Design, synthesis, and evaluation of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives as antimicrobial agents

Article abstract of DOI:10.1007/s00044-013-0813-z

A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives was designed, synthesized, and evaluated for their antimicrobial activities against six strains of bacteria and five fungi in vitro. The synthesized compounds were characterized by spectral methods. The bioactive assays showed that most of the compounds exhibited moderate antimicrobial activities against the tested strains. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0813-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2169–2177
DOI 10.1007/s00044-013-0813-z
ORIGINAL RESEARCH
Design, synthesis, and evaluation of novel 1-methyl-3-substituted
quinazoline-2,4-dione derivatives as antimicrobial agents
•
Qing-Gang Ji Dan Yang Qiao Deng
•
•
•
Zhi-Qiang Ge Lv-Jiang Yuan
Received: 20 July 2013 / Accepted: 24 September 2013 / Published online: 10 October 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of novel 1-methyl-3-substituted qui-
nazoline-2,4-dione derivatives was designed, synthesized,
and evaluated for their antimicrobial activities against six
strains of bacteria and five fungi in vitro. The synthesized
compounds were characterized by spectral methods. The
bioactive assays showed that most of the compounds
exhibited moderate antimicrobial activities against the
tested strains.
Quinazoline-2,4-dione nucleus which resembles with the
quinolone nucleus but lacks the quinolone keto acid is an
interesting pharmacophore. Quinazoline-2,4-dione nucleus
and its derivatives have emerged abundantly due to the
advance of modern organic chemistry and these compounds
have a variety of promising medical applications as anti-
bacterial (Beylin et al., 2007), antifungal (Ryu et al., 2004),
anticancer (Oger et al., 2010), antihypertensive (Ismail et al.,
2006), antidiabetic (Feng et al., 2007), anti-inflammatory
(Ukrainets et al., 2006), and antitumor (Caldwell et al., 2011)
agents. 8-Methyl-quinazoline-2,4-dione has been shown to
overcome quinolone-resistant bacteria.(Aldred et al., 2012).
Amides derivatives possessed a variety of medical applica-
tions such as antiviral (Bylov et al., 1999), antiproliferative
(Nemmani et al., 2009), anti-inflammatory (Spasova et al.,
2008), antibacterial (Priya et al., 2005), and antifungal
(Bansode et al., 2009) agents.
Keywords Quinazoline-2,4-dione ꢀ Amide ꢀ
Antibacterial ꢀ Antifungal agents
Introduction
In recent years, the widespread use of various antibiotics
have led to the development of drug resistance (Zervosen
et al., 2012) and antimicrobial resistance has become a
global public health problem. The consequences of antimi-
crobial resistance are serious when pathogens are resistant to
antimicrobials that are currently used in the treatment of
human disease, for the use of the standard antibacterial
therapies has resulted in failures; however, the use of
increasingly costly and toxic antimicrobials would extend
hospital stays and increase morbidity, mortality, and costs
(Gonzales and Maisch, 2012; Canno et al., 2009). Although a
large number of antibiotics and chemotherapeutics are
available for medical use, the emergence of resistant bacte-
rial strains constitutes an urgent need for new classes of
antibacterial agents (Theuretzbacher, 2012; Sutcliffe, 2003).
Due to the diverse range of the pharmacological activ-
ities of quinazolinone-2,4-dione derivatives and amide
derivatives, there has been an interest in developing of
hybrid molecules through the combination of the two
pharmacophores in one frame that may lead to compounds
with interesting biological and pharmacological profiles.
Thus, a series of novel quinazoline-2,4-dione derivatives
was designed through combining the quinazoline-2,4-dione
with amide by a linker (Fig. 1), synthesized, and evaluated
for their antimicrobial activity in vitro.
Results and discussion
Chemistry
Q.-G. Ji (&) ꢀ D. Yang ꢀ Q. Deng ꢀ Z.-Q. Ge ꢀ L.-J. Yuan
School of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, People’s Republic of China
e-mail: jiqing@swu.edu.cn
The synthetic route used to prepare the title compounds
is outlined in Scheme 1. The starting material methyl
123

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Med Chem Res (2014) 23:2169–2177
O
to afford 1-methylquinazoline-2,4-dione 4, which reacted with
2-chloroethanol in DMF to form 1-methyl-3-substituted qui-
nazoline-2,4-dione 5. Under the catalysis of DMAP, 5 reacted
with 2-((tert-butoxycarbonyl)amino)acetic acid in the pre-
sence of DCC to obtain 2-(1-methyl-2,4-dioxo-1,2-dihydro-
quinazolin-3-yl)-ethyl-2-((tert-butoxycarbonyl)amino)acetate
6. The protective group of 6 was removed by trifluoroacetate to
obtain 2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3-yl)-
ethyl-2-aminoacetate 7. Finally, the compound 7 reacted with
the aromatic acyl chloride to form the corresponding target
compounds 9a–9m. The structures of the new compounds
were confirmed by 1H NMR, 13C NMR, and MS spectra.
R1
O
X
Het/Ar
N
R
N
R
H
O
N
R2
O
N
O
Het/Ar
N
N
H
R
O
O
Linker
Fig. 1 Design of novel 1-methyl-3-substituted quinazoline-2,4-dione
derivatives
Antimicrobial activity
aminobenzoate 1 was reacted with methyl iodide in the pre-
sence of sodium hydroxide in DMF to form methyl 2-(meth-
ylamino)benzoate 2 which was hydrolyzed to produce
2-(methylamino)benzoic acid 3. The acid 3 reacted with urea
All the newly synthesized compounds wereevaluated fortheir
antibacterial activity against six strains of bacteria including
three Gram-positive organisms viz. Staphylococcus aureus
O
O
O
MeI, NaOH, DMF
NaOH, MeOH, H2O
70 oC, 1h
rt-50 oC, 7h
OH
OMe
OMe
67%
NH2
90%
N
N
H
H
2
1
3
O
N
O
N
2-chloroethanol, NaOH
DMF, 80 oC, 5h
urea, 150 oC, 7h
65%
OH
NH
N
O
O
55%
4
5
O
N
(i) TFA, CH2Cl2, rt, overnight
(ii) KHCO3, MeOH, rt, 5h
BocNHCH2COOH, DMAP
CH2Cl2, 0 oC-rt, 4h
O
Boc
N
N
H
O
O
75%
52%
6
O
O
N
O
RCOCl, (Et)3N, CH2Cl2
0-5 oC, 1h.
O
N
O
NH2
N
N
R
H
O
O
N
O
O
9
11%-83%
7
X
Y
Z
9a-j R=
9a:X=Y=Z=H
9e:X=CH3,Y=Z=H
9i:X=Z=H,Y=NO2
9b:X=Z=H,Y=F
9f:X=Y=H,Z=NO2
9j:X=Y=H,Z=Cl
9c:X=Y=H,Z=F
9d:X=Cl,Y=Z=H
9g:X=Y=H,Z=OCH3 9h:X=Y=H,Z=CH3
S
O
9k:R=
9l: R=
9m: R=
Scheme 1 Preparation of 1-methyl-3-substituted quinazoline-2,4(1H,3H)-dione derivatives
123

Med Chem Res (2014) 23:2169–2177
2171
ATCC 25923, Bacillus subtilis ATCC 6633, and methicillin-
resistant S. aureus N 315 (MRSA) and three Gram-negative
organisms viz. Bacillus proteus, Escherichia coli JM 109, and
Pseudomonas aeruginosa CR 56; and antifungal activity
against five fungi viz. Cryptococcus Neoformans (extracted
from patient), Candida mycoderma, Candida albicans ATCC
76615, Saccharomyces cerevisiae CGMCC2.145, and
Aspergillus flavus 3905 by disk diffusion method in vitro.
Streptomycin and fluconazole were used as positive control
for antibacterial and antifungal activity, respectively.
Screening results of antibacterial activity are summarized in
Table 1 and the results of antifungal activity are deposited in
Table 2.
Most synthesized compounds showed moderate to good
antibacterial activities against the tested bacteria, some
compounds showed higher antibacterial activities than
streptomycin. All compounds exhibited high activities
against MRSA and B. subtilis while showed weak activities
against S. aureus. Compounds 9g, 9k, and 9m showed
good activity against B. subtilis with the MIC values of
4 lg/mL while the MIC value of streptomycin was 32 lg/
mL. Compounds 9b, 9c, 9e, 9f, 9i, 9l, and 9m showed good
Table 1 The antibacterial activities of compouds 9a–9m expressed as MIC (lg/mL)
Compounds
Yield (%)
m.p. (°C)
Gram-positive bacteria
Gram-negative bacteria
S. aureus
MRSA
B. subtilis
E. coli
B. proteus
P. aeruginosa
9a
33.3
83.3
57.6
50.3
31.6
31.6
45.9
76.6
34
169.0–170.0
167.0–168.0
171.0–172.0
144.0–145.0
176.0–177.0
233.0–234.0
123.0–124.0
131.0–131.0
157.0–158.0
127.0–128.0
183.0–185.0
166.0–167.0
150.0–151.0
256
128
256
512
512
256
512
512
128
128
256
512
128
32
[512
32
512
256
128
64
128
128
64
[512
512
512
128
32
[512
128
256
128
256
64
9b
9c
4
9d
[512
32
512
32
9e
64
9f
8
512
4
128
512
512
16
128
512
32
9g
256
512
4
128
128
512
256
128
64
9h
64
9i
256
128
4
128
256
128
64
9j
11.5
60.1
29
512
[512
32
256
4
9k
9l
32
64
9m
16
4
4
16
256
16
[512
64
Streptomycin
512
32
64
Table 2 The antifungal activities of compounds 9a–9m expressed as MIC (lg/mL)
Compounds
Candida
mycoderma
Candida
albicans
Saccharomyces
cerevisiae
Aspergillus
flavus
Cryptococcus
neoformans
9a
[512
512
64
512
16
–
64
64
64
128
128
–
32
9b
–
256
16
9c
32
–
9d
64
32
–
128
16
9e
512
64
512
512
32
–
9f
–
–
9g
512
512
16
–
128
64
64
32
64
64
32
32
64
32
9h
32
–
16
9i
64
–
128
32
9j
512
64
64
–
9k
32
–
–
128
256
8
9l
512
512
8
512
512
32
9m
–
Polyoxine D
Fluconazole
16
0.03125
0.03125
8
16
[512
123

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Med Chem Res (2014) 23:2169–2177
activity against MRSA, especially, compounds 9c, 9i, and
9m showed promising activities with the MIC values of
4 lg/mL while MIC of streptomycin was higher than
512 lg/mL. The tested compounds showed much higher
activities against E. coli and P. Aeruginosa than against B.
proteus, compounds 9e, 9i, 9k, and 9m showed antibac-
terial activity against E. coli with MIC values of 32, 16, 4,
and 32 lg/mL, respectively. Compounds 9f and 9l exhib-
ited antibacterial activity against P. Aeruginosa as well as
the control drug whose value is 64 lg/mL.
and 9m showed good activity against MRSA with the MIC
values of 4 lg/mL. The antifungal activities against A. flavus
of all the compounds except for compounds 9d, 9e, 9f, and 9g
were comparable to fluconazole. It was concluded that polar
substituent group on para-position improved the biological
activity of these compounds against MRSA.
Experimental
Similarly, the antifungal evaluation in vitro revealed that
all the synthesized compounds exhibited moderate to good
antifungal activities against all tested fungi except for S.
cerevisiae on which the experiment in vitro showed that all
compounds have no effect in test concentration.
Chemicals and analysis
All chemicals and solvents used were of reagent grade
without purification but CHCl3 and CH2Cl2 used for pre-
paring the target compounds 9a–9m were dried before use.
Melting points were measured on X-6 precise micro
As seen in Table 2, Compounds 9b, 9c, 9d, 9g, 9h, and
9k showed excellent activity against C. albicans. The MIC
values of compounds 9c, 9d, 9i, 9k, and 9l were equiva-
lency with the positive control drug polyoxin D whose
MIC was 32 lg/mL; compound 9b showed excellent
activity against C. albicans with the MIC value of 16 lg/
mL. For the A. flavus, all the compounds except com-
pounds 9d, 9e, 9f, and 9g have shown good antifungal
activity that are comparable to fluconazole. But these
compounds showed weak activities against the C. Neofor-
mans, the best active compound 9m showed activity
against C. Neoformans with the MIC value of 8 lg/mL.
From the in vitro antimicrobial activity data, preliminary
structure–activity relationship of the synthesized compounds
9a–9m was studied. The compounds 9a–9m exhibited mod-
erate to good antibacterial activity against B. subtilis, methi-
cillin-resistant S. aureus, E. coli, and P. Aeruginosa and
antifungal activity against fungi C. albicans and A. flavus.
Different amides have different effects on the bioactivities of
compounds; the non-aromatic amide, for example, compound
9m exhibited more activity than aromatic amides against
bacteria. Meanwhile, in aromatic amides, the aromatic ring
with strong polarity substituent group was beneficial for anti-
bacterial activity, such as compound 9c (Z = F, MIC = 4 lg/
mL), which showed higher activity against MRSA, and also
exhibited higher inhibitory effect against E. coli than com-
pound 9h (Z = CH3, MIC = 512 lg/mL) bearing weak
polarity substituent group. Moreover, the position of sub-
stituentgroup hassome effects on antibacterialactivity,and the
substituent group on para-position was beneficial.
1
melting point apparatus and are uncorrected. H NMR and
13C NMR spectra were recorded on BrukerAv 300 MHz
spectrometer using DMSO-d6 or CDCl3 as solvent.
Chemical shifts are given in ppm with TMS as an internal
reference. Mass spectral data were obtained on a HTC
liquid gromatograph and mass spectro ESI–MS (m/z).
Reactions were monitored by thin-layer chromatography
(TLC) on glass plates coated with Silica Gel GF-254.
Synthetic procedure for methyl 2-(methylamino)benzoate
(2)
To a solution of methyl 2-aminobenzoate 1 (16.00 g,
0.11 mol) suspended in DMF (80 mL), sodium hydroxide
(5.04 g, 0.13 mol) was added, and the mixture was stirred at
room temperature for 10 min. Iodomethane (15.68 g,
0.11 mol) in DMF (20 mL) was added dropwise over 30 min.
The reaction mixture was stirred at room temperature for
further 1 h and then heated at 50 °C for 7 h. The reaction
mixture was cooled to room temperature and water (200 mL)
was added to quench the reaction. The mixture solution was
extracted with EtOAc (60 mL 93) and the organic layer was
dried over anhydrous MgSO4, concentrated to give the crude
product which was purified by column chromatography on
silica gel (petroleum ether/EtOAc = 50:1) to afford com-
pound 2 as flavescens liquid (11.65 g, 67 %); 1H NMR
(CDCl3, 300 Mz) d: 2.92 (s, 3H, N–CH3), 3.86 (s, 3H, O–
CH3), 6.59–6.71 (m, 2H, Ar-3, 5-H), 7.40 (t, J = 6 Hz, 1H,
Ar-4-H), 7.92 (t, J = 6 Hz, 1H, Ar-6-H). 13C NMR (75 MHz,
CDCl3) d: 29.5(N–CH3), 51.2(O–CH3), 110.4(1-C), 113.4(3-
C), 117.1(5-C), 130.1(6-C), 133.2(4-C), 149.2(2-C),
166.5(C=O). MS(ESI) m/z: 166(M?H)?.
In summary, a series of 1-methyl-3-substituted quinazo-
line-2,4-dione derivatives was designed, synthesized, and
evaluated for their antibacterial and antifungal actions. The
evaluation in vitro for the antibacterial and antifungal actions
showedthatmostofthenewlycompoundsexhibitedmoderate
to good antimicrobial activities. Almost all designed com-
pounds showed activities against MRSA which has emerged
resistance against streptomycin, especially compounds 9c, 9i,
Synthetic procedure for 2-(methylamino)benzoic acid (3)
Compound 2 (9.242 g, 0.061 mol) was dissolved in the
mixture solution of water (40 mL) and methanol (30 mL),
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Med Chem Res (2014) 23:2169–2177
2173
NaOH (4.200 g, 0.105 mol) was added, and the mixture
reaction was heated at 60 °C for 1 h. Methanol was
removed by evaporation and the residue was adjusted pH
7–8 with diluted HCl aqueous solution. The desired prod-
uct (3) was obtained by filtration and then washed with
water (30 mL 93) as white powder solid (7.54 g, 90 %);
quinazolone-1-CH3), 3.94 (t, J = 15 Hz, 2H, CH2), 4.38 (t,
J = 12 Hz, 2H, CH2), 7.22–7.32 (m, 2H, quinazolone-5,6-
H), 7.71 (t, J = 15 Hz, 1H, quinazolone-7-H), 8.23 (d,
J = 6 Hz, quinazolone-8-H). 13C NMR (75 MHz, CDCl3)
d: 32.6(N–CH3), 43.4(3-N–CH2–), 57.6(–CH2–OH),
115.2(8-C), 117.1(10-C), 124.2(6-C), 127.5(5-C), 132.6 (7-
C), 136.6(9-C), 152.2(2-C=O), 159.1(4-C=O). MS(ESI) m/
z: 177(M?H)?.
1
m.p. 182–184 °C; H NMR (CDCl3, 300 Mz) d: 2.96 (s,
3H, N–CH3), 6.66 (t, J = 15 Hz, 1H, Ar-5-H), 6.73 (d,
J = 6 Hz, Ar-3-H), 7.45 (t, J = 15 Hz, 1H, Ar-4-H), 7.99
(d, J = 6 Hz, Ar-6-H). 13C NMR (75 MHz, CDCl3) d:
28.9(N–CH3), 109.1(1-C), 112.8(3-C), 118.1(5-C),
130.5(6-C), 133.6(4-C), 150.2(2-C), 170.1(C=O). MS(ESI)
m/z: 152(M?H)?.
Synthetic procedure for N-[(1,1-dimethylethoxy)carbonyl]-
glycine-2-(1,4-dihydro-1-methyl-2,4-dioxo-3(2H)-
quinazolinyl)ethyl ester (6)
Compound 5 (3.20 g, 0.015 mol) was dissolved in CH2Cl2
(50 mL) and cooled with ice bath, and DCC (3.40 g,
0.016 mol), DMAP (0.11 g, 0.90 mmol) were then added.
Then 2-((tert-butoxycarbonyl)amino)acetic acid (3.025 g,
0.017 mol) in CH2Cl2 (20 mL) was added dropwise over
30 min. The reaction mixture was stirred for 4 h at 0 °C.
After filtration, filtrate was washed with saturated sodium
bicarbonate aqueous solution (50 mL 93) and water
(50 mL 93), and dried with anhydrous MgSO4. The sol-
vent was removed to obtain the desired compound 6 as
white solid (4.301 g, 75 %); m.p. 113–114 °C; 1H
NMR(CDCl3-d1) d (ppm): 1.37 (s, 9H), 3.62 (s, 3H, qui-
nazolone-1-CH3), 3.92(s, 2H, CH2), 3.94 (t, J = 15 Hz,
2H, CH2), 4.38 (t, J = 12 Hz, 2H, CH2), 7.22–7.32 (m, 2H,
quinazolone-5,6-H), 7.71 (t, J = 15 Hz, 1H, quinazolone-
7-H), 8.23 (d, J = 6 Hz, quinazolone-8-H). 13C NMR
(75 MHz, CDCl3) d: 28.1(CH3, 3C), 32.6(N–CH3), 40.4(20-
C), 42.3(2-C), 60.4(10-C), 79.6(tert-C), 114.2(800–C),
1115.3(1000-C), 124.5(600-C), 127.7(500-C), 132.4 (700-C),
136.4(900-C), 151.2(200-C=O), 156.3(4-C=O), 159.5(400-
C=O), 169.5(1-C=O), MS(ESI) m/z: 378(M?H)?.
Synthetic procedure for 1-methylquinazoline-2,4(3H)-
dione (4)
Compound 3 (7.01 g, 0.046 mol) and urea (28.00 g,
0.47 mol) were mixed and stirred at 150 °C for 5 h. The
mixture was cooled below 100 °C and then water (70 mL)
was added to quench the reaction. The crude product was
obtained by filtration and then washed in sequence with
water (50 mL 93) and EtOAc (30 mL 93) to give
flavescens powder solid 8.23 g, which was recrystallized
from the mixture solution of acetone (10 mL) and water
(100 mL) to afford compound 4 as white powder solid
(5.25 g, 64.3 %); m.p. 278–279 °C; 1H NMR (CDCl3,
300 Mz) d: 3.43 (s, 3H, N–CH3), 7.26 (t, J = 12 Hz, 1H,
quinazolone-6-H), 7.41 (d, J = 12 Hz, 1H, quinazolone-5-
H), 7.75 (t, J = 15 Hz, 1H, quinazolone-7-H), 7.98 (d,
J = 6 Hz, 1H, quinazolone-8-H), 11.54 (s, 1H, CO–NH).
13C NMR (75 MHz, CDCl3) d: 32.9(N–CH3), 115.1(8-C),
116.2(10-C), 124.1(6-C), 127.5(5-C), 132.6(7-C), 136.6
(9-C), 152.2(2-C=O), 158.1(4-C=O). MS(ESI) m/z:
177(M?H)?.
Synthetic procedure for glycine-2-(1,4-dihydro-1-methyl-
Synthetic procedure for 3-(2-hydroxyethyl)-1-
2,4-dioxo-3(2H)-quinazolinyl)ethyl ester (7)
methylquinazoline-2,4(1H,3H)-dione (5)
Compound 6 was dissolved in CH2Cl2 and cooled down to
0 °C with ice-water bath, and TFA (3.4 mL) was added
slowly. Then reaction mixture was stirred at room temper-
ature for overnight. The solvent was removed by evapora-
tion, methanol (15 mL) and KHCO3 (1.90 g, 0.019 mol)
were added to the residue, and the resulting mixture was
stirred for 5 h at room temperature. After filtration, the fil-
trate was dried over anhydrous MgSO4, concentrated, and
the crude product was recrystallized from EtOAc to obtain
the desired product 7 as white powder solid (1.501 g,
51.7 %); m.p. 175–176 °C; 1H NMR (300 MHz, CDCl3) d:
3.43(s, 2H, CO–CH2–H), 3.60(s, 3H, quinazolone-1-CH3),
4.39(t, J = 9 Hz, 2H, CH2), 4.52(t, J = 9 Hz, 2H,
CH2), 7.22(t, J = 15 Hz, 1H, quinazolone-6-H), 7.28(d,
J = 9 Hz, 1H, quinazolone-5-H), 7.69(t, J = 15 Hz, 1H,
To a solution of compound 4 (5.00 g, 0.028 mol) and
sodium hydroxide (1.3 g, 0.032 mol) in DMF (10 mL),
2-chloroethanol (2.64 g, 0.033 mol) in DMF (10 mL) was
added, and the reaction mixture was heated up to 80 °C for
5 h. After completion of the reaction, the solution was
cooled down to room temperature; water (100 mL) was
added to quench the reaction. The mixture solution was
extracted with EtOAc (50 mL 93), the combined organic
layer was washed with water (30 mL 93), dried over
anhydrous MgSO4, and the organic solvent was removed to
get crude product 4.12 g. The crude product was recrys-
tallized from EtOAc to obtain the desired product 5 as
white granular fluffy solid (3.37 g, 54.8 %); m.p.
1
154–155 °C; H NMR (CDCl3–d1) d (ppm): 3.62 (s, 3H,
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Med Chem Res (2014) 23:2169–2177
quinazolone-7-H), 8.20(d, J = 9 Hz, quinazolone-8-H). 13
C
118.8(6-C), 122.6(9-C), 123.2(700-C), 128.8(80-C), 130.2(5-C),
135.4(900-C), 150.9(200-C=O), 160.9(400-C=O), 163.2(7-C),
164.2(4-C=O), 169.7(1-C=O). ESI–MS (m/z): 400[M?H]?.
NMR (75 MHz, CDCl3) d: 28.1(CH3, 3C), 32.6(N–CH3),
40.4(2-C), 40.3(20-C), 60.4(10-C), 115.7(800-C), 116.3(1000-
C), 124.5(500-C), 127.7 (400-C), 132.4 (600-C), 136.4(900-C),
151.2(200-C=O), 159.5(400-C=O), 169.5(1-C=O), MS(ESI)
m/z: 278(M?H)?.
N-(4-fluorobenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
dioxo-3(2H)-quinazolinyl)ethyl ester (9c)
1
General procedure for synthesis of the target
Yield 58 %; m.p. 171.0–172.0 °C; H NMR (300 MHz,
compounds (9a–9m)
CDCl3) d: 3.59 (s, 3H, quinazolone-1-CH3), 4.22 (d,
J = 3 Hz, 2H, CH2), 4.44 (t, J = 12 Hz, 2H, CH2), 4.54 (t,
J = 12 Hz, 2H, CH2), 6.76 (s, 1H, NH), 7.11 (t,
J = 18 Hz, 2H, benzene-3,5-H), 7.21–7.23 (m, 2H, qui-
nazolone-5,6-H), 7.71 (t, J = 15 Hz, 1H, quinazolone-7-
H), 7.83–7.88 (m, 2H, benzene-2,6-H), 8.17(d, J = 6 Hz,
quinazolone-8-H); 13C NMR (75 MHz, CDCl3) d: 30.8(N–
CH3), 40.3 (20-C), 42.9(2-C), 62.3(10-C), 114.8 (7,9-2C),
115.8(800-C), 124.2(1000-C), 127.7(600-C), 128.9(500-C),
128.9(6,10-2C), 129.7(5-C), 132.4(700-C), 140.5(900-C),
150.7(200-C=O), 162.0(400-C=O), 166.2(8-C), 167.9(4-
C=O), 169.8(1-C=O), ESI–MS (m/z): 400[M?H]?.
Compound 7 (0.60 mmol) was dissolved in DCM (10 ml)
and cooled with ice bath, the solution of the aromatic acyl
chloride compound (0.7 mmol) in DCM was added drop-
wise, and then triethylamine was added. The mixture was
stirred for 1 h at 0 °C and quenched with water. The water
phase was extracted with DCM; the combined organic
layer was washed with saturated NaHCO3 (10 mL 92) and
water (10 mL 93), and dried over anhydrous MgSO4.
After filtration, the filtrate was concentrated and crude
product was recrystallized from EtOAc to obtain the target
compounds (9a–9m).
N-(2-chlorobenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
N-benzoyl-glycine-2-(1,4-dihydro-1-methyl-2,4-dioxo-
dioxo-3(2H)-quinazolinyl)ethyl ester (9d)
3(2H)-quinazolinyl)ethyl ester (9a)
1
Yield 51 %; m.p. 144.0–145.0 °C; H NMR (300 MHz,
1
Yield 83 %; m.p. 167.0–168.0 °C; H NMR (300 MHz,
CDCl3) d: 3.57 (s, 3H, quinazolone-1-CH3), 4.25 (d,
J = 9 Hz, 2H, CH2), 4.43 (t, J = 12 Hz, 2H, CH2), 4.54
(d, J = 9 Hz, 2H, CH2), 6.85 (s, 1H, NH), 7.11 (t,
J = 12 Hz, 2H, benzene-5,6-H), 7.21–7.30 (m, 2H, qui-
nazolone-5,6-H), 7.71 (t, 1H, quinazolone-7-H), 7.83–7.88
(m, 2H, benzene-3,4-H), 8.17(d, J = 9 Hz, 1H, quinazo-
lone-8-H); 13C NMR (75 MHz, CDCl3) d: 30.9(N–CH3),
40.6(20-C), 42.2(2-C), 62.8(10-C), 113.8(800-C), 123.3(1000-
C), 127.1(600-C), 128.9(500-C), 129.0(9-C), 130.3(10-C),
131.0(7-C), 131.5(6-C), 131.7(5-C), 131.7(700-C), 133.5(8-
C), 140.6(900-C), 150.8 (200-C=O), 162.1(400-C=O), 166.5(4-
C=O), 169.6(1-C=O), ESI–MS (m/z): 416[M?H]?.
CDCl3) d: 3.58 (s, 3H, quinazolone-1-CH3), 4.21–4.23 (d,
J = 6 Hz, 2H, CH2), 4.43 (t, J = 9 Hz, 2H, CH2), 4.52 (t,
J = 6 Hz, 2H, CH2), 6.83 (s, 1H, NH), 7.22 (t, J = 12 Hz,
1H, quinazolone-6-H), 7.27 (d, J = 6 Hz, 1H, quinazo-
lone-5-H), 7.40–7.45 (t, J = 15 Hz, 2H, benzene-3,5-H),
7.51 (t, J = 9 Hz, 1H, benzene-4-H), 7.71 (t, J = 18 Hz,
1H, quinazolone-7-H), 7.81–7.83 (m, 2H, benzene-2,6-H),
8.17 (d, J = 6 Hz, quinazolone-8-H); 13C NMR (75 MHz,
CDCl3) d: 30.8(N–CH3), 40.2(20-C), 42.9(2-C), 62.4(10-C),
114.8(800-C), 115.8(1000-C), 124.4(600-C), 127.5(500-C),
127.7(8-C), 129.0(60,100-2C), 129.1(700-C), 132.3(70,90-2C),
134.3(5-C), 140.4(900-C), 150.7(200-C=O), 162.1(400-C=O),
167.8(4-C=O), 169.6(1-C=O); ESI–MS(m/z): 392[M?H]?.
N-(2-methylbenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
dioxo-3(2H)-quinazolinyl)ethyl ester (9e)
N-(3-fluorobenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
1
dioxo-3(2H)-quinazolinyl)ethyl ester (9b)
Yield 32 %; m.p. 176.0–177.0 °C; H NMR (300 MHz,
CDCl3) d: 2.42 (s, 3H, benzene-CH3), 3.64 (s, 3H, qui-
nazolone-1-CH3), 4.21 (d, J = 6 Hz, 2H, CH2), 4.42 (t,
J = 9 Hz, 2H, CH2), 4.53 (s, J = 9 Hz, 2H, CH2), 6.42 (s,
1H, NH), 7.15–7.23 (m, 3H, quinazolone-6-H, benzene-
3,5-H), 7.27–7.32 (m, 2H, quinazolone-5-H, benzene-4-H),
7.41 (d, J = 6 Hz, 1H, benzene-6-H), 7.70 (t, J = 15 Hz,
1H, quinazolone-7-H), 8.14 (d, J = 9 Hz, 1H, quinazo-
lone-8-H); 13C NMR (75 MHz, CDCl3) d: 18.23(Ph-CH3),
30.76(N–CH3), 40.58(20-C), 42.96(2-C), 62.34(10-C),
115.80 (800-C), 115.86(1000-C), 124.27(600-C), 127.66(9-
C),127.76(10-C), 128.78(500-C), 131.53(7-C), 132.46(8-C),
Yield 33 %; m.p. 169.0–170.0 °C; 1H NMR (300 MHz,
CDCl3) d: 3.59 (s, 3H, quinazolone-1-CH3), 4.21–4.23 (d,
J = 6 Hz, 2H, CH2), 4.43 (t, J = 9 Hz, 2H, CH2), 4.53 (t,
J = 12 Hz, 2H, CH2), 6.85 (s, 1H, NH), 7.20–7.24 (m, 3H,
benzene-4-H, quinazolone-5,6-H), 7.37–7.44 (m, 1H, ben-
zene-5-H), 7.58 (t, J = 21 Hz, 2H, benzene-2,6-H), 7.70 (t,
J = 15 Hz, 1H, quinazolone-7-H), 8.17 (d, J = 6 Hz, 1H,
quinazolone-8-H); 13C NMR (75 MHz, CDCl3) d: 30.8
(N–CH3), 40.5(20-C), 42.1(2-C), 62.8(10-C), 113.9(800-C),
114.4(1000-C), 114.7(600-C), 115.17(10-C), 118.5(500-C),
123

Med Chem Res (2014) 23:2169–2177
2175
132.57(700-C),
137.28(5-C),139.25(900-C),
140.46(6-
C), 132.37(700-C), 140.45(900-C), 141.86(8-C), 150.71(200-
C=O), 162.06(400-C=O), 167.85(4-C=O), 169.75(1-C=O),
ESI–MS (m/z): 396[M?H]?.
C),,150.81(200-C=O), 162.03(400-C=O), 167.51(4-C=O),
169.58(1-C=O). ESI–MS (m/z): 396[M?H]?.
N-(4-nitrobenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
N-(3-nitrobenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
dioxo-3(2H)-quinazolinyl)ethyl ester (9f)
dioxo-3(2H)-quinazolinyl)ethyl ester (9i)
1
Yield 45 %; m.p. 233.0–234.0 °C; 1H NMR (300 MHz,
CDCl3) d: 3.60 (s, 3H, quinazolone-1-CH3), 4.25 (d,
J = 6 Hz, 2H, CH2), 4.45 (t, J = 9 Hz, 2H, CH2), 4.56 (s,
J = 9 Hz, 2H, CH2), 6.95 (s, 1H, NH), 7.23–7.30(m, 2H,
quinazolone-5,6-H), 7.72 (t, J = 15 Hz, 1H, quinazolone-7-
H), 8.02 (d, J = 9 Hz, 2H, benzene-2,6-H), 8.15 (d,
J = 9 Hz, 1H, quinazolone-8-H), 8.32 (d, J = 9 Hz, 2H,
benzene-3,5-H); 13C NMR (75 MHz, CDCl3) d: 30.76(N–
CH3), 40.68(20-C), 42.78(2-C), 62.58(10-C), 115.72(7,9-2C),
115.87(800-C), 123.89(1000-C), 123.97(600-C), 127.46(500-C),
127.76(6,10-2C), 132.37(700-C), 133.15 (900-C), 141.46(5-C),
150.75(8-C), 151.31(200-C=O), 162.09(400-C=O), 167.85(4-
C=O),169.55(1-C=O). ESI–MS (m/z): 427[M?H]?.
Yield 51 %; m.p. 183.0–185.0 °C; H NMR (300 MHz,
CDCl3) d: 3.61 (s, 3H, quinazolone-1-CH3), 4.25 (d,
J = 3 Hz, 2H, CH2), 4.45 (t, J = 12 Hz, 2H, CH2), 4.56 (t,
J = 9 Hz, 2H, CH2), 6.99 (s, 1H, NH), 7.21–7.29 (m, 2H,
quinazolone-5,6-H), 7.64–7.73 (m, 3H, benzene-5-H, qui-
nazolone-7-H), 8.16 (d, J = 9 Hz, 1H, quinazolone-8-H),
8.21 (d, J = 6 Hz, 1H, benzene-4-H), 8.39 (d, J = 9 Hz,
1H, benzene-6-H), 8.70 (s, 1H, benzene-2-H); 13C NMR
(75 MHz, CDCl3) d: 30.73(N–CH3), 40.56 (20-C), 42.74(2-
C), 62.54(10-C), 114.97(800-C), 115.72(6-C), 122.65(1000-
C), 124.51(8-C), 127.37(600-C), 128.07(500-C), 129.79(9-C),
132.36(700-C), 133.69(10-C), 135.19(5-C), 140.46(900-C),
148.14(7-C), 150.74(200-C=O), 162.09(400-C=O), 166.22(4-
C=O), 169.73(1-C=O). ESI–MS (m/z): 427[M?H]?.
N-(4-methoxybenzoyl)-glycine-2-(1,4-dihydro-1-methyl-
2,4-dioxo-3(2H)-quinazolinyl)ethyl ester (9g)
N-(4-chlorobenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
dioxo-3(2H)-quinazolinyl)ethyl ester (9j)
1
Yield 29 %; m.p. 157.0–158.0 °C; H NMR (300 MHz,
CDCl3) d: 3.58 (s, 3H, quinazolone-1-CH3), 3.85 (s, 3H,
O–CH3), 4.21 (d, J = 3 Hz, 2H, CH2), 4.43 (t, J = 9 Hz,
2H, CH2), 4.52 (t, J = 12 Hz, 2H, CH2), 6.72 (s, 1H, NH),
6.91 (d, 2H, benzene-3,5-H), 7.20–7.29 (m, 2H, quinazo-
lone-5,6-H), 7.70 (t, J = 15 Hz, 1H, quinazolone-7-H),
7.79 (d, J = 6 Hz, 2H, benzene-2,6-H), 8.20 (d, 1H, qui-
nazolone-8-H); 13C NMR (75 MHz, CDCl3) d: 30.76(N–
CH3), 40.48(20-C), 42.86(2-C), 55.92(O–CH3), 62.46(10-
Yield 50 %; m.p. 166.0–167.0 °C; 1H NMR (300 MHz,
CDCl3) d: 3.59 (s, 3H, quinazolone-1-CH3), 4.22 (d,
J = 6 Hz, 2H, CH2), 4.44 (t, J = 12 Hz, 2H, CH2), 4.53 (t,
J = 6 Hz, 2H, CH2), 6.80 (s, 1H, NH), 7.21–7.30 (m, 2H,
quinazolone-5,6-H), 7.41 (d, J = 6 Hz, benzene-3,5H),
7.69–7.79 (m, 3H, quinazolone-7-H, benzene-2,6-H), 8.15 (d,
J = 9 Hz, quinazolone-8-H); 13C NMR (75 MHz, CDCl3) d:
30.73(N–CH3), 40.25(20-C), 42.87(2-C), 62.36(10-C),
115.78(800-C), 115.83(1000-C), 124.45(600-C), 127.75(500-C),
128.89(6,10-2C), 130.36(7,9-2C), 132.40(5,700-2C), 136.8(900-
C),140.46(8-C), 150.72(200-C=O), 162.04(400-C=O), 167.65(4-
C=O), 169.57(1-C=O). ESI–MS (m/z): 416[M?H]?.
C),
114.26(7,9-2C),
115.48(800-C),
115.75(1000-C),
115.81(600-C), 124.46(5-C), 126.46(600-C), 127.76(6,10-
2C), 131.96(700-C), 132.86(900-C), 150.75(200-C=O),
162.23(400-C=O), 164.05(8-C), 167.85(4-C=O), 169.56(1-
C=O). ESI–MS (m/z): 412[M?H]?.
N-(2-furanylcarbonyl)-glycine-2-(1,4-dihydro-1-methyl-
N-(4-methylbenzoyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
2,4-dioxo-3(2H)-quinazolinyl)ethyl ester (9k)
dioxo-3(2H)-quinazolinyl)ethyl ester (9h)
Yield 47 %; m.p. 123.0–124.0 °C; 1H NMR (300 MHz,
CDCl3) d: 3.60 (s, 3H, quinazolone-1-CH3), 4.18 (d, J = 6 Hz,
2H, CH2), 4.43 (t, J = 9 Hz, 2H, CH2), 4.50 (t, J = 6 Hz, 2H,
CH2), 6.47–6.49 (m, 1H, furan-4-H), 6.9 (s, 1H, NH), 7.12 (d,
1H, furan-2-H), 7.20–7.30 (m, 2H, quinazolone-5,6-H), 7.41 (s,
1H, furan-5-H), 7.70 (t, J = 18 Hz, 1H, quinazolone-7-H),
8.21 (d, J = 6 Hz, quinazolone-8-H); 13C NMR (75 MHz,
CDCl3) d: 30.84(N–CH3), 40.76(20-C), 42.89(2-C), 62.54(10-
C), 111.76(7-C), 112.17(6-C), 115.67(800-C), 115.85(1000-C),
124.46(600-C), 127.78(500-C), 132.39(700-C), 140.46(900-C),
143.83(8-C), 147.06(5-C), 150.72(200-C=O), 158.65(400-C=O),
162.02(4-C=O), 169.58(1-C=O). ESI–MS (m/z): 372[M?H]?.
1
Yield 63 %; m.p. 157.0–158.0 °C; H NMR (300 MHz,
CDCl3) d: 3.58 (s, 3H, quinazolone-1-CH3), 3.85 (s, 3H,
O–CH3), 4.21 (d, J = 3 Hz, 2H, CH2), 4.43 (t, J = 9 Hz,
2H, CH2), 4.52 (t, J = 12 Hz, 2H, CH2), 6.72 (s, 1H, NH),
6.91 (d, 2H, benzene-3,5-H), 7.20–7.29 (m, 2H, quinazo-
lone-5,6-H), 7.70 (t, J = 15 Hz, 1H, quinazolone-7-H),
7.79 (d, J = 6 Hz, 2H, benzene-2,6-H), 8.20 (d, 1H, qui-
nazolone-8-H); 13C NMR (75 MHz, CDCl3) d: 21.37(Ph-
CH3), 30.72(N–CH3), 40.48(20-C), 42.89(2-C), 62.38
(10-C), 115.72(800-C), 115.76(1000-C), 124.43(600-C),
127.46(6,10-2C), 127.76(500-C), 129.18(7,9-2C), 131.26(5-
123

2176
Med Chem Res (2014) 23:2169–2177
N-(2-thienylcarboyl)-glycine-2-(1,4-dihydro-1-methyl-2,4-
inhibitory concentration (MIC) which was the lowest
concentration of the test compound that resulted in no
visible growth on the plate. Streptomycin was used as the
positive control drug.
dioxo-3(2H)-quinazolinyl)ethyl ester (9l)
Yield 77 %; m.p. 131.0–131.0 °C; 1H NMR (300 MHz,
CDCl3) d: 3.60 (s, 3H, quinazolone-1-CH3), 4.20 (d, 2H,
J = 6 Hz, CH2), 4.44 (t, J = 9 Hz, 2H, CH2), 4.53 (t,
J = 9 Hz, 2H, CH2), 6.65 (s, 1H, NH), 7.08 (t, 1H, thiophene-
4-H), 7.021–7.29(m, 2H, quinazolone-5,6-H), 7.49(d,
J = 6 Hz, 1H, thiophene-5-H), 7.61 (d, J = 6 Hz, 1H, thio-
phene-3-H), 7.7 (t, 15 Hz, 1H, quinazolone-7-H), 8.19 (d,
J = 9 Hz, 1H, quinazolone-8-H); 13C NMR (75 MHz,
CDCl3) d: 30.9(N–CH3), 40.6(20-C), 42.9(2-C), 62.6(10-C),
115.6(800-C), 115.9(1000-C), 124.5(600-C), 127.8(500-C),
129.1(7-C), 130.4(700-C), 131.9(8-C), 132.3(900-C), 137.6(6-
C), 140.5(5-C), 150.8(200-C=O), 161.7(400-C=O), 162.1(4-
C=O), 169.7 (1-C=O), ESI–MS (m/z): 388[M?H]?.
The antifungal activity was evaluated against five fungi.
The media was modified Sabouraud chloramphenicol agar
containing 1 % peptone, 2 % Glucose, and solid media as
well as 15 % agar. Stock solutions were as previously
described. The antifungal activity was evaluated by disk dif-
fusion method. The tests were incubated overnight at 25 °C
and the minimum inhibitory concentrations (MIC, lg/mL)
were recorded. Fluconazole was used as the compared drug.
References
Aldred KJ, McPherson SA, Wang P, Kerns RJ, Graves DE,
Turnbough CL Jr, Osheroff N (2012) Drug interactions with
Bacillus anthracis topoisomerase IV: biochemical basis for
quinolone action and resistance. Biochem 51(1):370–381
Bansode TN, Shelke JV, Dongre VG (2009) Synthesis and antimi-
crobial activity of some new N-acyl substituted phenothiazines.
Eur J Med Chem 44(12):5094–5098
N-[(2Z)-1-oxo-3-phenyl-2-propen-1-yl]-glycine-2-(1,4-
dihydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl)ethyl ester
(9m)
1
Beylin V, Boyles DC, Curran TT, Macikenas D, Parlett RVIV, Derek V
(2007)Thepreparationoftwo, preclinicalamino-quinazolinediones
as antibacterial agents. Org Process Res Dev 11(3):441–449
Bylov IE, Vasylyev MV, Bilokin YV (1999) Synthesis and anti-
inflammatory activity of N-substituted 2-oxo-2H-1-benzopyran-
3-carboxamides and their 2-iminoanalogues. Eur J Med Chem
34(11):997–1001
Caldwell JJ, Welsh EJ, Matijssen C, Anderson VE, Antoni L, Boxall K,
Urban F, Hayes A, Raynaud FI, Rigoreau LJM et al (2011)
Structure-based design of potent and selective 2-(quinazolin-2-
yl)phenol inhibitors of checkpoint kinase 2. J Med Chem
54(2):580–590
Canno RD, Lamping E, Holmes AR, Niimi K, Baret PV, Keniya MV,
Tanabe K, Niimi M, Goffeau A, Monk BC (2009) Efflux-mediated
antifungal drug resistance. Clin Microbiol Rev 22(2):232–291
Feng J, Zhang ZY, Wallace MB, Stafford JA, Kaldor SW, Kassel DB,
Navre M, Shi L, Skene RJ, Asakawa T, Takeuchi K, Xu R, Webb
DR, Gwaltney SL (2007) Discovery of alogliptin: a potent,
selective, bioavailable, and efficacious inhibitor of dipeptidyl
peptidase IV. J Med Chem 50:2297–2300
Yield 42 %; m.p. 150.0–151.0 °C; 1H NMR (300 MHz,
CDCl3) d: 3.61 (s, 3H, quinazolone-1-CH3), 4.16 (d,
J = 6 Hz, 2H, CH2), 4.43 (t, J = 9 Hz, 2H, CH2), 4.52 (t,
J = 9 Hz, 2H, CH2), 6.36 (s, 1H, NH), 6.48 (d, J = 18 Hz,
1H, alkene-H), 7.23 (t, J = 15 Hz, 2H, quinazolone-6-H,
benzene-4-H), 7.3–7.38 (m, 3H, benzene-3,5-H, quinazo-
lone-5-H), 7.50 (t, J = 9 Hz, 2H, benzene-2, 6-H), 7.60 (s,
1H, CH = CH-H), 7.69(t, J = 18 Hz, 1H, quinazolone-7-
H), 8.21(d, J = 9 Hz, quinazolone-8-H); 13C NMR
(75 MHz, CDCl3) d: 30.8(N–CH3), 40.3(20-C), 41.9(2-C),
62.7(10-C), 113.7(6-C), 115.2(800-C), 120.0(1000-C),
123.2(600-C), 127.8(8,12,-2C), 128.8(9,11-2C), 128.9(500-
C), 129.7(10-C), 134.7(700-C), 135.4(900-C), 140.5(7-C),
141.4(6-C), 150.9(200-C=O), 162.1(400-C=O), 165.8(4-
C=O), 169.8(1-C=O). ESI–MS (m/z): 408[M?H]?.
GonzalesFP, MaischT (2012)Photodynamic inactivationfor controlling
Candida albicans infections. Fungal Biol 116(1):1–10
Antibacterial screening
Ismail MA, Barker S, Abou EDA, Abouzid KA, Toubar RA, Todd
MH (2006) Design and synthesis of new tetrazolyl- and carboxy-
biphenylylmethyl-quinazolin-4-one derivatives as angiotensin II
AT1 receptor antagonists. J Med Chem 49:1526–1535
Nemmani KVS, Mali SV, Borhade N, Pathan AR, Karwa M,
Pamidiboina V, Senthilkumar SP, Gund M, Jain AK, Mangu NK
(2009) Gastric-sparing nitric oxide-releasable prodrugs of non-
steroidal anti-inflammatory drugs. Bioorg Med Chem Lett
19(18):5297–5301
The antibacterial activity of the synthesized compounds
was evaluated against six different strains of Gram-positive
and Gram-negative bacteria by the agar diffusion method.
The media used in this assay was Beef Extract-peptone
media containing 1 % peptone, 0.3 % beef extract, 0.5 %
sodium chloride in distilled water, the solid media as well
as 15 % agar. Stock solutions of all target compounds in
DMSO were diluted to give serial 2-fold dilutions that were
added to each medium resulting in concentrations ranging
from 0.5 to 512 lg/mL. The final concentration of DMSO
in the assay did not exceed 0.3 %. The antibacterial activity
was evaluated by disk diffusion method. Tests were incu-
bated overnight at 37 °C prior to recording the minimum
Oger F, Lecorgne A, Sala E, Nardese V, Demay F, Chevance S,
´
Desravines DC, Aleksandrova V, Le Guevel R, Lorenzi S,
Beccari AR, Barath P, Hart DJ, Bondon A, Carettoni D,
Simonneaux G, Salbert G (2010) Biological and biophysical
properties of the histone deacetylase inhibitor suberoylanilide
hydroxamic acid are affected by the presence of short alkyl
groups on the phenyl ring. J Med Chem 53:1937–1950
Priya BS, Swamy SN, Rangappa KS (2005) Synthesis and charac-
terization of novel 6-fluoro-4-piperidinyl-1,2-benzisoxazole
123

Med Chem Res (2014) 23:2169–2177
2177
amides and 6-fluoro-chroman-2-carboxamides: antimicrobial
studies. Bioorg Med Chem 13(7):2623–2628
Ryu CK, Shim JY, Yi YJ, Choi IH, Chae MJ, Han JY, Jung OJ (2004)
Synthesis and antifungal activity of 5,8-quinazolinedione deriv-
Theuretzbacher U (2012) Accelerating resistance, inadequate anti-
bacterial drug pipelines and international responses. Int J
Antimicrob Agents 39:295–299
Ukrainets IV, Sidorenko LV, Gorokhova OV, Jaradat NA (2006)
4-Hydroxy-2-quinolones. Synthesis and biological properties of
2-hydroxy-4-imino-1, 4-dihydroquinoline-3-carboxylic acid
N-R-amides. Chem Heterocycl Compd 42(4):475–487
atives modified at positions
27(10):990–996
6 and 7. Arch Pharm Res
Spasova M, Philipov S, Glomb LN, Galabov AS, Milkova TS (2008)
Cinnamoyl- and hydroxycinnamoyl amides of glaucine and their
antioxidative and antiviral activities. Bioorg Med Chem
16(15):7457–7461
`
Zervosen A, Sauvage E, Frere JM, Charlier P, Luxen A (2012)
Development of new drugs for an old target—the penicillin
binding proteins. Molecules 17:12478–12505
Sutcliffe JA (2003) Antibacterial agents: solutions for the evolving
problems of resistance. Bioorg Med Chem Lett 13:4159–4161
123