Synthesis and biological activities of some 1,3-benzoxazol-2(3H)-one derivatives as anti-quorum sensing agents

Article abstract of DOI:10.1055/s-0032-1312590

Antibiotics are commonly used to treat microbial infections. Due to misuse or large-scale use of antibiotics, many pathogens have gained resistance which makes antibiotic treatments ineffective. The discovery that many bacteria use quorum sensing (QS) to regulate their virulence factor and pathogenicity production makes the QS system an attractive target for antimicrobial therapy. A series of 1,3-benzoxazol-2(3H)-one derivatives were designed and synthesized as QS inhibitors (QSIs) and tested for their QS inhibitory activities. In vitro quorum sensing inhibitor screen (QSIS) assay indicated that the 1,3-benzoxazol-2(3H)-one (compound 1), 5-chloro-1,3-benzoxazol-2(3H)-one (compound 6), 6-methyl-1,3-benzoxazol-2(3H)-one (compound 11), and 5-methyl-1,3-benzoxazol-2(3H)-one (compound 16), inhibit QS system in quorum sensing selector (QSIS)1 strain. These 4 QSIs also significantly reduced elastase production, biofilm formation and swarming motility of Pseudomonas aeruginosa PA01 strain. These results suggest that compound 1, 6, 11 and 16 may provide a starting point for the design and development of new anti-pathogenic drugs that restrict virulence of P. aeruginosa and possibly other clinically important human pathogens. In addition, these QSI molecules could potentially be used in combination with conventional antibiotics to increase the efficiency of disease control and to extend the life span of established antimicrobials. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1312590

330 Original Article
Synthesis and Biological Activities of Some
1,3-Benzoxazol-2(3H)-One Derivatives as Anti-Quorum
Sensing Agents
Authors
A. M. Miandji1, S. Ulusoy2, Y. Dündar1, S. Özgen3, F. K. Onurdağ3, G. Boşgelmez-Tınaz2, 4, N. Noyanalpan1
Affiliations
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey
2 Department of Biology, Faculty of Arts and Sciences, Suleyman Demirel University, Isparta, Turkey
3 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Gazi University, Ankara, Turkey
4 Department of Clinical Microbiology, Faculty of Medicine, Marmara University, İstanbul, Turkey
Key words
Abstract
▼
2(3H)-one (compound 16), inhibit QS system in
quorum sensing selector (QSIS)1 strain. These 4
QSIs also significantly reduced elastase produc-
tion, biofilm formation and swarming motility
of Pseudomonas aeruginosa PA01 strain. These
results suggest that compound 1, 6, 11 and 16
may provide a starting point for the design and
development of new anti-pathogenic drugs that
restrict virulence of P. aeruginosa and possibly
other clinically important human pathogens. In
addition, these QSI molecules could potentially
be used in combination with conventional anti-
biotics to increase the efficiency of disease con-
trol and to extend the life span of established
antimicrobials.
▶
acyl homoserine lactone
quorum sensing inhibitors
1,3-benzoxazol-2(3H)-one
●
▶
●
Antibiotics are commonly used to treat micro-
bial infections. Due to misuse or large-scale
use of antibiotics, many pathogens have gained
resistance which makes antibiotic treatments
ineffective. The discovery that many bacte-
ria use quorum sensing (QS) to regulate their
virulence factor and pathogenicity production
makes the QS system an attractive target for
antimicrobial therapy. A series of 1,3-benzox-
azol-2(3H)-one derivatives were designed and
synthesized as QS inhibitors (QSIs) and tested
for their QS inhibitory activities. In vitro quorum
sensing inhibitor screen (QSIS) assay indicated
that the 1,3-benzoxazol-2(3H)-one (compound
1), 5-chloro-1,3-benzoxazol-2(3H)-one (com-
pound 6), 6-methyl-1,3-benzoxazol-2(3H)-one
(compound 11), and 5-methyl-1,3-benzoxazol-
▶
●
Supporting information available online at
http://www.thieme-connect.de/ejournals/toc/
amf
received 27.03.2012
accepted 16.04.2012
Bibliography
Introduction
▼
tease, hemolysins, exotoxin A, rhamnolipid bio-
surfactants and phospholipase contribute to the
virulence of P. aeruginosa. These extracellular
factors are collectively capable of causing exten-
sive tissue damage in humans and other mam-
mals [8,9]. P. aeruginosa utilizes QS to coordinate
the expression of virulence genes. In P. aerugi-
nosa, QS is mediated by 3-oxo-C12-HSL(OdDHL)
synthesized by LasI, C4-HSL (BHL) synthesized by
DOI http://dx.doi.org/
10.1055/s-0032-1312590
Published online:
May 15, 2012
Arzneimittelforschung 2012;
62: 330–334
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0004-4172
Bacterial cell to cell communication can regulate
community-wide behaviors including biofilm
formation, conjugation, swarming, motility, the
production of virulence factors, bioluminescence
and antibiotic biosynthesis through a process
called quorum sensing (QS) [1–3]. QS depends on
the production of diffusible signal molecules
termed auto-inducers that are synthesized intra-
cellular. Different bacteria may use different
auto-inducers to communicate intercellular.
N-acylated-L-homoserine lactones (AHLs) are the
most common signaling molecules found in
Gram-negative bacteria while cyclic peptides are
the major class of auto-inducers used by Gram-
positive bacteria [4]. P. aeruginosa is an impor-
tant human pathogen which is responsible for
opportunistic infections in cancer, AIDS and
cystic fibrosis (CF) patients [5–7]. A wide variety
of extracellular enzymes including elastase, pro-
RhlI and by 2-alkyl-4-quinolones (Pseudomonas
Correspondence
Y. Dündar, PhD
Department of Pharmaceutical
Chemistry
Faculty of Pharmacy
Gazi University
Taç SK
06330 Etiler
Ankara
T u r k e y
▶
quinolone signal PQS) [10–12] ( Fig. 1) .
●
P. aeruginosa also employs QS to control the for-
mation of biofilms [13]. Biofilms are dense extra-
cellular polymeric matrices in which the bacteria
embed themselves. Biofilm growth also occurs in
otitis media, chronic rhinosinusitis, chronic
osteomyelitis and prosthetic joint infection and it
is the handicap for the medical devices such as
catheters, stents, prostheses and artificial heart
valves [14–17]. Biofilm formation is thought to
protect the microorganisms from host defenses
Tel.: +90/31/2202 3237
Fax: +90/31/2223 5018
yasemina@gazi.edu.tr
Miandji AM et al. Some Anti-quorum Sensing Agents… Arzneimittelforschung 2012; 62: 330–334

Original Article 331
and provide increased resistance to antibiotics [14–19]. With
the widespread appearance of antibiotic-resistant bacteria,
there is an increasing demand for new strategies to control
infectious diseases. Consequently, inhibitors and antagonists of
bacterial quorum sensing are important research tools and
potential therapeutic agents. Up to date, many acylhomoserine
lactone analogs, furanone derivatives and different heterocycles
Materials and Methods
▼
Experimental procedures, spectral characterization data were
given in Supporting Information Part.
Results and Discussion
have been reported to possess QS inhibitory activity [14–
▼
▶
16,19,20], ( Fig. 2). However, most of these QS inhibitors are
The synthetic routes for the synthesized compounds are out-
●
▶
unsuitable for human use. Toxicity and in vivo efficacy tests sig-
nificantly narrow down the potential candidates.
In the present study, we describe the synthesis and preliminary
biological evaluation of 2(3H)-benzoxazolone, 5-chloro-1,3-
lined in Fig. 3. The starting compound, 1,3-benzoxazol-2(3H)-
●
one (1) was readily prepared by the reaction of urea and
o-aminophenol under microwave irradiation (MWI) and the pro-
cedures is in accordance with a previously published method [21].
Other starting compounds, 6-methyl-1,3-benzoxazol-2(3H)-one
(11) and 5-methyl-1,3-benzoxazol-2(3H)-one (16), were pre-
pared by the reaction of urea and 5-methyl-2-aminophenol/4-
methyl-2-aminophenol under MWI. Acylation of core rings with
acyl chloride derivatives was carried out in tetrahydrofurane
(THF) by using microwave assisted method. The 1,3-benzoxazol-
2(3H)-one [21], 5-methyl-1,3-benzoxazol-2(3H)-one [22,23],
6-methyl-1,3-benzoxazol-2(3H)-one [22,24,25] and 3-decanoyl-
1,3-benzoxazol-2(3H)-one [26] was previously reported.
benzoxazol-2(3H)-one,
6-methyl-1,3-benzoxazol-2(3H)-one
and 5-methyl-1,3-benzoxazol-2(3H)-one and their N-long chain
▶
acyl derivatives ( Fig. 2). These compounds were screened for
●
their QS inhibitory activities. 4 compounds, 1,3-benzoxazol-
2(3H)-one (compound 1), 5-chloro-1,3-benzoxazol-2(3H)-one
(compound 6), 6-methyl-1,3-benzoxazol-2(3H)-one (compound
11) and 5-methyl-1,3-benzoxazol-2(3H)-one (compound 16),
showed significant inhibition of QS regulated phenotypes in
human pathogen P. aeruginosa.
All the synthesized 1,3-benzoxazol-2(3H)-one derivatives were
first tested for their antibacterial activity [27] against reference
strains, P. aeruginosa ATCC 27853, E. coli ATCC 25922, E. coli ATCC
35218, K. pneumoniae RSKK 574 and clinical isolates of these
microorganisms. The minimum inhibitory concentration (MIC)
values were determined by microdilution method. Ampicillin,
gentamicin sulfate, ofloxacin, tetracycline, ceftriaxone, mero-
penem and amoxicilin-clavulanic acid were used as the refer-
O
O
O
O
O
NH
NH
O
O
H
H
OdDHL
BHL
Fig. 1 Acylhomoserine lactone molecules in P. aeruginosa.
ence. Antibacterial activity results of the synthesized compounds
▶
are summarized in Table 1. The results indicated that among
●
the synthesized compounds, compound 5 displayed antibacte-
rial activity against various tested bacterial strains when com-
pared to the other synthesized compounds. All of the test
compounds did not show significant activity against E. coli ATCC
25922, E. coli ATCC 35218, E. coli isolates while they exhibited
moderate inhibitory effect with MIC values between 64 and
32μg/ml against P. aeruginosa ATCC 27853 and P. aeruginosa
isolate.
In order to determine the QS inhibitory potential of the synthe-
sized compounds, they were initially screened by QSIS1 assay
based on recombinant bacteria background giving rise to a blue
circle of growth on X-Gal supplemented medium at concentra-
tion (sub-MIC) as described by Rasmussen et al. [28]. Patulin
used as a positive control. Of the 18 compounds screened, sig-
Cl
H
H
O
Br
Br
Br
O
O
O
HN
O
R
NH
O
O
O
O
R1
R2
R1
R2
R1: H, CH3, Cl
R2: H, CH3
R3
N
O
HN
O
R3: alkyl group
nificant QS inhibitory activity was detected in Compounds 1, 6,
O
O
▶
11 and 16 ( Fig. 4). N-acyl derivatives of these compounds did
●
O
not show any inhibition. Compound 6 (chlorzoxazon) was dis-
covered previously to be an inhibitor of QS in P. aeruginosa[20].
However, there is no published data on anti QS activities of com-
pounds 1, 11 and 16. In agreement with Yang’s study [20], our
findings have further verified Compound 6 (chlorzoxazon) as a
QS inhibitor. Interestingly, Compounds 1 and 16 displayed a
Fig. 2 General structure of AHL, synthetic furanone derivatives,
chlorzoxazon and synthesized compounds.
(CH2)n
higher level of inhibition in QSIS1 assay than known QSI com-
O
O
R1
R2
H
N
NH2
OH
R1
R2
R1
R2
▶
NH2
NH2
i
ii
pound 6 (chlorzoxazon) ( Fig. 4) .
●
N
O
+
O
We tested the effects of compounds 1, 6, 11 and 16 on the pro-
duction of 3 QS-regulated virulence factors such as elastase, bio-
film formation and swarming motility of human pathogen P.
aeruginosa PA01 strain. The production of elastase by the P. aer-
uginosa PA01 strain was examined by the Elastin Congo Red
assay [29]. P. aeruginosa PA01 was grown in the presence and
O
O
Fig. 3 Synthesis of 1,3-benzoxazol-2(3H)-one derivatives, compounds
1–18. Reagents: (i) MWI, 10min; (ii) Acylhalide, triethylamine, tetrahy-
drofurane, reflux under MWI, 20min. R1: H, CH3, Cl. R2: H, CH3.
n: 5–8.
Miandji AM et al. Some Anti-quorum Sensing Agents… Arzneimittelforschung 2012; 62: 330–334

332 Original Article
Table 1 Antibacterial activities of the synthesized compounds.
R3
N
R1
R2
O
O
Comp.
R1
R2
R3
A
B
C
D
E
F
G
1
H
H
H
128
128
128
128
64
128
64
128
128
128
64
64
64
64
64
64
64
64
64
64
64
64
64
64
64
64
64
64
64
–
32
64
64
32
32
32
64
64
32
64
32
64
64
32
64
32
64
32
–
64
64
128
128
128
128
64
2
H
H
Heptanoyl
Octanoyl
Nonanoyl
Decanoyl
H
128
128
128
64
3
H
H
64
4
H
H
128
32
5
H
H
6
Cl
Cl
Cl
Cl
Cl
H
H
128
128
128
128
128
128
128
128
128
128
128
128
128
4
128
128
128
128
128
128
128
128
128
128
128
128
128
64
64
128
64
128
128
128
128
128
128
128
128
128
128
128
128
128
64
7
H
Heptanoyl
Octanoyl
Nonanoyl
Decanoyl
H
128
128
128
128
128
128
128
128
128
128
128
128
64
8
H
64
9
H
128
64
10
H
11
C H 3
C H 3
C H 3
C H 3
C H 3
H
128
32
12
H
Heptanoyl
Octanoyl
Nonanoyl
Decanoyl
H
13
H
64
14
H
128
64
15
H
16
C H 3
C H 3
C H 3
128
128
128
2
17
H
Heptanoyl
Nonanoyl
18
H
Ampicillin
Gentamicin
O floxacin
0.25
0.015
0.5
0.25
–
256
32
0.25
1
2
<0,0125
0.25
0.25
2
<0,0125
0.5
2
Tetracycline
Ceftriaxone
Meropenem
Amoxicillin/clavulanic acid
–
256
512
<0,0125
64
8
8
4
0.12
–
64
0.25
–
64
4
<0.25*
<0,0125
64
<0,0125
4
<0,0125
8
<0,0125
1
–
A: E. coli ATCC 25922, B: E. coli ATCC 35218, C: E. coli isolate, D: P. aeruginosa ATCC 27853, E: P.aeruginosa isolate, F: K. pneumoniae RSKK 574, G: K. pneumoniae isolate, *E.coli
and K. pneumoniae isolates have ESBL and P. aeruginosa isolate is resistant to ceftriaxone
strain with these 4 compounds resulted in significant reduction
Fig. 4 Samples
in the biofilm formation capacity as follows: PA01 100% produc-
screened for QSI activ-
tion, compound 1 60%; compound 6, 53.8%; compound 11,
ity using QSIS1 strain
P; Patulin (positive
control), compounds 1,
6, 11 and 16.
11
16
▶
47.7%; compound 16, 46.5% ( Fig. 6). The compounds did not
●
inhibit growth at the concentration used.
The ability of the compounds to reduce the swarming motility of
PA01 was also tested [33]. The results showed that swarming
motility was significantly reduced by these four compounds
▶
compared to untreated P. aeruginosa PA01 ( Fig. 7). We con-
●
1
6
firmed that the compounds do not affect the growth of P. aeru-
ginosa PA01 at concentrations used in the swarming assay (data
not shown). Yang et al. [20] have reported that chlorzoxazon
(Compound 6) is capable of decreasing the production of a range
of QS-regulated virulence factors such as exogenous proteases,
pyoverdin, rhamnolipid and biofilm formation in P. aeruginosa.
In this study, we showed that elastase production and swarming
motility in P. aeruginosa were also inhibited by chlorzoxazon. In
addition, Yang et al. [20] also discovered that salicylic acid and
nifuroxazide were capable of interfering with QS in P. aerugi-
nosa. Up to now, a large number of synthetic QS inhibitors have
been discovered. A range of recognized drugs have been shown
to have quorum sensing inhibitory activities. For example, some
macrolide and nonmacrolide antibiotics have been shown to
have effects upon AHL-mediated quorum sensing in Gram-neg-
ative bacteria. Skindersoe et al. [34] identified that ceftazidime
and iprofloxacin reduced QS-regulated gene expression in P.
aeruginosa. The sub-inhibitory concentration of antibiotic
▶
absence of compounds 1, 6, 11 and 16. As shown in Fig. 5, all
●
compounds, showed significant reductions in the elastase produc-
tion. Among them, compound 6 had the greatest inhibitory activity
(83.1%). This was followed by compounds 11, 16 and 1 which
decreased elastase activity by 42.2%, 34.1% and 20.4%, respectively.
QS has been reported to play an important role in the matura-
tion of P. aeruginosa biofilms and biofilm related antibiotic toler-
ance [30–32]. We, therefore, examined the effect of compounds
1, 6, 11 and 16 on P. aeruginosa PA01 strain biofilm formation.
Biofilms were grown on LB medium in 96-well polystyrene
plates in the presence or absence of sub-MIC concentrations of
the compounds 1, 6, 11 and 16. Treatment of P. aeruginosa PA01
Miandji AM et al. Some Anti-quorum Sensing Agents… Arzneimittelforschung 2012; 62: 330–334

Original Article 333
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
*
*
*
*
*
*
*
*
PAO1
11
16
1
6
PAO1
11
16
1
6
Fig. 5 Inhibition of elastase production in P. aeruginosa. PA01,
Fig. 6 Results of biofilm formation capacity. PA01, untreated; 11, com-
pound 11, treated PA01; 16, compound 16 treated PA01; 1, compound 1
treated PA01; 6, compound 6 treated PA01. Values represent the mean of
3 independent experiments ±SD.
untreated; 11, compound 11, treated PA01; 16, compound 16 treated
PA01; 1, compound 1 treated PA01; 6, compound 6 treated PA01. Values
represent the mean of three independent experiments ±SD.
Fig. 7 E ffect of compounds 1, 6, 11 and 16 on
swarming motility of
P. aeruginosa PA01.
Compound 1
Compound 6
PA01 control (no compounds)
Compound 11
Compound 16
tobramycin has also been reported to reduce elastase produc-
tion in P. aeruginosa[35]. Although compounds 1, 11 and 16 syn-
thesized in this study are known molecules, anti QS activities of
these compounds have not been reported earlier.
compounds 1, 11 and 16. The capability of these compounds to
inhibit bacterial QS has not been reported earlier. In conclusion,
these compounds appear to provide a starting point for the
design and development of the novel and more active QS inhibi-
tors that restrict pathogenesis of P. aeruginosa and other clini-
cally significant pathogens. The interruption of QS system can
render pathogenic bacteria non-virulent.
Conclusions
▼
In this study, the effects of compounds 1, 6, 11, 16 and their
N-long chain acyl derivatives on the production of extracellular
virulence factors of P. aeruginosa were investigated. Our results
showed that four compounds, compounds 1, 6, 11, and 16, but
not their N-long chain acyl derivatives, inhibited quorum-sens-
ing regulated phenotypes such as elastase production, swarming
motility, and biofilm formation in P. aeruginosa. Among these
compounds, compound 6 (chlorzoxazone) was identified previ-
ously to be a QS inhibitor. Our screening identified 3 new QSIs,
Conflict of Interest
▼
The authors declare that they have no conflict of interest.
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