiflavanones A showed potent activity
against S. aureus S. epidermidis, and Enterococcus sp., how-
ever, remangiflavanones C consisting of two remangi-
flavanones A subunits linked together by a methylene group
was totally inactive against the above bacteria [105]. These
results seem to suggest that formation of dimmers between
flavonoids reduces the antibacterial activity.
3. STRUCTURE-ACTIVITY RELATIONSHIP
The structure-activity relationships for flavonoids as an-
tibacterial agents have been discussed in several previous
reviews [16, 22, 79, 80, 106]. Based on them, a brief sum-
mary on the structural requirements of flavonoids as antibac-
terial agents was draw before the discussion: Flavone: O-acl
or O-alkylamino chain at C-7. Flavanone: 2',4' or 2',6'-
dihydroxylation of the B ring ; 5,7-dihydroxylation of the A
ring; 6 or 8 position with a long chain aliphatic group such as
lavandulyl or geranyl. Isoflavanone: 5-hydroxyl group plus
one, two or three additional hydroxyl groups at the 7, 2', 4'
positions. Chalcones: 2' or 4' hydroxylation; lipopholicity of
ring A. Flavan-3-ol class: substitution with C8 and C10
chains. Here in, an update on the structure-activity relation-
ships was made.
The recent studies (2011~2014) have exhibited that 5,7-
dihydroxyl substitution pattern is an indictor for antibacterial
activity for flavones, and additional hydroxyl group at 4'
position greatly increases the activity, while the methylation
of these hydroxyl groups reduces the activity with different
degrees; besides, addition of 3-hydroxyl group seems to en-
hance the activity, indicating flavonols may be better anti-
bacterial agents than flavones [69, 107, 108]. In addition to
the simple hydroxyl or methoxyl groups, some hydrocar-
bonly and nitrogen or oxygen-containing substituents may
significantly affect the antibacterial activity of flavones. As
shown in Table 1, almost all the hydrophobic substituents
increase the activity, and the substitution by straight aliphatic
chain and 6 member heterocyclic moieties such as mor-
pholinyl and piperidinyl groups significantly enhance the
activity. Interestingly, the proper length of the aliphatic chain
for maximum activity of hesperetin derivates has been found
to be twelve carbon atoms [47]. Generally, the saturation of
C3-C4 bond has been known to influence the affinities of

OH

OH
HO O
O O
OH HO
OH
HO O HO O

OH O OH O

OH O

OH O
Amentoflavone 5,7,3',5'',7'',4'''-hexahydroxy (4'-O-3''')-biflavone

OH

O O
OH HO

O OH OH O

Remangiflavanones C

Fig. (9). Structures of antibacterial bioflavonoids.

144 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.

Table 1. Effects of hydrocarbonyl substitution on the antibacterial activity of flavones.

Flavones Flavones Position Substitution Effect Ref.

7,3',4'-Trihydroxylflavone 8H = [28, 128]

5,7,2',4'-Pentahydroxylflavone 3-C,8-C ‡ [27]

Oroxylin A 7OH ‡ [30]

Oroxylin A 7OH ‡ [30]

Chrysin 7OH-(CH2)3-6 ‡ [31, 32]

Chrysin 7OH-(CH2)3-6 ‡ [31, 32]

Chrysin 7OH-(CH2)3 ‡‡ [32]

Chrysin 7OH-(CH2)3 ‡‡ [32]

Chrysin 7OH-(CH2)5 ‡‡ [31]

Chrysin 7OH-(CH2)5 ‡‡ [31]

Apigenin 8-C CH2-N-(CH2)n-CH3 ‡ [34]

Apigenin 8-C ‡‡ [34]

Apigenin 8-C ‡ [34]

Apigenin 8-C ‡‡ [34]

flavonoids for proteins and their biological activities [109-

111]. For antibacterial activity, it has been revealed that
flavanone showed higher activity than the corresponding
flavone. Notably, lots of the active antibacterial flavanones
are prenylated. As shown in Table 2A, prenyl flavanones
mostly show activity against gram-positive bacteria. Di-
prenylated flavanones exhibit higher activity than the ones
with single prenyl group. In addition, compared the activity
of geranyl and lavandulyl flavanones against S. aureus and
MRSA (Table 2B), it is found that both geranyl group and
lavandulyl group ensure the activity of flavanones, and either
hydroxylation or oxidation of the two groups will reduce or
even eliminate the activity. More over, the substitutive
prenyl group is able to form a heterocyclic ring with the ad-
jacent hydroxyl group on the ring of flavonoids, which in-
crease the antibacterial activity in some cases. For instance,
as shown in Table 3, when the 6 prenyl group joins with the
7 hydroxyl group, compound 2 turns into compound 19, with
about two times increasing activity against MRSA and seven
times that against S. aurue.
4. MECHANISM
There are plenty of literatures concerning the antibacte-
rial mechanism of flavonoids. Cushnie and Lamb [22] have
suggested in their review that the direct antibacterial activity
of flavonoids was mainly attributed to three mechanisms: (1)
Inhibition of nucleic acid synthesis: for example, it has been
observed that the global synthesis of DNA and RNA in V.
harveyi cells was dramatically inhibited after addition of
genistein for 15mins [112]. (2) Inhibition of cytoplasmic
membrane function: for example, galangin has exhibited its
antibacterial activity by causing marked increase in potas-
sium loss from S. aureus cells, indicating a direct damage to
the cytoplasmic membrane of S. aureus cell wall [113]. (3)
Inhibition of energy metabolism: for example, Eumkeb and
Chukrathok have recently suggested that apigenin and
Antibacterial Activities of Flavonoids Current Medicinal Chemistry, 2015, Vol. 22, No. 1 145

Table 2. Active antibacterial prenyl flavanones (A) and active geranyl and lavandulyl flavanones against S. aureus and MRSA (B).

Table 2A.

Activities (MIC, ug/mL)

Position Other Subsitutions Ref.
Gram Positive Gram Negative

8, 5' # 5,7,2',4'-OH(S) S. aureus/1.56; MRSA/1.56 - [39]

8, 5'# 5,7, 4'-OH, 2'-OCH3(S) S. aureus/3.13; MRSA/3.13 - [39]

8, 5'# 5,7,2',4'-OH S. aureus/3.13; MRSA/3.13 - [39]

8 5,7,2',-OH(S) S. aureus/5.0 ; B. Subtilis/5.0 - [53]

8#, 5' 5,7,4'-OH M. Luteus/0.5* E. coil/0.5* [129]

6#, 5' 5,7,4'-OH M. Luteus/0.5* E. coil/0.5* [129]

8 5,7,2',4'-OH(S) S. aureus/5.0 ; B. Subtilis/2.5 - [53]

8 5,7,2',4'-OH, 5'-OCH3 (S) S. aureus/10 ; B. Subtilis/10 - [53]

6 5,7,2',4'-OH, 5'-OCH3 (S) S. aureus/10 ; B. Subtilis/10 - [53]

8 5,7,3' -OH, 8-OCH3 (S) S. aureus/100 - [41]

6 5,7,3'-OH, 6-OCH3 (S) S. aureus/100 - [41]

5' 7,3' -OH, 4'-OCH3 (S) S. aureus/0.5*; B. Subtilis/0.1* E.coli/0.01*, [97]

3' 5,7,4'-OH, 5'-OCH3 S. aureus/16; MRSA/16 - [130]

3' 5,7,4'-OH, 6'-OCH3 S. aureus/16; MRSA/16 - [130]

* Minimum growth inhibition amount on TLC (µg); #:

Table 2B.

No Geranyl Lavandulyl Other Subsitutions MIC(ug/mL) Ref.

1 - 5,7,2',4'-OH (S) inactive [53]

8,

2 - 5,7,2',4'-OH(S) S. aureus/5.0; [53]

8,

3 - 5,7,2',4'-OH(S) S. aureus/2.5; [53]

8,

4 - 5,7,2'-OH(S) inactive [53]

8,

5 - 5,7,2'-OH(S) S. aureus/5.0 [53]

8,

6 - 5-OCH3;7,2',4'-OH(S) S. aureus/2.5 [53]

8,

7 - 5-OCH3;7,2',4'-OH(S) S. aureus/7.1 [131]

8,
146 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.

(Table 2B) contd….

No Geranyl Lavandulyl Other Subsitutions MIC(ug/mL) Ref.

8 - 5-OCH3;7,2',4'-OH(S) S. aureus/219 [131]

8,

9 - 5-OCH3;7,2',4'-OH(S) inactive [53]

8,

10 - 3'-OCH3;5,7 ,4'-OH(S) S. aureus/16 [52]

6,

11 - 3'-OCH3;5,7 ,4'-OH(S) inactive [52]

6,

12 - 3'-OCH3;5,7 ,4'-OH(S) S. aureus/8 [52]

6,

13 - 3'-OCH3;5,7,4',5'-OH(S) S. aureus/2 [52]

6,

S. aureus/4
14 - 3'-OCH3;5,7,4',5'-OH(S) [46]
6, MRSA/4~8

15 - 3',5'-OCH3;5,7,4'-OH(S) S. aureus/4 [52]

6,

S. aureus/2
16 - 3',5'-OCH3;5,7,4'-OH(S) [46]
6, MRSA/4~8

S. aureus/2
17 - 5,7, 3',5'4'-OH(S) [46]
6, MRSA/2~4

S. aureus/8
18 - 3'-OCH3;5,7 ,4'-OH(S) [46]
6, MRSA/8~16

S. aureus/>64
19 - 3'-OCH3;5,7 ,4'-OH [46]
MRSA/≥64
6,

S. aureus/16
20 - 3'-OCH3;5,7 ,4'-OH(S) [46]
MRSA/16~64
6,

S. aureus/64
21 - 3'-OCH3;5,7 ,4'-OH(S) [46]
6, MRSA/8~64

22 - 3'-OCH3;5,7 ,4'-OH(S) inactive [46]

6,

23 - 3'-OCH3;5,7 ,4'-OH inactive [46]

6,

24 - 2',4',6' -OH MRSA/12.5 [43]

6,

25 - 2',4',6' -OH MRSA/12.5 [43]

8,

26 - 2',4',6' -OH MRSA/3.13~12.5 [43]

6,
Antibacterial Activities of Flavonoids
No Geranyl Lavandulyl
27
8,
28
3'
29
6,
30
6,
31
2'
32
3',
1: Kushenol P; 2: Kushenol Q; 3: Kushenol R; 4: Kushenol T; 5: 8-Lavandulyl- 5,7,2'-trihydroxylflavanone; 6: 8-Lavandulyl-5-methoxyl-7,2',4'-trihydroxyflavanone; 7: Kurarinone;
8: Kurarinol; 9: 5-Methoxykushenol P ; 10: tomentodiplacone; 11: tomentodiplacone B; 12: 3'-O-methyldiplacone; 13/14: 3'-O-methyl-5'-hydroxydiplacone; 15/16: 3'O-methyl-5'-O-
methydiplacone; 17: 6-Greanyl-5,7, 3',5',4'-pentaflavanone; 18: tomentodiplacone B ; 19~22: Tomentodiplacone C, D, E, F; 23: Tomentodiplacone I; 24: Exiguaflavanone C; 25:
Exiguaflavanone G; 26 Sophoraflavanone D; 27:Sophoraflavanone E; 28: Myrsininone B; 29: Nymphaenol A; 30: Prokinawan; 31: Isonymphaeol B; 32: propolin B.
naringenin altered the outer and cytoplasmic membrane of E.
cloacae cell, consequently disturbed the exchange of nutri-
ents and metabolites and finally inhibited the energy supply
for the bacterium [114]. In another review, the inhibition of
cell membrane synthesis and the aggregatory effect on whole
bacterial cells also have been assumed to be possible mecha-
nism of antibacterial activity of flavonoids [16].
Here in, based on the former reviews, the latest ad-
vancements on the antibacterial mechanism of flavonoids are
covered and discussed. Recently, the inhibitory mechanism
of a series of flavone-based analogues on DNA gyrase of
E.coli has been studied, and the inhibitors were demonstrated
to inhibit the activity of gyrase through intercalating into
DNA, while another natural product simocyclinone D8 acted
as the competitive binders of DNA to handle the function of
gyrase [115]. Concerning the activity of EGCG against E.
coli, it has been found that EGCG interacts with the porin
protein of the outer membrane of E. coli, thereby inhibiting
the major function of the porin, namely the transport of small
hydrophilic molecules such as glucose, finally leading to
inhibition against the growth of E. coli [116]. Besides, it has
been revealed that the proanthocyanidin offers protection
against both sensitive as well as multi-drug resistant strains
of E. coli by inhibiting the adherence of multi-drug resistant
strains on uroepithelial cells [67]. Similar mechanism has
also been proposed for tea components inhibiting the at-
tachment and subsequent biofilm formation of S. mutans on
tooth surfaces. It is suggested that flavonoids coat the sur-
faces of cells, probably altering cell surface properties and
consequently disturbing the interactions between bacterial
cells and the surface of the substratum [117]. In addition to
the direct antibacterial activity, the synergistic and antibiot-
ics resistance modulating activity of flavonoids has gotten
better understanding. The investigation on synergistic effect
of apigenin and ceftazidime combination against ceftaz-
idime-resistant E. cloacae strains has revealed three possible
mechanisms of action by apigenin including the peptidogly-
can synthesis inhibition, the inhibition the activity of certain
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 147
(Table 2B) contds….
Other Subsitutions MIC(ug/mL) Ref.
- 2',4',6' -OH MRSA/6.25~12.5 [43]
- 5,7 ,4'-OH(S) MRSA/1.9 [44]
- 5,7,3',4'-OH(S) S. aureus/4 [132]
- 5,7,3',4'-OH(S) inactive [132]
- 5,7,3',4'-OH(S) S. aureus/16 [132]
- 5,7,3',4'-OH(S) inactive [132]
β-lactamase enzymes and the alteration of the outer and cy-
toplasmic membrane permeabilization [114]. In addition, the
mechanism of inhibition on the efflux pump of antibiotic
resistant bacteria has been further proposed on the synergis-
tic effects of flavonoids isolated from A. katsumadai in com-
bination with rifampicin against M. smegmatis [118]. Be-
sides, the synergy of a ciprofloxacin–pomegranate pericarp
extract combination was exhibited against extended-
spectrum β-lactamase and metallo-β-lactamase producing
Gram-negative bacilli, which was attributed to the bacterial
efflux pump inhibitor activity of the polyphenolic constitu-
ents of the pomegranate pericarp extract [119]. Some times,
multi mechanism was observed for antibacterial activity, a
flavonoid rich extract of Glycyrrhiza glabra has exerted anti-
H. pylori activity possibly by inhibiting protein synthesis,
DNA gyrase and dihydrofolate reductase [120].
Besides of the antibacterial activity, flavonoids may
show activity of reducing the harm of bacteria to the host
organism. In the U937cells and monocytes infected by S.
typhimurium, flavonoids such as resveratrol and quercetin
reduced the NO production, inhibited the cell viability and
proliferation in the infected cells, and consequently protected
the host cells from the toxic effects of bacterial infection and
decreased programmed cell death [121]. Isoliquiritigenin and
liquiritigenin have also shown their oral infection therapeutic
potential by targeting host cell receptors activated by three
periodontopathogens [122]. In addition, naringenin and taxi-
folin have been found to attenuate the production of quorum
sensing (QS)-controlled virulence factors in P. aeruginosa
[123]. More over, some prenylated isoflavones from roots of
Flemingia philippinensis have proven to be active com-
pounds for inhibition against bacterial neuraminidase which
is one of the key enzymes involved in pathogenesis of
inflammation during infection. The structure–activity analy-
sis showed a 4-hydroxyl group within the B-ring was essen-
tial for neuraminidase inhibitory activity, and the di-prenyl
substituents also seemed to be important for the activity
[124].
148 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.

Table 3. Active antibacterial prenylated flavanols.

No Prenyl Subsitutions Other Subsitutions Antibactrial (MIC, ug/mL) Ref.

C. albicans/25 ; S. Cerevisiae/12.5 ; E. Coli/20 ; S. Typhimu-

1 5,7,2',4'-OH [27]
6,5' rim/25 ; S. epidermis/10 ; S. Aureus/15

2 *5,7,2',4'-OH(S) MRSA/62.5; S. aureus/125 [55]

6,

3 *5,7,2',4'-OH(S) MRSA/62.5; S. aureus/62.5 [55]

8,

4 *5,2',4'-OH(S) B. cereus/<50; B. subtilis/<50 [133]

7-O,

5 *5,7,4'-OH(S) B. cereus/200; B. subtilis/200 [133]

6,

6 *5,7,4'-OH, 3'-OCH3 (S) B. cereus/<25; B. subtilis/50 [133]

6,

7 8, *5,7,2',6'-OH,4'-OCH3 S. epidermis/20 ; S. Aureus/20 [27]

6,

6, S.aureus/24.6 ; B. subtilis/12.3 ; S.typhimurium/12.3 ;

8 *5,7,2',4'-OH(S) [131]
P. vulgaris/6.14

8,

9 *5,7,2',4'-OH(S) S. aureus/10; B. subtilis/10 [53]

8,

S.aureus/27.5 ; B. subtilis/13.8 ; S.typhimurium/27.5 ;

10 *7,2',4'-OH, 5-OCH3(S) [53]
P. vulgaris/27.5
8,

S.aureus/27.5 ; B. subtilis/13.8 ; S.typhimurium/27.5 ;

11 *7,2',4'-OH, 5-OCH3(R) [53]
P. vulgaris/27.5
8,

S.aureus/236 ; B. subtilis/118 ; S.typhimurium/236 ;

12 5,7,4'-OH [53]
P. vulgaris/118
8,

B. cereus, L. monocytogenes, S. aureus & S. epidermidis/2 ;

13 *5,7,4'-OH,3'-OCH 3 (S) [46, 52]
6, B. subtilis & E. faecalis/4 ; (S. aureus/4, MRSA/4~8)

14 5,7,3',4'--OH S. aureus/32, B. subtilis/32, P. Aeruginosa/16 [132]

6,

15 2', 5,7,3',4'--OH S. aureus/64, B. subtilis/64, P. Aeruginosa/64 [132]

16 5,7,3',4'--OH S. aureus/64, B. subtilis/64, P. Aeruginosa/64 [132]

6,

17 4'-OCH3; 5,2',4'-OH S. aureus/2.01 ;S. sciuri/2.01 ; S. xylosus/2.01 [54]

6,7,
Antibacterial Activities of Flavonoids
No Prenyl Subsitutions Other Subsitutions
18 *4'-OCH3; 5,2',4'-OH(S)
6,7,
19 *5,2',4'--OH(S)
6,7,
20 *5, 4'-OH(S)
7,8,
21 *5, 3',4'-OH(S)
7,8,
* : dihydroflavnol; S/R: configurations (1) Papyriflavonol A (2) 6-prenyl-5,7,2',4'-pentahydroxyl –dihydroflavanol (3)8-prenyl-5,7,2',4'-pentahydroxyldihydroflavanol(4) 5,3',4'-
Trihydroxy-7- (γ,γ-dimethylallyloxy)dihydroflavonol (5) 5,7,4'-Trihydroxy-6-(a,a-dimethylallyl)dihydroflavonol (6) 5,7,4-Trihydroxy-3'-O-methyl-6- (a,a-dimethylallyl)dihydrofla-
vonol (7) Kenusanone C (8) Kushenol M (9) Kushenol X (10) Kushenol I(11) Kushenol N (12) 8-lavandulylkaempferol (13) 3'-O-methyldiplacol (14) Solophenol D (15) Solophenol
B (16) Solophenol C (17) Lanneaflavonol (18) Dihydrolanneaflavonol (19) 6,7-(2'',2''-dimethylpyrano)- 5,2',4'-trihydroxyldihydroflavanol (20) Yokuvanol (21) 3'-Hydroxylyokuvanol
CONCLUDING REMARK
With this review the structure-activity relationships for
flavonoids as antibacterial agents were discussed. It is con-
cluded that hydroxyl groups on special sites are favorable for
the activity, such as 5,7-dihydroxyl substitution for flavone
[3]
and flavanone, and 2' or 4' hydroxylation for chalcones. The
hydroxyl group at 3 position on the C ring also increases the
activity of flavone. However, the methylation of the hy-
droxyl groups generally decreases the activity. The
lipopholicity of the ring A is of great importance for the ac-
tivity of chalcones. Hydrophobic substituents such as prenyl [5]
groups, alkylamino chains, alkyl chains, and nitrogen or
oxygen containing heterocyclic moieties usually enhance the
activity for all the flavonoids. In addition, the antibacterial
mechanisms of flavonoids are summed as follows: inhibition
of nucleic acid synthesis, inhibition of cytoplasmic mem-
brane function, inhibition of energy metabolism, inhibition
of the attachment and biofilm formation, inhibition of the
porin on the cell menbrane, alteration of the membrane per-
meability, and attenuation of the pathogenicity. Although the
current knowledge on the antibacterial activity of flavonoids
is far from clear, the huge potentials of flavonoids for con- [8]
trolling the prevalence of antibiotic resistance microorgan-
isms are basically confirmed. However, it is noted that most
of the antibacterial activity of flavonoids were tested in vitro,
only few studies have investigated the activity in vivo [125,
126]. Hence, further studies is ought to pay more attention to
the relationships between the bioavailability and antibacterial
activity of flavonoids. The possibility of resistance of bacte-
ria to flavonoids should also be evaluated in advance. Never-
theless, flavonoids have surely become an alternative choice
for tackling the so called “antibiotic resistance crisis” [127].
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
[14]
ACKNOWLEDGEMENTS
The authors thank for the financial support from National
Natural Science Foundation of China (21175155 &
21276282).
Current Medicinal Chemistry, 2015, Vol. 22, No. 1 149
(Table 3) contd….
Antibactrial (MIC, ug/mL) Ref.
S. aureus/2.00 ;S. sciuri/2.00 ; S. xylosus/2.00 [54]
MRSA/31.3; S. aureus/15.6 [55]
MRSA/31.3; S. aureus/31.3 [55]
MRSA/15.6; S. aureus/15.6 [55]
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Received: March 13, 2014 Revised: June 21, 2014 Accepted: June 21, 2014
 154 Current Medicinal Chemistry, 2015, Vol. 22, No. 1 Xie et al.
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