Synthesis and biological evaluation of novel N-acyl substituted quinolin-2(1H)-one derivatives as potential antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2012.07.081

A series of novel N-acyl substituted quinolin-2(1H)-one derivatives were synthesized and screened in vitro for their antibacterial and antifungal activities by disc diffusion method. All the compounds exhibited moderate to good antimicrobial activities, some of these compounds displayed comparable or better antibacterial or antifungal activities against some tested strains compared to the reference drugs Streptomycin and Fluconazole.

Full text of DOI:10.1016/j.bmcl.2012.07.081

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5845–5848
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel N-acyl substituted
quinolin-2(1H)-one derivatives as potential antimicrobial agents
⇑
Hong-Bin Liu, Hui Tang, Dan Yang, Qiao Deng, Lv-Jiang Yuan, Qing-Gang Ji
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel N-acyl substituted quinolin-2(1H)-one derivatives were synthesized and screened
in vitro for their antibacterial and antifungal activities by disc diffusion method. All the compounds
exhibited moderate to good antimicrobial activities, some of these compounds displayed comparable
or better antibacterial or antifungal activities against some tested strains compared to the reference
drugs Streptomycin and Fluconazole.
Received 18 May 2012
Revised 18 July 2012
Accepted 24 July 2012
Available online 1 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Quinolin-2(1H)-one
Amide
Antibacterial
Antifungal
Quinolones, an important class of heterocyclic compounds are
part of the quinoline alkaloid family,1 represent an interesting class
of compounds possessing a broad spectrum of biological activities
such as antibacterial,2 antifungal,3 anticancer,4 antiviral,5 antianx-
iety,6 antimalarial7 and so on. Especially antimicrobial activities,
based on their improved activities have been developed four gen-
erations antibiotic in clinic. Undoubtedly, the quinolones have be-
come the most important drugs in the anti-infective chemotherapy
field. However, the abuse of anti-infectives has led to increasingly
worrisome resistance at a disturbing rate, which has posed serious
problems in the treatment of infectious diseases. This trend has
highlighted the urgent need for designing and developing novel
compounds endowed with antimicrobial activity, which were dis-
tinct from those of well-known classes of antimicrobial agents.8 In
recent years, a novel series of quinolin-2(1H)-ones exhibited prom-
ising biological activities such as anticancer,9 antiviral,10 chitin
synthase inhibitor11 and also have shown potent antimicrobial
activity.12 Several works have showed that quinolin-2(1H)-ones
backbone in combination with some nitrogen-containing moieties
such as isoxazole, Schiff base, thiazolidinone could significantly in-
crease the antimicrobial efficiency (Fig. 1). However, to the best of
our knowledge, quinolin-2(1H)-one derived amide has been not
reported. It is of great interest for us to investigate quinolin-
2(1H)-one derived amide as a new type of antimicrobial agents.
It is well known that amide compounds play an important role
in modern medicinal chemistry. Generally, compounds possessing
an amide moiety have a wide range of biological activities such as
antimicrobial,13 anti-inflammatory,14 antiviral,15 and antimalar-
ial.16 Nowadays, a series of the amides derived from chloroacetyl
chloride have received significant attention and chloroacetyl deriv-
atives of some amines for their biological activities such as antibac-
terial,17 antifungal18 and antitumor19 have been reported in
literatures. In view of these conceptions and further expand the
scope of quinolin-2(1H)-one derivatives as potential antibacterial
and antifungal agents, thus a series of novel N-acyl substituted
quinolin-2(1H)-one derivatives were designed and synthesized
and evaluated for their antibacterial and antifungal efficiency
(Fig. 2). A lot of works showed that nitrogen-containing heterocy-
cles could modulate the physicochemical properties and thus
R2
N
OH
R3
R4
R1
N
N
N
N
N
H
O
N
H
O
R5
II
R1 R2
I
N
H
O
O
N
OH
N
O
Ar
N
O
N
H
H
V
III
⇑
Corresponding author. Tel./fax: +86 23 68254000.
E-mail address: jiqing@swu.edu.cn (Q.-G. Ji).
Figure 1. Report quinolin-2(1H)-one derivatives as antimicrobial agents.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.081

5846
H.-B. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5845–5848
R1 R2
The in vitro antimicrobial activities of all synthesized com-
R'
N
pounds were evaluated for three Gram-positive organisms viz.
Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 6633,
methicillin-resistant Staphylococcus aureus N 315 (MRSA) and
two Gram-negative organisms viz. Bacillus proteus, Escherichia coli
JM 109, as well as two fungi viz. Candida mycoderma and Candida
albicans ATCC 76615 by disc diffusion method.22 All target com-
pounds were evaluated at the concentrations ranging from 0.5 to
H
N
R/ Het
Ar/ Het
N
H
O
O
R'
N
O
512
lg/mL and scored for minimal inhibitory concentrations
(MICs,
lg/mL). The minimum inhibitory concentration (MIC) was
Het /R
NH
the lowest concentration of the test compound compared with that
of the current antimicrobial drugs Streptomycin and Fluconazole in
clinic, which resulted in no visible growth on the plate. The anti-
bacterial and antifungal datas were depicted in Table 1.
N
O
H
The investigation of antibacterial screening datas revealed that
all the tested compounds showed moderate to good inhibition
against both Gram-positive and Gram-negative bacteria, even
comparable to the reference drug Streptomycin. As seen in Table
1, for the tested aliphatic amines 4a–f exhibited moderate activi-
ties against all the tested bacterial strains with MIC values ranging
Figure 2. Design of novel N-acyl substituted quinolin-2(1H)-one derivatives using
molecular hybridization approach.
improve biological potency. With the aim of better understanding
of structure–activity relationship and increasing flexibilities, dif-
ferent amines were introduced into the target compounds to inves-
tigate the influences on bioactivity.
from 8 to 256 lg/mL. Particularly, MRSA has emerged to resistance
against Streptomycin, but sensitive to the novel compounds. Com-
pound 4a with dipropylamine group exhibited good activities
against the tested bacterial strains with MIC values ranging from
In this work, N-acyl substituted quinolin-2(1H)-one derivatives
were prepared via multistep reactions from 5-amino-3,4-dihydro-
quinolin-2(1H)-one 1 and their synthetic process was outlined in
Scheme 1. The raw material 1, prepared according to the reference
described,20 was reacted with chloroacetyl chloride to give
2-chloro-N-(1,2,3,4-tetrahydro-2-oxoquinolin-5-yl)acetamide 2 in
75% yield, The target N-acyl substituted quinolin-2(1H)-one 3a–f
were conveniently and efficiently obtained in 50–80% yields by
the reaction of 2 with different aliphatic amines in ethanol at
85 °C using sodium bicarbonate as base. Under the same condition
above, nitrogen-containing heterocycles 5a–g were obtained in
30–60% yield. The acidification of 3a–f and 5a–g by hydrochloric
acid yielded their corresponding hydrochloride 4a–f and 6a–g in
good yields after purification. Some synthetic data were given in
Table 1. These new compounds were confirmed by 1H NMR, 13C
NMR and MS spectra.21
8 to 64 lg/mL except B. proteus. Some compounds exhibited better
inhibition against several bacterial strains in comparison with ref-
erence drug Streptomycin. For example, tertbutyl and benzyl
derivatives 4c and 4f gave comparable activities against S. aureus,
compound 4b with diethylamino exhibited activities against E. coli
with MIC value of 8 lg/mL. The antibacterial activity of compound
4d with dibenzyl group is weaker than the benzyl derivative 4f,
while 4e with dihydroxyethyl which was a polar and medium size
group, exhibited moderate antibacterial activity.
The nitrogen-containing heterocycles derivatives 6a–g, in con-
trast to aliphatic amines analogs, showed broader antimicrobial
spectrum and could effectively inhibit the growth of the tested
strains in vitro. These compounds showed good inhibition against
MRSA with MIC values ranging from 32 to 64 lg/mL, which were
O
O
O
R
R
N
R1
Cl
N
R1
HN
HN
NH2
HN
b
c
a
.HCl
N
H
3a-f
O
N
H
O
N
H
O
N
H
4a-f
O
1
2
d
R1=
(CH2)2CH3
CH2CH3
(CH2)2CH3
CH2CH3
a, R=
b, R=
c, R=
3, 4:
R1=
R1=
O
O
Het
Het
C(CH3)3
CH2
H
H
HN
HN
.HCl
R1=
R1=
R1=
CH2
d, R=
e, R=
c
(CH2)2OH
(CH2)2OH
N
O
N
H
6a-g
O
H
5a-g
f, R=
CH2
HN
N
N
N
N
e, Het=
f, Het=
g, Het=
a, Het=
5, 6:
N
b, Het=
c, Het=
N
O
N
N Boc
N
d, Het=
N
Scheme 1. Synthesis of novel series of N-acyl substituted quinolin-2(1H)-one derivatives. Reagents and conditions: (a) chloroacetyl chloride, Et3N, CH2Cl2, 20 °C, 4 h; (b)
aliphatic amines, ethanol, KI, NaHCO3, 85 °C, 18–24 h; (c) HCl, CH3OH; (d) azacyclo, ethanol, KI, NaHCO3, 85 °C, 18–24 h.

H.-B. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5845–5848
5847
Table 1
Some characteristic in vitro antibacterial and antifungal activities as MIC (
lg/mL) of compounds 4a–f and 6a–g
Compds
Mp (°C)
Yield (%)
Gram-Positive bacteria
Gram-Negative bacteria
Fungi
S.aureus
MRSA
B.subtilis
B.proteus
E .coli
C.albicans
C.mycoderma
4a
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
212–213
129–131
272–274
140–141
188–189
164–165
181–183
208–209
182–184
>300
63.8
56.0
51.3
81.7
76.2
79.4
55.1
43.0
40.1
42.0
43.1
31.1
51.5
—
8
128
32
128
128
32
32
16
128
16
64
64
64
128
128
64
256
64
64
32
32
32
32
64
32
256
32
128
64
16
256
256
256
32
128
64
128
64
128
256
16
64
8
256
256
16
128
4
32
128
16
64
256
32
32
128
—
16
32
32
256
128
32
256
16
32
32
4
32
64
128
64
32
64
32
32
128
32
16
16
—
32
128
128
64
32
32
275–276
177–179
211–213
—
32
64
32
—
128
128
64
128
32
—
6g
32
512
—
Streptomycin
Fluconazole
32
—
—
—
—
4
8
8 to 16-fold more potent than Streptomycin. Particularly, piperidyl,
pyrrolidyl and N-Boc-piperazinyl derivatives 6a and 6f–g exhibited
good activities against the tested bacteria strains except B. proteus.
Especially, compound 6b with imidazolyl group showed more po-
tential antibacterial activities against all the tested bacteria strains
References and notes
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rated that smaller and more polar group could improve the activity.
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values of 16 lg/mL, which were close to Fluconazole. More impor-
tantly, diethanolamino and piperazinyl compounds 4e and 6e
respectively exhibited better inhibition against C. albicans and C.
mycoderma (MIC = 4
lg/mL) than the reference drug Fluconazole
(MIC = 8 g/mL), indicating they were possible to be further inves-
l
tigated as antifungal agents. This suggested that these compounds
using smaller, more polar substituents help to improve the anti-
fungal activity.
In summary, a series of N-acyl substituted quinolin-2(1H)-one
derivatives were synthesized for the first time via an easy, conve-
nient and economic synthetic procedure starting from 5-amino-
3,4-dihydroquinolin-2(1H)-one, and all these new compounds
were confirmed by 1H NMR, 13C NMR and MS spectra. The
in vitro antibacterial and antifungal evaluation showed that all
the synthesized N-acyl substituted quinolin-2(1H)-one derivatives
exhibited moderate to good antimicrobial activities. Noticeably, all
the target compounds showed activities against MRSA which has
emerged resistance against Streptomycin, compound 4a and 4b
respectively showed excellent antibacterial efficacy against S. aur-
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21. Experimental: Melting points are uncorrected and were recorded on X-6
melting point apparatus, 1H NMR and 13C NMR spectra were recorded on a
Bruker AV 300 or Varian 400 spectrometer using TMS as an internal standard.
Chemical shifts were given in d ppm and signals are described as singlet (s),
doublet (d), triplet (t), quartet (q), broad (br) and multiplet (m). The mass
spectra were recorded on LC-MS-2010A. TLC analyses were done using pre-
coated silica gel plates and visualization was done using UV lamp at 254 nm.
Synthesis of 2-chloro-N-(1,2,3,4-tetrahydro-2-oxoquinolin-5-yl) acetamide (2). To
a mixture of 5-amino-3,4-dihydroquinolin-2(1H)-one (1, 1.0 g, 6.2 mmol) and
triethylamine (0.69 g, 6.8 mmol) in dry CH2Cl2 was added chloroacetyl chloride
(0.77 g, 6.8 mmol) and the reaction was stirred at room temperature for 4 h,
after the reaction came to the end (monitored by TLC), CH2Cl2 was removed by
a rotary evaporator and the residue was poured into ice-water (20 mL), the
precipitate was filtered and washed with water to give compound 2 (1.1 g) as
brown solid, yield 75%. mp: 153–154 °C; 1H NMR (300 MHz, DMSO-d6) d: 2.40
(t, J = 7.5 Hz, 2H, Quin 3-H); 2.73 (t, J = 7.5 Hz, 2H, Quin 4-H); 4.29 (s, 2H, CH2);
eus (MIC = 8
folds more potent than Streptomycin. The compound 4e and 6e
exhibited better inhibition against the test fungus (MIC = 4 g/
mL) than the reference drug Fluconazole. These findings demon-
strated that N-acyl substituted quinolin-2(1H)-one derivatives
have biological significance, which have the perspective to become
a new member of antimicrobial agents.
lg/mL) and E. coli (MIC = 8 lg/mL), which were 2–4
l
Acknowledgments
This work was partially supported by the Fundamental Re-
search Funds for the Central Universities (XDJK 2009C092) and
Natural Science Foundation of Chongqing (CSTC 2009BB5296).

5848
H.-B. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5845–5848
6.74 (d, J = 3.9 Hz, 1H, Quin 6-H); 6.98 (d, J = 3.9 Hz, 1H, Quin 8-H); 7.13 (t,
J = 7.8 Hz, 1H, Quin 7-H); 9.83 (s, 1H, Quin 1-H); 10.13 (s, 1H, Quin 5-H) ppm.
Synthesis of 2-(tert-butylamino)-N-(1,2,3,4-tetrahydro-2-oxoquinolin-5-yl)
acetamide hydrochloride (4c). a suspension of compound 2 (0.24 g, 1.0 mmol)
and KI (0.18 g, 1.1 mmol) in ethanol (25 mL) was stirred at 85 °C for 30 min,
then to the mixture added NaHCO3 (0.093 g, 1.1 mmol) and tert-butylamine
(0.077 g, 1.05 mmol), the reaction continued to stirr at 85 °C for 20 h, after the
reaction came to the end (monitored by TLC), the solvent was removed in
vacuum, the residue was recrystallized from ether to yield 3c (0.18 g).
Treatment of this material with concentrated hydrochloric acid in methanol
provided its hydrochloride 4c (0.16 g) in 51.3% yield. mp: 272–274 °C; 1H NMR
(300 MHz, D2O) d: 1.26 (s, 9H, 3 Â CH3); 2.44 (t, J = 7.2 Hz, 1H, Quin 3-H); 2.69
(t, J = 7.5 Hz, 1H, Quin 4-H); 3.95 (s, 2H, CH2); 6.77 (d, J = 8.4 Hz, 1H, Quin 6-H);
6.89 (d, J = 8.4 Hz, 1H, Quin 8-H); 7.13 (t, J = 8.4 Hz, 1H, Quin 7-H) ppm; 13C
NMR (75 MHz, DMSO-d6) d: 20.5, 29.7, 31.3, 45.7, 49.5, 117.3, 124.2, 126.7,
130.1, 136.5, 168.5, 170.5 ppm; ESI-MS (m/z): 276 [M]+.
22. Anand, K. H.; Deepti, B.; Rakesh, D. Bioorg. Med. Chem. Lett. 2007, 17, 341.