Synthesis and antimicrobial activities of 2-azetidinyl- 4-quinazolinone derivatives of diclofenac analogue

Article abstract of DOI:10.1007/s00044-010-9345-y

A new class of 2-azetidinyl-4-quinazolinones 6a-k was synthesized by multi-step process, starting from 2-[2-(2,6-dichlorophenyl)amino]phenyl acetic acid 1. Acid 1 was easily converted to acid chloride 2, which on cyclization reaction with 5-bromo anthrani

Full text of DOI:10.1007/s00044-010-9345-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:511–521
DOI 10.1007/s00044-010-9345-y
ORIGINAL RESEARCH
Synthesis and antimicrobial activities of 2-azetidinyl-
4-quinazolinone derivatives of diclofenac analogue
•
Navin B. Patel Jaymin C. Patel
Received: 7 November 2009 / Accepted: 3 March 2010 / Published online: 19 March 2010
Ó Springer Science+Business Media, LLC 2011
Abstract A new class of 2-azetidinyl-4-quinazolinones
6a–k was synthesized by multi-step process, starting from
2-[2-(2,6-dichlorophenyl)amino]phenyl acetic acid 1. Acid
1 was easily converted to acid chloride 2, which on
cyclization reaction with 5-bromo anthranilic acid yielded
benzoxazinone 3. The condensation reaction of 3 with
benzene-1,4-diamine afforded 4-quinazolinone 4. Finally
the title compound 6a–k was synthesized from 4-quinaz-
olinone 4 by Schiff base formation 5a–k with aromatic
aldehyde and then cyclization reaction with chloroacetyl-
chloride. The in vitro antimicrobial activity of compounds
5a–k and 6a–k were tested. These compounds showed
pronounced antimicrobial activity when 4-Cl and 4-OCH3
groups were present.
activities. Schiff base has good antibacterial (Parekh et al.,
2005), antifungal (Gursoy et al., 2005; Mishra et al., 2005),
antitubercular (Joshi et al., 2008), antioxidant (Yuksek
et al., 2006), antitumor (Ren et al., 2002) and pharmaco-
logical applications. b-Lactam (4-membered cyclic amide)
ring structure constitutes the dominant class of agents
currently employed for the chemotherapy of bacterial
infections. Various 2-azetidinones have been reported to
possess antibacterial (Halve et al., 2006; Suryavanshi and
Pai, 2006), antifungal (Havaldar and Khatri, 2006; Panwar
et al., 2006), anti-inflammatory (Gurupadayya et al., 2008),
anthelminthic (Srivastava et al., 2004), antiviral (Pandey
et al., 2005) and anticonvulsant (Rajasekaran and Murug-
esan, 2005) activities.
Diclofenac is available as generic drug in a number of
formulations. Over the counter use is approved in some
countries for minor aches and pains and fever associated
with common infections. In the United Kingdom, India
and the United States, it may be supplied as either
the sodium or potassium salt, in China most often as the
sodium salt, while in some other countries only as the
potassium salt. Diclofenac is often used to treat chronic
pain associated with cancer, particularly if inflammation
is also present. Diclofenac has been found to be effective
against all strains of multi-drug resistant Escherichia coli.
Therefore, it may be suggested that diclofenac has the
capacity to treat UTI (uncomplicated urinary tract infec-
tions) caused by E. coli (Mazumdar et al., 2006). The
diclofenac analogue compounds displayed antibacterial
(Dutta et al., 2000), antimycobacterial (Sriram et al.,
2006), anti-inflammatory, analgesic, ulcerogenic, lipid
peroxidation (Amir and Shikha, 2004; Bhandari et al.,
2008), antitumor (Barbaric et al., 2007) and transthyretin
amyloid fibril formation inhibitor (Oza et al., 2002)
activities.
Keywords Antimicrobial activity ꢀ 2-Azetidinone ꢀ
Diclofenac ꢀ 4-Quinazolinone
Introduction
The synthetic studies of 4-quinazolinone derivatives have
been presented due to the chemical and biological interest.
4-Quinazolinone derivatives possesses antibacterial, anti-
fungal (Grover and Kini, 2006), hypolipidemic (Kurogi
et al., 1996), antitumor (Baek et al., 2004), anti-inflam-
matory (Kumar et al., 2007), antimalarial (Jiang et al.,
2005), CNS depressant, anticonvulsant (Jatav et al., 2008),
analgesic (Alagarsamy et al., 2007), antitubercular
(Mosaad et al., 2004) and antiviral (Saleh et al., 2002)
N. B. Patel (&) ꢀ J. C. Patel
Department of Chemistry, Veer Narmad South Gujarat
University, Surat 395 007, Gujarat, India
e-mail: drnavin@satyam.net.in
123

512
Med Chem Res (2011) 20:511–521
We have synthesized 2,3-disubstituted 4-quinazolinone
ene)aryl]-6-bromoquinazolin-4(3H)ones 5a–k and 2-
[2-(2,6-dichlorophenyl)amino]benzyl-3-{4-[4-(2-substituted-
phenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-bromoquinazo-
lin-4(3H)one 6a–k as illustrated in Scheme 1. Structures of
all the compounds were established on the basis of elemental
derivatives in which C-2 position was occupied by 2-[(2,6-
dichlorophenyl)amino]benzyl unit from lead molecule
diclofenac and 3rd position was replaced with various
substituted aryls (Patel and Lilakar, 2001), aryl acetamides
(Patel and Chaudhari, 2006), 4-thiazolidinones (Patel and
Patel, 2007a, b), 2-azetidinones (Patel and Patel, 2008) and
aryl sulfonamides (Patel and Chaudhari, 2008). We
observed that these synthesized compounds showed very
good antimicrobial activity and henceforth we enhanced
this work with diclofenac analogue of 4-quinazolinone
5a–k and 6a–k. The synthetic route is shown in Scheme 1.
The structure of 5a–k and 6a–k was firmly established by
elemental analyses, IR and NMR spectral data. Preliminary
microbiological test showed that most of the compounds
possessed good antimicrobial activity in vitro.
1
analyses, IR, H NMR and 13C NMR spectral data. The
required benzoxazinone 3 was prepared by the cyclization
between 5-bromoanthranilic acid and 2-[(2,6-dichloro-
phenyl)amino]phenyl acetyl chloride 2 using pyridine (Gao
et al., 2007). Formation of the product was confirmed by a
sharp band at 1695 cm-1 for C=O group along with a band at
1140 cm-1 for C–O–C stretching in IR spectrum. Com-
pound 3 was converted to quinazolin-4(3H)one 4, by its
condensation with benzene-1,4-diamine (Laddha et al.,
2006). Insertion of the nitrogen atom of benzene-1,4-dia-
mine in benzoxazinone ring was confirmed by the disap-
pearance of C–O–C stretching band at 1140 cm-1 and also
gave a strong C=O stretching vibration of quinazolinone at
1685 cm-1 instead in gave a band at 1695 cm-1 of ben-
zoxazinone. Further confirmed by 13C NMR spectrum,
which showed C=O and C=N signals of quinazolinone at d
160.4 ppm and d 164.5 ppm, respectively. When compound
4 was treated with substituted aromatic aldehydes in the
presence of glacial acetic acid as a catalyst, Schiff bases 5a–k
were formed (Archana et al., 2002), which were confirmed
by the presence of strong –N=CH– stretching vibration of
Results and discussion
Chemistry
We have synthesized a series of heterocyclic compounds, 2-
[2-(2,6-dichlorophenyl) amino]benzyl-3-[4-(2-substitutedarylid-
1
Schiff bases at around 1632 cm-1 and H NMR spectra
showed singlet at around d 6 ppm due to one proton of Schiff
base. Further cyclization reaction of Schiff bases 5a–k with
chloroacetylchloride in presence of triethylamine as a cata-
lyst at 0–5 °C gave the desired compounds azetidinyl-qui-
nazolin-4(3H)ones 6a–k (Halve et al., 2006). IR spectra of
compounds 6a–k showed strong stretching vibration at
around 1750 cm-1 due to C=O group of b-lactam ring. 1H
NMR spectra of 6a–k showed doublet at around d 3.35 ppm
and d 3.25 ppm equivalent to one proton due to[CH–Ar and
[CH–Cl of b-lactam ring respectively.
Antimicrobial activity
The results of preliminary antibacterial testing of the
compounds 5a–k and 6a–k are shown in Tables 1 and 2.
All these compounds were compared with control drug
penicillin-G. It can be seen from the calculated potency
that the Schiff base derivatives showed good antibacterial
activity but when they were converted to 2-azetidinone
derivatives, the results found different depending upon the
substituents. Schiff bases 5e, 5f, 5g, 5h and 5i possessed
moderate activities (50–53.85%) against Staphylococcus
aureus while 2-azetidinone derivatives 6e, 6f, 6g, 6h and 6i
displayed very good activities (58.33–66.67%) against
S. aureus. On the other hand, Schiff bases 5f and 5g were
found very active (59.79 and 63.91%, respectively) while
Scheme 1 Protocol for the synthesis of compounds 5a–k and 6a–k
123

Med Chem Res (2011) 20:511–521
513
Table 1 Gram positive antibacterial activity of 5a–k and 6a–k
Compound
R
S. aureus
Potency (%)
B. subtilis
Potency (%)
Std: Penicillin-G
Std: Penicillin-G
UH
UL
SH
SL
UH
UL
SH
SL
5a
5b
5c
5d
5e
5f
2-NO2
3
3
5
4
6
6
7
6
6
0
0
4
3
6
5
8
8
8
7
7
0
0
2
1
3
3
3
4
4
3
4
0
0
2
1
3
3
4
5
4
4
4
0
0
12
12
12
12
12
12
13
12
12
12
12
12
12
12
12
12
12
13
12
12
12
12
7
6
7
8
7
8
7
7
6
7
6
7
6
7
8
7
8
7
7
6
7
6
28.43
29.73
42.87
34.85
50.98
50.88
53.85
50.98
50.00
0
5
3
5
4
6
9
9
8
7
0
0
6
4
6
5
6
8
8
7
7
0
0
3
2
3
2
3
5
5
4
4
0
0
3
2
3
3
3
5
4
5
4
0
0
15
15
15
15
15
15
14
15
15
14
15
15
14
15
15
15
14
14
15
16
15
15
9
9
9
8
9
8
8
8
9
7
8
9
8
9
8
8
7
8
9
9
9
9
36.00
24.99
36.00
30.50
42.68
59.79
63.91
53.33
47.81
0
3-NO2
2-OH
4-OH
2-Cl
4-Cl
5g
5h
5i
4-OCH3
3,4,5-(OCH3)3
2-OH-4-OCH3
4-N(CH3)2
2-OH-4-N(C2H5)2
2-NO2
5j
5k
6a
6b
6c
6d
6e
6f
0
0
36.75
29.73
50.98
44.44
65.76
66.67
60.94
58.33
58.33
0
42.68
32.65
42.68
35.08
41.48
57.44
57.14
46.48
44.69
0
3-NO2
2-OH
4-OH
2-Cl
4-Cl
6g
6h
6i
4-OCH3
3,4,5-(OCH3)3
2-OH-4-OCH3
4-N(CH3)2
2-OH-4-N(C2H5)2
6j
6k
0
0
2-azetidinone derivatives 6f and 6g showed decreased
activities (57.44 and 57.14%, respectively) against Bacillus
subtilis. Schiff base derivatives 5d, 5e, 5f, 5g and 5h
showed moderate activities (44.44–52.88%) against Pseu-
domonas aeruginosa while 2-azetidinone derivatives 6d,
6e, 6f, 6g and 6h exhibited very good activities
(58.33–65.76%). Schiff base derivatives 5f, 5g, 5h and 5i
showed moderate to very good activities (42.86–64.33%)
as compared to 2-azetidinone derivatives 6f, 6g, 6h and 6i
which showed moderate activities (50–53.33%) against
E. coli. In addition, Schiff base 5g (64.33%) was found
very active than 2-azetidinone 6g (53.33%); on the other
hand, 2-azetidinones 6f and 6i exhibited higher activities
(51.09 and 50%, respectively) than Schiff bases 5f and 5i
(49.68 and 42.86%, respectively) against E. coli.
The results of antifungal testing of compounds 5a–k and
6a–k are shown in Table 3. The results of antifungal
activity revealed that Schiff base derivatives 5f and 5g as
well as 2-azetidinone derivatives 6f and 6g exhibited
comparatively good activity (2 mm at 50 lg/mL and
3–5 mm at 100 lg/mL) against fungi Candida albicans as
compared to control drug amphotericine-B. The remaining
compounds showed moderate to poor activities.
Conclusion
A series of 2-azetidinyl-4-quinazolinones 6a–k exhibited
comparatively good antimicrobial activity, most in case
when they restrain chloro and methoxy group. Schiff base
123

514
Med Chem Res (2011) 20:511–521
Table 2 Gram negative antibacterial activity of 5a–k and 6a–k
Compound
R
P. aeruginosa
Potency (%)
E. coli
Std: Penicillin-G
Potency (%)
Std: Penicillin-G
UH
UL
SH
SL
UH
UL
SH
SL
5a
5b
5c
5d
5e
5f
2-NO2
4
3
4
5
5
6
6
5
4
0
0
6
4
6
7
7
8
8
7
6
0
0
2
1
2
2
3
3
3
2
2
0
0
3
2
4
4
4
5
4
4
3
0
0
13
12
12
12
12
13
12
12
12
12
12
13
12
12
12
12
13
12
12
12
12
12
8
8
8
7
8
7
8
8
8
7
8
7
7
6
6
7
7
7
6
7
6
6
35.33
33.92
38.83
44.55
44.44
46.93
52.88
47.09
38.83
0
4
3
5
4
5
7
9
7
6
0
0
5
4
6
5
6
7
8
7
7
0
0
2
1
3
2
3
5
5
4
4
0
0
3
2
3
2
3
3
4
3
4
0
0
14
14
14
14
14
14
14
14
14
14
15
14
14
14
14
14
14
15
14
14
14
15
8
8
7
7
8
8
7
7
7
8
8
8
8
7
7
8
8
8
7
7
8
8
32.65
28.39
36.74
31.50
37.56
49.68
64.33
50.00
42.86
0
3-NO2
2-OH
4-OH
2-Cl
4-Cl
5g
5h
5i
4-OCH3
3,4,5-(OCH3)3
2-OH-4-OCH3
4-N(CH3)2
2-OH-4-N(C2H5)2
2-NO2
5j
5k
6a
6b
6c
6d
6e
6f
0
0
46.93
36.75
50.00
58.33
58.33
61.79
65.76
58.33
50.98
0
37.56
32.65
43.53
37.89
44.56
51.09
53.33
50.00
50.00
0
3-NO2
2-OH
4-OH
2-Cl
4-Cl
6g
6h
6i
4-OCH3
3,4,5-(OCH3)3
2-OH-4-OCH3
4-N(CH3)2
2-OH-4-N(C2H5)2
6j
6k
0
0
derivative with 4-methoxy group showed good activity
against gram positive as well as gram negative bacteria
among the series but the result seems different after
cyclization of Schiff base to 2-azetidinone. It shows that
the activity got increase against S. aureus and P. aeru-
ginosa, while decrease against B. subtilis and E. coli.
2-Azetidinone derivatives with 2-chloro and 4-chloro
group displayed good activity against S. aureus. 4-Chloro
and 4-methoxy group containing 2-azetidinone derivatives
possessed good activity against P. aeruginosa. Whereas
Schiff base derivative with 4-methoxy group exhibited
good activity against B. subtilis and E. coli. Schiff base as
well as 2-azetidinone derivatives containing 4-chloro and
4-methoxy group showed good antifungal activity against
C. albicans. 2-Azetidinone derivatives were found more
active than that of Schiff base derivatives.
Experimental
General
Melting points (m.p.) were determined in one-end-open
capillary tubes on a Mel-Temp apparatus and are uncor-
rected. Infrared (IR) absorption spectra were recorded on
Perkin-Elmer RX-1 FTIR spectrometer using potassium
bromide (KBr) pellet and the wave numbers were given in
cm-1. The 1H NMR spectra were recorded in deutero
123

Med Chem Res (2011) 20:511–521
515
Table 3 Antifungal activity (zone of inhibition in mm) of 5a–k and 6a–k
Compound
R
C. albicans
50 lg/mL
100 lg/mL
5a
2-NO2
1
1
0
0
1
2
2
1
0
0
0
1
1
0
0
2
2
2
1
0
0
0
4
2
2
1
1
2
4
3
2
0
1
0
2
2
0
0
3
5
4
2
1
1
0
9
5b
3-NO2
5c
2-OH
5d
4-OH
5e
2-Cl
5f
4-Cl
5g
4-OCH3
3,4,5-(OCH3)3
2-OH-4-OCH3
4-N(CH3)2
2-OH-4-N(C2H5)2
2-NO2
5h
5i
5j
5k
6a
6b
3-NO2
6c
2-OH
6d
4-OH
6e
2-Cl
6f
4-Cl
6g
4-OCH3
3,4,5-(OCH3)3
2-OH-4-OCH3
4-N(CH3)2
2-OH-4-N(C2H5)2
–
6h
6i
6j
6k
Amphotericine-B
Synthesis of 2-[2-(2,6-dichlorophenyl)amino]benzyl-
chloroform (CDCl3) on a Bruker Avance II 400 NMR
spectrometer (400 MHz). The 13C NMR spectra were
recorded in deutero chloroform (CDCl3) on a Bruker Avance
II 400 NMR spectrometer operating at 100 MHz. The
chemical shifts are reported in part per million (d ppm) using
tetramethylsilane (TMS) as an internal standard. The
microanalyses were performed on a Perkin-Elmer 240C
elemental analyzer. The purities of the compounds were
checked by thin layer chromatography (TLC) using ready-
made silica gel plates (Merck) and benzene:methanol (8:2)
as a solvent system. The spots were developed in an iodine
chamber and visualized under ultraviolet (UV) lamp.
2-[(2,6-Dichlorophenyl)amino]phenyl acetyl chloride 2 was
synthesized by literature procedure (Furniss et al., 1989).
6-bromo-3,1-benzoxazin-4(H)one (3)
A mixture of 2-[(2,6-dichlorophenyl)amino]phenyl acetyl
chloride (2) (0.02 mol) and 5-bromo anthranilic acid
(0.02 mol) in pyridine (40 mL) were stirred at 0–5 °C for
1 h, further stirred for 1 h at room temperature. A pasty mass
obtained which was washed thoroughly with sodium bicar-
bonate (5%) to remove unreacted acid. A solid separated was
filtered, dried and recrystallized from methanol to give (3).
Yield = 55%, m.p. 194–198 °C; IR (KBr) cm-1: 3445
(NH), 2928, 2852 (CH2), 1695 (C=O of benzoxazinone),
1615 (C=N), 1320 (C–N), 1140 (C–O–C), 784 (C–Cl), 630
(C–Br); 1H NMR (CDCl3): d 9.25 (s, 1H, NH), 6.15–7.58 (m,
123

516
Med Chem Res (2011) 20:511–521
10H, ArH), 3.58 (s, 2H, CH2); 13C NMR (CDCl3): d 164.3,
159.2, 148.5, 138.3, 138.1, 135.3, 135.2, 129.2, 129.1, 127.6,
127.4, 126.7, 124.1, 121.5, 121.2, 119.1, 118.5, 118.2, 32.5;
Anal. Calcd. for C21H13N2O2BrCl2: C, 52.97; H, 2.75; N,
5.88. Found: C, 52.95; H, 2.78; N, 5.85.
148.8, 147.8, 146.3, 138.5, 136.5, 135.3, 135.2, 132.4,
132.3, 131.2, 130.1, 129.8, 129.4, 128.3, 127.8, 127.7,
126.8, 124.6, 124.1, 123.2, 122.9, 122.5, 121.7, 121.3,
119.2, 118.4, 28.6; Anal. Calcd. for C34H22O3N5BrCl2: C,
58.39; H, 3.17; N, 10.01. Found: C, 58.31; H, 3.09; N, 9.96.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-(4-
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(3-
nitroarylidene)aryl]-6-bromoquinazolin-4(3H)one (5b)
aminoaryl)-6-bromoquinazolin-4(3H)ones (4)
A mixture of (3) (0.01 mol) and benzene-1,4-diamine
(0.01 mol) in pyridine (20 mL) was refluxed on an oil bath
for 5–6 h. After completion of the reaction, the oily mass
obtained, which was slowly poured onto crushed ice-cold
water contained concentrated HCl (36% 10 mL) with
occasional stirring. The product obtained was filtered and
washed several times with water. The crushed product was
dried and crystallized from ethanol to provide (4).
Yield = 58%, m.p. 209–211 °C; IR (KBr) cm-1: 3505
(NH2), 3438 (NH), 2922, 2849 (CH2), 1685 (C=O of qui-
nazolinone), 1613 (C=N), 1317 (C–N), 784 (C–Cl), 627
Yield = 57%, m.p. 157–161 °C; IR (KBr) cm-1: 3441
(NH), 2928, 2855 (CH2), 1678 (C=O of quinazolinone),
1632 (N=CH), 1613 (C=N), 1545, 1358 (NO2), 1340
(C–N), 787 (C–Cl), (C–Br); 1H NMR (CDCl3): d 9.25 (s, 1H,
NH), 6.53–7.85 (m, 18H, ArH), 6.17 (s, 1H, N=CH), 3.58 (s,
2H, CH2); 13C NMR (CDCl3): d 164.6, 162.1, 161.2, 148.7,
148.2, 146.4, 138.4, 136.6, 135.4, 135.3, 134.7, 132.4, 131.3,
129.8, 129.7, 129.3, 127.7, 127.6, 126.8, 126.2, 124.5, 123.3,
122.8, 122.7, 122.6, 121.8, 121.4, 119.1, 118.3, 28.5; Anal.
Calcd. for C34H22O3N5BrCl2: C, 58.39; H, 3.17; N, 10.01.
Found: C, 58.35; H, 3.08; N, 9.98.
1
(C–Br); H NMR (CDCl3): d 9.30 (s, 1H, NH), 6.30–7.60
(m, 14H, ArH), 5.73 (s, 2H, NH2), 3.62 (s, 2H, CH2); 13C
NMR (CDCl3): d 164.5, 160.4, 146.2, 144.1, 138.6, 136.4,
135.4, 132.4, 129.8, 129.5, 127.9, 127.8, 126.8, 124.7,
123.1, 122.8, 122.5, 121.8, 121.2, 119.1, 118.3, 116.6,
28.9; Anal. Calcd. for C27H19ON4BrCl2: C, 57.27; H, 3.38;
N, 9.89. Found: C, 57.22; H, 3.32; N, 9.83.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(2-
hydroxyarylidene)aryl]-6-bromo quinazolin-4(3H)one (5c)
Yield = 55%, m.p. 155–160 °C; IR (KBr) cm-1: 3450
(NH), 3255 (OH), 2928, 2853 (CH2), 1680 (C=O of qui-
nazolinone), 1635 (N=CH), 1618 (C=N), 1335 (C–N), 784
(C–Cl), (C–Br); 1H NMR (CDCl3): d 9.25 (s, 1H, NH), 6.57-
7.86 (m, 18H, ArH), 6.15 (s, 1H, N=CH), 4.85 (s, 1H, OH),
3.62 (s, 2H, CH2); 13C NMR (CDCl3): d 164.2, 161.1, 160.2,
159.3, 148.8, 146.5, 138.6, 136.6, 135.5, 132.6, 132.5, 131.3,
130.6, 129.6, 129.2, 127.8, 127.6, 126.9, 124.3, 123.5, 122.7,
122.5, 121.7, 121.5, 121.3, 119.3, 118.5, 118.2, 116.3, 28.5;
Anal. Calcd. for C34H23O2N4BrCl2: C, 60.92; H, 3.46; N,
8.36. Found: C, 60.83; H, 3.37; N, 8.29.
General procedure for the preparation
of 2-[2-(2,6-dichlorophenyl)amino]benzyl-3-[4-
(substitutedarylidene)aryl]-6-bromoquinazolin-
4(3H)ones (5a–k)
A mixture of (4) (0.005 mol) and substituted aromatic
aldehyde (0.005 mol) was taken in absolute ethanol
(40 mL) and added few drops of glacial acetic acid. Then
the mixture was refluxed for 4–6 h on water bath. The
excess solvent was distilled off, poured in to ice cold water.
The separated solid was filtered, washed and recrystallized
from ethanol to provide (5a–k).
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(4-
hydroxyarylidene)aryl]-6-bromo quinazolin-4(3H)one (5d)
Yield = 57%, m.p. 163–165 °C; IR (KBr) cm-1: 3448
(NH), 3245 (OH), 2918, 2852 (CH2), 1673 (C=O of qui-
nazolinone), 1630 (N=CH), 1615 (C=N), 1345 (C–N), 785
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(2-
nitroarylidene)aryl]-6-bromoquinazolin-4(3H)one (5a)
1
(C–Cl), (C–Br); H NMR (CDCl3): d 9.28 (s, 1H, NH),
6.52–7.84 (m, 18H, ArH), 6.20 (s, 1H, N=CH), 4.88 (s, 1H,
OH), 3.67 (s, 2H, CH2); 13C NMR (CDCl3): d 164.4, 160.8,
160.3, 159.5, 148.5, 146.3, 138.4, 136.7, 135.3, 132.5,
131.4, 130.6, 129.5, 129.3, 127.7, 127.5, 126.5, 126.4,
124.4, 123.6, 122.8, 122.7, 121.6, 121.4, 119.2, 118.3,
116.3, 28.6; Anal. Calcd. for C34H23O2N4BrCl2: C, 60.92;
H, 3.46; N, 8.36. Found: C, 60.85; H, 3.38; N, 8.31.
Yield = 56%, m.p. 167–170 °C; IR (KBr) cm-1: 3443
(NH), 2925, 2852 (CH2), 1674 (C=O of quinazolinone),
1635 (N=CH), 1615 (C=N), 1542, 1360 (NO2), 1342
1
(C–N), 785 (C–Cl), (C–Br); H NMR (CDCl3): d 9.30 (s,
1H, NH), 6.55–7.84 (m, 18H, ArH), 6.20 (s, 1H, N=CH),
3.60 (s, 2H, CH2); 13C NMR (CDCl3): d 165.3, 161.2, 160,
123

Med Chem Res (2011) 20:511–521
517
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(2-
chloroarylidene)aryl]-6-bromo quinazolin-4(3H)one (5e)
9.32 (s, 1H, NH), 6.44–7.79 (m, 16H, ArH), 5.95 (s, 1H,
N=CH), 3.85 (s, 6H, OCH3), 3.68 (s, 3H, OCH3), 3.63 (s,
2H, CH2); 13C NMR (CDCl3): d 164.2, 161.5, 160.2, 150.9,
148.4, 146.3, 141.5, 138.2, 136.5, 135.3, 132.3, 131.2,
129.5, 129.3, 128.1, 127.7, 127.5, 126.6, 124.4, 123.6,
122.6, 122.4, 121.7, 121.2, 119.3, 118.3, 106.6, 55.1, 54.6,
29.5; Anal. Calcd. for C37H29O4N4BrCl2: C, 59.69; H,
3.93; N, 7.53. Found: C, 59.62; H, 3.84; N, 7.47.
Yield = 54%, m.p. 142–145 °C; IR (KBr) cm-1: 3444
(NH), 2922, 2848 (CH2), 1677 (C=O of quinazolinone),
1632 (N=CH), 1617 (C=N), 1335 (C–N), 787 (C–Cl),
1
(C–Br); H NMR (CDCl3): d 9.18 (s, 1H, NH), 6.57-7.87
(m, 18H, ArH), 6.25 (s, 1H, N=CH), 3.78 (s, 2H, CH2); 13
C
NMR (CDCl3): d 165.1, 161.2, 160.1, 148.7, 146.4, 138.3,
136.3, 135.4, 133.9, 133.4, 132.5, 132.3, 131.3, 130.6,
129.5, 129.2, 128.9, 127.9, 127.6, 127.2, 126.6, 124.7,
123.3, 122.8, 122.4, 121.5, 121.2, 119.3, 118.3, 29.1; Anal.
Calcd. for C34H22ON4BrCl3: C, 59.28; H, 3.22; N, 8.13.
Found: C, 59.24; H, 3.14; N, 8.08.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(2-hydroxy-
4-methoxyarylidene)aryl]-6-bromoquinazolin-4(3H)one
(5i)
Yield = 63%, m.p. 171–174 °C; IR (KBr) cm-1: 3425
(NH), 3250 (OH), 2925, 2848 (CH2), 1678 (C=O of qui-
nazolinone), 1632 (N=CH), 1614 (C=N), 1317 (C–N), 1198,
1109 (C–O–C), 775 (C–Cl), 625 (C–Br); 1H NMR (CDCl3):
d 9.25 (s, 1H, NH), 6.49–7.73 (m, 17H, ArH), 5.85 (s, 1H,
N=CH), 4.75 (s, 1H, OH), 3.91 (s, 3H, OCH3), 3.65 (s, 2H,
CH2); 13C NMR (CDCl3): d 164.9, 164.3, 162.1, 161.5,
160.8, 148.5, 146.4, 138.5, 136.5, 135.4, 132.4, 131.6, 131.4,
129.5, 129.3, 127.8, 127.5, 126.7, 124.2, 123.6, 122.9, 122.6,
121.6, 121.4, 119.2, 118.4, 110.8, 107.2, 102.1, 55.8, 28.6;
Anal. Calcd. for C35H25O3N4BrCl2: C, 60.02; H, 3.60; N,
8.00. Found: C, 59.94; H, 3.51; N, 7.94.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(4-
chloroarylidene)aryl]-6-bromo quinazolin-4(3H)one (5f)
Yield = 56%, m.p. 160–163 °C; IR (KBr) cm-1: 3446
(NH), 2925, 2845 (CH2), 1679 (C=O of quinazolinone),
1636 (N=CH), 1619 (C=N), 1332 (C–N), 783 (C–Cl), (C–
1
Br); H NMR (CDCl3): d 9.20 (s, 1H, NH), 6.51-7.85 (m,
18H, ArH), 6.28 (s, 1H, N=CH), 3.75 (s, 2H, CH2); 13C
NMR (CDCl3): d 165, 162.2, 160.8, 148.5, 146.2, 138.5,
136.7, 136.6, 135.4, 132.3, 131.8, 131.3, 130.5, 129.6,
129.4, 128.7, 127.8, 127.6, 126.7, 124.3, 123.5, 122.7,
122.5, 121.5, 121.3, 119.1, 118.2, 28.7; Anal. Calcd. for
C34H22ON4BrCl3: C, 59.28; H, 3.22; N, 8.13. Found: C,
59.28; H, 3.16; N, 8.06.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(4-N-
dimethylaminoarylidene)aryl]-6-bromoquinazolin-
4(3H)one (5j)
Yield = 65%, m.p. 174–177 °C; IR (KBr) cm-1: 3435
(NH), 2920, 2845 (CH2), 1686 (C=O of quinazolinone),
1633 (N=CH), 1615 (C=N), 1317 (C–N), 784 (C–Cl), 614
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(4-
methoxyarylidene)aryl]-6-bromo quinazolin-4(3H)one (5g)
Yield = 62%, m.p. 161–164 °C; IR (KBr) cm-1: 3425
(NH), 2920, 2840 (CH2), 1670 (C=O of quinazolinone),
1628 (N=CH), 1610 (C=N), 1310 (C–N), 1196, 1100 (C–O–
C), 778 (C–Cl), 630 (C–Br); 1H NMR (CDCl3): d 9.30 (s, 1H,
NH), 6.58–7.85 (m, 18H, ArH), 5.93 (s, 1H, N=CH), 3.80 (s,
3H, OCH3), 3.60 (s, 2H, CH2); 13C NMR (CDCl3): d 164.8,
162.7, 161.2, 160.9, 148.2, 146.4, 138.3, 136.5, 135.3, 132.4,
131.4, 130.5, 129.5, 129.3, 127.7, 127.4, 126.5, 126.3, 124.4,
123.6, 122.5, 122.3, 121.7, 121.3, 119.2, 118.3, 114.5, 55.3,
28.4; Anal. Calcd. for C35H25O2N4BrCl2: C, 61.42; H, 3.68;
N, 8.19. Found: C, 61.33; H, 3.59; N, 8.13.
1
(C–Br); H NMR (CDCl3): d 9.20 (s, 1H, NH), 6.45–7.81
(m, 18H, ArH), 5.95 (s, 1H, N=CH), 3.62 (s, 2H, CH2),
2.89 (s, 6H, N–(CH3)2); 13C NMR (CDCl3): d 165.8, 161.4,
160.2, 151.8, 148.3, 146.5, 138.2, 136.4, 135.2, 132.5,
131.3, 130.1, 129.4, 129.3, 127.6, 127.5, 126.6, 124.6,
123.7, 123.3, 122.4, 122.2, 121.6, 121.4, 119.3, 118.2,
114.4, 41.1, 28.4; Anal. Calcd. for C36H28ON5BrCl2: C,
62.00; H, 4.05; N, 10.04. Found: C, 61.91; H, 3.96; N, 9.97.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(2-hydroxy-
4-N-diethylaminoarylidene) aryl]-6-bromoquinazolin-
4(3H)one (5k)
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-[4-(3,4,5-
trimethoxyarylidene)aryl]-6-bromo quinazolin-4(3H)one
(5h)
Yield = 58%, m.p. 144–148 °C; IR (KBr) cm-1: 3445
(NH), 3244 (OH), 2923, 2847 (CH2), 1685 (C=O of qui-
nazolinone), 1637 (N=CH), 1618 (C=N), 1316 (C–N), 785
(C–Cl), 620 (C–Br); 1H NMR (CDCl3): d 9.23 (s, 1H, NH),
6.15–7.85 (m, 17H, ArH), 5.84 (s, 1H, N=CH), 3.57 (s, 2H,
CH2), 3.44 (q, 4H, N–(CH2)2), 1.28 (t, 6H, CH3); 13C NMR
(CDCl3): d 164.9, 162.2, 161.5, 160.2, 153.3, 148.3, 146.3,
Yield = 59%, m.p. 150–155 °C; IR (KBr) cm-1: 3430
(NH), 2923, 2845 (CH2), 1675 (C=O of quinazolinone),
1630 (N=CH), 1615 (C=N), 1313 (C–N), 1195, 1105
1
(C–O-C), 780 (C–Cl), 632 (C–Br); H NMR (CDCl3): d
123

518
Med Chem Res (2011) 20:511–521
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(2-
hydroxyphenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6c)
138.4, 136.4, 135.5, 132.5, 131.5, 131.3, 129.7, 129.6,
127.8, 127.5, 126.7, 124.3, 123.5, 122.6, 122.4, 121.6,
121.4, 119.3, 118.2, 108.2, 107.3, 99.1, 44.6, 28.9, 13.2;
Anal. Calcd. for C38H32O2N5BrCl2: C, 61.55; H, 4.35; N,
9.44. Found: C, 61.47; H, 4.26; N, 9.39.
Yield = 55%, m.p. 163–167 °C; IR (KBr) cm-1: 3448
(NH), 3250 (OH), 2923, 2852 (CH2), 1753 (C=O of aze-
tidinone), 1681 (C=O of quinazolinone), 1613 (C=N), 1338
General procedure for the preparation of 2-[2-(2,6-
dichlorophenyl)amino]benzyl-3-{4-[4-(2-
1
(C–N), 785 (C–Cl), 625 (C–Br); H NMR (CDCl3): d 9.28
(s, 1H, NH), 6.58–7.93 (m, 18H, ArH), 4.85 (s, 1H, OH),
3.63 (s, 2H, CH2), 3.36 (d, 1H, CH–Ar), 3.28 (d, 1H, CH–
Cl); 13C NMR (CDCl3): d 164.5, 163.1, 160.9, 154.3,
146.4, 138.5, 137.5, 136.6, 135.4, 132.5, 130.8, 129.5,
129.2, 128.4, 128.3, 128.1, 127.8, 127.5, 126.8, 124.3,
123.4, 121.7, 121.5, 121.4, 121.2, 119.2, 118.3, 115.6,
61.7, 55.6, 28.7; Anal. Calcd. for C36H24N4O3Cl3Br: C,
57.89; H, 3.24; N, 7.50. Found: C, 57.81; H, 3.16; N, 7.43.
substitutedphenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)ones (6a–k)
A solution of (5) (0.0025 mol) in dry dioxane (20 mL) was
added to a well-stirred mixture of chloroacetylchloride
(0.0025 mol) and triethylamine (0.0025 mol) in dry dioxane
at 0–5 °C. The reaction mixture was stirred for 10–12 h and
kept for 2 days at room temperature. The product was iso-
lated and recrystallized from ethanol to provide (6a–k).
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(4-
hydroxyphenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6d)
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(2-
nitrophenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6a)
Yield = 61%, m.p. 170–175 °C; IR (KBr) cm-1: 3450
(NH), 3247 (OH), 2920, 2853 (CH2), 1755 (C=O of aze-
tidinone), 1675 (C=O of quinazolinone), 1618 (C=N), 1340
Yield = 58%, m.p. 174–176 °C; IR (KBr) cm-1: 3440
(NH), 2926, 2853 (CH2), 1746 (C=O of azetidinone), 1682
(C=O of quinazolinone), 1613 (C=N), 1545, 1355 (NO2),
1335 (C–N), 788 (C–Cl), (C–Br); 1H NMR (CDCl3): d 9.25
(s, 1H, NH), 6.51–7.85 (m, 18H, ArH), 3.52 (s, 2H, CH2),
3.32 (d, 1H, CH–Ar), 3.23 (d, 1H, CH–Cl); 13C NMR
(CDCl3): d 164.3, 162.6, 160.5, 147.3, 146.2, 138.4, 137.4,
137.3, 136.4, 135.3, 134.6, 132.3, 129.7, 129.5, 128.4,
127.9, 127.7, 127.6, 127.4, 126.7, 124.5, 123.5, 123.3,
121.7, 121.5, 121.2, 119.1, 118.3, 62.3, 55.4, 28.1; Anal.
Calcd. for C36H23O4N5BrCl3: C, 55.73; H, 2.99; N, 9.03.
Found: C, 55.66; H, 2.91; N, 8.95.
1
(C–N), 787 (C–Cl), 621 (C–Br); H NMR (CDCl3): d 9.25
(s, 1H, NH), 6.55–7.90 (m, 18H, ArH), 4.90 (s, 1H, OH),
3.60 (s, 2H, CH2), 3.35 (d, 1H, CH–Ar), 3.30 (d, 1H, CH–
Cl); 13C NMR (CDCl3): d 164.7, 162.3, 160.3, 156.5,
146.4, 138.5, 137.7, 136.7, 136.1, 135.3, 132.6, 129.4,
129.3, 128.5, 128.3, 127.6, 127.4, 126.5, 124.5, 123.7,
121.8, 121.7, 121.5, 119.1, 118.2, 115.7, 61.9, 55.8, 28.5;
Anal. Calcd. for C36H24N4O3Cl3Br: C, 57.89; H, 3.24; N,
7.50. Found: C, 57.85; H, 3.18; N, 7.45.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(2-
chlorophenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6e)
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(3-
nitrophenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6b)
Yield = 63%, m.p. 157–160 °C; IR (KBr) cm-1: 3448
(NH), 2923, 2850 (CH2), 1740 (C=O of azetidinone), 1675
(C=O of quinazolinone), 1615 (C=N), 1330 (C–N), 784
(C–Cl), 635 (C–Br); 1H NMR (CDCl3): d 9.28 (s, 1H, NH),
6.52–7.85 (m, 18H, ArH), 3.52 (s, 2H, CH2), 3.36 (d, 1H,
CH–Ar), 3.29 (d, 1H, CH–Cl); 13C NMR (CDCl3): d 164.7,
163.2, 161.2, 146.5, 143.5, 138.3, 137.6, 136.3, 135.4,
132.4, 132.2, 129.6, 129.2, 128.6, 128.4, 128.3, 128.2,
127.8, 127.5, 126.7, 126.6, 124.7, 123.4, 121.7, 121.5,
121.3, 119.3, 118.4, 62.4, 54.3, 29.2; Anal. Calcd. for
C36H23O2N4BrCl4: C, 56.50; H, 3.03; N, 7.32. Found: C,
56.44; H, 2.94; N, 7.27.
Yield = 56%, m.p. 165–168 °C; IR (KBr) cm-1: 3445
(NH), 2925, 2850 (CH2), 1740 (C=O of azetidinone), 1680
(C=O of quinazolinone), 1615 (C=N), 1543, 1351 (NO2),
1338 (C–N), 786 (C–Cl), 628 (C–Br); 1H NMR (CDCl3): d
9.35 (s, 1H, NH), 6.53–7.87 (m, 18H, ArH), 3.48 (s, 2H,
CH2), 3.31 (d, 1H, CH–Ar), 3.22 (d, 1H, CH–Cl); 13C
NMR (CDCl3): d 164.2, 162.2, 160.3, 147.7, 146.5, 144.5,
138.5, 137.4, 136.5, 135.4, 133.2, 132.3, 129.6, 129.5,
129.4, 128.5, 127.6, 127.5, 126.9, 124.4, 123.5, 123.4,
121.8, 121.7, 121.6, 121.5, 119.3, 118.4, 62.6, 55.6, 28.6;
Anal. Calcd. for C36H23O4N5BrCl3: C, 55.73; H, 2.99; N,
9.03. Found: C, 55.67; H, 2.93; N, 8.99.
123

Med Chem Res (2011) 20:511–521
519
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(4-
chlorophenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6f)
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(2-
hydroxy-4-methoxyphenyl)-3-chloro-2-oxo-
azetidinyl]aryl}-6-bromoquinazolin-4(3H)one (6i)
Yield = 57%, m.p. 172–176 °C; IR (KBr) cm-1: 3445
(NH), 2926, 2852 (CH2), 1748 (C=O of azetidinone), 1685
(C=O of quinazolinone), 1612 (C=N), 1328 (C–N), 786
(C–Cl), 630 (C–Br); 1H NMR (CDCl3): d 9.22 (s, 1H, NH),
6.50–7.87 (m, 18H, ArH), 3.55 (s, 2H, CH2), 3.37 (d, 1H,
CH–Ar), 3.28 (d, 1H, CH–Cl); 13C NMR (CDCl3): d 164.7,
163.5, 160.2, 146.3, 141.5, 138.6, 137.7, 136.6, 135.4,
132.7, 132.4, 129.5, 129.4, 128.6, 128.5, 128.3, 127.8,
127.6, 126.7, 124.3, 123.4, 121.8, 121.5, 121.4, 119.2,
118.3, 62.1, 54.6, 29.3; Anal. Calcd. for C36H23O2N4BrCl4:
C, 56.50; H, 3.03; N, 7.32. Found: C, 56.46; H, 2.95; N,
7.28.
Yield = 54%, m.p. 184–188 °C; IR (KBr) cm-1: 3435
(NH), 3248 (OH), 2928, 2852 (CH2), 1748 (C=O of aze-
tidinone), 1678 (C=O of quinazolinone), 1615 (C=N), 1316
1
(C–N), 1195, 1110 (C–O–C), 778 (C–Cl), 627 (C–Br); H
NMR (CDCl3): d 9.28 (s, 1H, NH), 6.45–7.75 (m, 17H,
ArH), 4.81 (s, 1H, OH), 3.85 (s, 3H, OCH3), 3.58 (s, 2H,
CH2), 3.36 (d, 1H, CH-Ar), 3.26 (d, 1H, CH-Cl); 13C NMR
(CDCl3): d 164.6, 162.2, 161.4, 160.1, 155.2, 146.3, 138.4,
137.6, 136.5, 135.3, 132.5, 129.4, 129.3, 129.2, 128.5,
127.8, 127.6, 126.6, 124.2, 123.5, 123.2, 121.7, 121.6,
121.4, 119.1, 118.3, 106.7, 101.8, 63.6, 57.1, 55.8, 28.7;
Anal. Calcd. for C37H26O4N4BrCl3: C, 57.20; H, 3.37; N,
7.21. Found: C, 57.12; H, 3.28; N, 7.15.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(4-
methoxyphenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6g)
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(4-N-
dimethylaminophenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6j)
Yield = 65%, m.p. 168–170 °C; IR (KBr) cm-1: 3446
(NH), 2923, 2848 (CH2), 1740 (C=O of azetidinone), 1685
(C=O of quinazolinone), 1618 (C=N), 1349 (C–N), 1205,
1104 (C–O–C), 778 (C–Cl), 630 (C–Br); 1H NMR
(CDCl3): d 9.35 (s, 1H, NH), 6.55–7.84 (m, 18H, ArH),
3.82 (s, 3H, OCH3), 3.50 (s, 2H, CH2), 3.36 (d, 1H, CH–
Ar), 3.28 (d, 1H, CH–Cl); 13C NMR (CDCl3): d 164.1,
163.5, 159.8, 158.5, 146.3, 138.4, 137.6, 136.5, 135.7,
135.3, 132.5, 129.7, 129.5, 128.3, 127.9, 127.4, 127.2,
126.5, 124.4, 123.5, 121.8, 121.6, 121.4, 119.1, 118.2,
114.3, 63.5, 56.4, 54.5, 28.6; Anal. Calcd. for
C37H26O3N4BrCl3: C, 58.40; H, 3.44; N, 7.36. Found: C,
58.32; H, 3.36; N, 7.28.
Yield = 52%, m.p. 187–190 °C; IR (KBr) cm-1: 3437
(NH), 2923, 2851 (CH2), 1752 (C=O of azetidinone), 1686
(C=O of quinazolinone), 1614 (C=N), 1318 (C–N), 785
(C–Cl), 620 (C–Br); 1H NMR (CDCl3): d 9.30 (s, 1H, NH),
6.50–7.83 (m, 18H, ArH), 3.50 (s, 2H, CH2), 3.35 (d, 1H,
CH–Ar), 3.30 (d, 1H, CH–Cl) 2.89 (s, 6H, N–(CH3)2); 13
C
NMR (CDCl3): d 165.1, 163.3, 160.7, 147.6, 146.4, 138.3,
137.5, 136.5, 135.3, 133.2, 132.5, 129.6, 129.4, 128.4,
127.9, 127.8, 127.6, 126.6, 124.4, 123.6, 121.7, 121.5,
121.2, 119.2, 118.2, 114.1, 63.3, 56.3, 41.2, 28.6; Anal.
Calcd. for C38H29O2N5BrCl3: C, 58.97; H, 3.78; N, 9.05.
Found: C, 58.89; H, 3.68; N, 8.96.
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(3,4,5-
trimethoxyphenyl)-3-chloro-2-oxo-azetidinyl]aryl}-6-
bromoquinazolin-4(3H)one (6h)
2-[2-(2,6-Dichlorophenyl)amino]benzyl-3-{4-[4-(2-
hydroxy-4-N-diethylamino phenyl)-3-chloro-2-oxo-
azetidinyl]aryl}-6-bromoquinazolin-4(3H)one (6k)
Yield = 59%, m.p. 165–167 °C; IR (KBr) cm-1: 3448
(NH), 2925, 2850 (CH2), 1745 (C=O of azetidinone), 1675
(C=O of quinazolinone), 1613 (C=N), 1320 (C–N), 1189,
1095 (C–O–C), 780 (C–Cl), 632 (C–Br); 1H NMR
(CDCl3): d 9.28 (s, 1H, NH), 6.44–7.79 (m, 16H, ArH),
3.92 (s, 6H, OCH3), 3.65 (s, 3H, OCH3), 3.57 (s, 2H, CH2),
3.34 (d, 1H, CH–Ar), 3.25 (d, 1H, CH–Cl); 13C NMR
(CDCl3): d 164.2, 162.4, 161.4, 150.5, 146.2, 138.3, 137.7,
137.5, 137.3, 136.4, 135.3, 132.3, 129.4, 129.3, 128.4,
127.5, 127.3, 126.6, 124.5, 123.6, 121.7, 121.6, 121.3,
119.3, 118.3, 104.3, 64.2, 56.6, 55.2, 54.5, 28.7; Anal.
Calcd. for C39H30O5N4BrCl3: C, 57.06; H, 3.68; N, 6.82.
Found: C, 56.97; H, 3.59; N, 6.76.
Yield = 67%, m.p. 158–162 °C; IR (KBr) cm-1: 3446
(NH), 3247 (OH), 2924, 2848 (CH2), 1750 (C=O of aze-
tidinone), 1685 (C=O of quinazolinone), 1619 (C=N), 1317
1
(C–N), 784 (C–Cl), 625 (C–Br); H NMR (CDCl3): d 9.25
(s, 1H, NH), 6.23–7.88 (m, 17H, ArH), 3.58 (s, 2H, CH2),
3.42 (q, 4H, N–(CH2)2), 3.34 (d, 1H, CH–Ar), 3.28 (d, 1H,
CH–Cl), 1.25 (t, 6H, CH3); 13C NMR (CDCl3): d 164.5,
162.5, 161.5, 154.9, 149.2, 146.4, 138.5, 137.6, 136.5,
135.4, 132.5, 129.7, 129.5, 129.2, 128.3, 127.7, 127.5,
126.6, 124.4, 123.3, 121.8, 121.5, 121.4, 120.4, 119.2,
118.1, 106.7, 98.7, 62.4, 55.6, 44.7, 28.9, 13.3; Anal.
Calcd. for C40H33O3N5BrCl3: C, 58.73; H, 4.07; N, 8.56.
Found: C, 58.67; H, 3.98; N, 8.48.
123

520
Med Chem Res (2011) 20:511–521
1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as
nonulcerogenic derivatives. Bioorg Med Chem 16:1822–1831
Dutta NK, Annadurai S, Mazumdar K, Dastidar SG, Kristiansen JE,
Molnar J, Martins M, Amaral L (2000) The antibacterial action
of diclofenac shown by inhibition of DNA synthesis. Int J
Antimicrob Agents 14(3):249–251
Edwin JD, Marion BS (1945) Assay of antibiotic substances, p 459
Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (1989) Vogel’s
textbook of practical organic chemistry, 5th edn. Wiley, New
York, p 692
Gao X, Cai X, Yan K, Song B, Gao L, Chen Z (2007) Synthesis and
antiviral bioactivities of 2-aryl- or 2-methyl-3-(substituted-
benzalamino)-4(3H)-quinazolinone derivatives. Molecules 12:
2621–2642
Grover G, Kini S (2006) Synthesis and evaluation of new quinazolone
derivatives of nalidixic acid as potential antibacterial and
antifungal agents. Eur J Med Chem 41:256–262
Antimicrobial activity
The compounds 5a–k and 6a–k were tested for in vitro
antimicrobial activity by cup-plate method (Barry, 1976).
Antibacterial activity was screened against two gram
positive bacteria (Staphylococcus aureus ATCC 9144 and
Bacillus subtilis ATCC 6633), two gram negative bacteria
(Pseudomonas aeruginosa ATCC 9027 and Escherichia
coli ATCC 25922) whereas antifungal activity was
screened against fungi Candida albicans ATCC 10231.
Penicillin-G and Amphotericine-B were used as standard
drugs. Microbial cultures were obtained from National
Collection of Industrial Microorganisms (NCIM), National
Chemical Laboratory, Pune. The potency of the com-
pounds for antibacterial activity was calculated by using
the following formula (Edwin and Marion, 1945) and
antifungal activity was noted as the zone of inhibition only.
Gursoy A, Unal B, Karali N, Otuk G (2005) Synthesis, characteriza-
tion and primary antimicrobial activity evaluation of 3-phenyl-6-
methyl-4(3H)-quinazolinone-2-yl-mercaptoacetic acid aryl-
idenehydrazides. Turk J Chem 29:233–245
Gurupadayya BM, Gopal M, Padmashali B, Manohara YN (2008)
Synthesis and pharmacological evaluation of azetidin-2-ones and
thiazolidin-4-ones encompassing benzothiazole. Indian J Pharm
Sci 70(5):572–577
Halve AK, Dubey R, Bhadauria D, Bhaskar B, Gour P (2006)
Synthesis of some new azetidin-2-ones as potential antimicrobial
agents. J Ind Chem Soc 83:386–388
Havaldar FH, Khatri NK (2006) Synthesis of 2-trifluoromethyl-
phenothiazinoazetidin-2-ones as antibacterial and antifungal
agents. Ind J Heterocycl Chem 16:87–88
Jatav V, Mishra P, Kashaw S, Stables JP (2008) CNS depressant and
anticonvulsant activities of some novel 3-[5-substituted-1,3,4-
thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur J Med
Chem 43:1945–1954
Potency ¼ fantilog ½ðD=BÞ ꢁ Iꢂg ꢁ M ꢁ F
where F = dilution factor = 1 (same dilution used for
standard and test); M = potency of standard =
100; I = log(SH/SL); D = (UH ? UL) - (SH ? SL); B =
(UH - UL) ? (SH - SL); SH = zone of inhibition of
standard at 100 lg/mL; SL = Zone of inhibition of stan-
dard at 50 lg/mL; UH = zone of inhibition of unknown
at 100 lg/mL; UL = zone of inhibition of unknown at
50 lg/mL.
Acknowledgments The authors wish to place their thanks to Pro-
fessor and Head, Department of Chemistry, VNSGU, Surat. Thanks to
SAIF, Punjab University, Chandigarh, for spectral analysis.
Jiang S, Zeng Q, Gettayacamin M, Tungtaeng A, Wannaying S, Lim
A, Hansukjariya P, Okunji CO, Zhu S, Fang
D (2005)
Antimalarial activities and therapeutic properties offebrifugine
analogs. Antimicrob Agents Chemother 49:1169–1176
Joshi SD, Vagdevi HM, Vaidya VP, Gadaginamath GS (2008)
Synthesis of new 4-pyrrol-1-yl-benzoic acid hydrazide analogs
and some derived oxadiazole, triazole and pyrrole ring systems:
a novel class of potential antibacterial and antitubercular agents.
Eur J Med Chem 43:1989–1996
Kumar A, Rajput CS, Bhati SK (2007) Synthesis of 3-[4-(p-chlo-
rophenyl)-thiazol-2-yl]-2-[(substitutedazetidinone/thiazolidinone)-
aminomethyl]-6-bromoquinazolin-4-ones as anti-inflammatory
agent. Bioorg Med Chem 15:3089–3096
Kurogi Y, Inoue Y, Tsutsumi K, Nakamura S, Nagao K, Yoshitsugu
H, Tsuda Y (1996) Synthesis and hypolipidemic activities of
novel 2-[4-[(diethoxyphosphoryl) methyl]phenyl]quinazolines
and 4(3H)-quinazolinones. J Med Chem 39:1433–1437
Laddha SS, Wadodkar SG, Meghal SK (2006) Studies on some
biologically active substituted 4(3H)-quinazolinones. Part 1.
Synthesis, characterization and anti-inflammatory-antimicrobial
activity of 6,8-disubstituted 2-phenyl-3-[substituted-benzothia-
zol-2-yl]-4(3H)-quinazolinones. Arkivoc 11:1–20
Mazumdar K, Dutta NK, Dastidar SG, Motohashi N, Shirataki Y
(2006) Diclofenac in the management of E. coli urinary tract
infections. In Vivo 20(5):613–619
Mishra P, Rajak H, Mehta A (2005) Synthesis of schiff bases of
2-amino-5-aryl-1,3,4-oxadiazoles and their evaluation for anti-
microbial activities. J Gen Appl Microbiol 51:133–141
Mosaad SM, Mohammed KI, Ahmed MA, Abdel-Hamide SG (2004)
Synthesis of certain new 6-iodoquinazolines as potential antitu-
bercular agents. J Appl Sci 4:302–307
References
Alagarsamy V, Solomon VR, Dhanabal K (2007) Synthesis and
pharmacological evaluation of some 3-phenyl-2-substituted-3H-
quinazolin-4-one as analgesic, anti-inflammatory agents. Bioorg
Med Chem 15:235–241
Amir M, Shikha K (2004) Synthesis and anti-inflammatory, analgesic,
ulcerogenic and lipid peroxidation activities of some new
2-[(2,6-dichloroanilino)phenyl]acetic acid derivatives. Eur
Med Chem 39:535–545
Archana, Srivastava VK, Kumar A (2002) Synthesis of newer
thiadiazolyl quinazolin-4(3H)-ones as potential anticonvulsant
agents. Eur J Med Chem 37:873–882
Baek D, Kang T, Kim HJ (2004) Synthesis of nonclassical quinaz-
olinone antifolates as thymidylate synthase inhibitors and their
antitumor activity in vitro. Bull Korean Chem Soc 25:1898–1906
Barbaric M, Kralj M, Marjanovic M, Husnjak I, Pavelic K, Filipovic-
Grcic J, Zorc D, Zorc B (2007) Synthesis and in vitro antitumor
effect of diclofenac and fenoprofen thiolated and nonthiolated
polyaspartamide-drug conjugates. Eur J Med Chem 42:20–29
Barry AL (1976) The antimicrobial susceptibility test, principles and
practices. Illus lea and Febiger, Philadelphia, PA, p 180
J
Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP, Mokale VJ
(2008) Design, synthesis and evaluation of antiinflammatory, anal-
gesic and ulcerogenicity studies of novel S-substituted phenacyl-
123

Med Chem Res (2011) 20:511–521
521
Oza VB, Smith C, Raman P, Koepf EK, Lashuel HA, Petrassi HM,
Chiang KP, Powers ET, Sachettinni J, Kelly JW (2002)
Synthesis, structure, and activity of diclofenac analogues as
transthyretin amyloid fibril formation inhibitors. J Med Chem
45:321–332
Pandey VK, Gupta VD, Upadhyay M, Singh VK, Tandon M (2005)
Synthesis, characterization and biological activity of 1,3,4-
substituted 2-azetidinones. Ind J Chem 44B:158–162
Panwar H, Verma RS, Srivastava VK, Kumar A (2006) Synthesis of
some substituted azetidinonyl and thiazolidinonyl-1,3,4-thiadiaz-
ino[6,5-b]indoles as prospective antimicrobial agents. Ind J
Chem 45B:2099–2104
Patel NB, Patel JC (2008) Synthesis and antimicrobial screening
of 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-{4-[4-(substi-
tutedphenyl)-3-chloro-2-oxo-azetidinyl]aryl}-7-chloro quinazo-
lin-4(3H)ones. J Saudi Chem Soc 12:121–130
Rajasekaran A, Murugesan S (2005) Synthesis and characterization of
some novel azetidinone derivatives as antibacterial and anticon-
vulsant agents. J Pharm Bioresour 2(2):162–168
Ren S, Wang R, Komatsu K, Bonaz-Krause K, Zyrianow Y,
McKenna CE, Csipke C, Tokes ZA, Lien EJ (2002) Synthesis,
biological evaluation and quantitative structure-activity relation-
ship analysis of new schiff bases of hydroxysemicarbazide as
potential antitumor agents. J Med Chem 45:410–419
Parekh J, Inamdhar P, Nair R, Baluja S, Chanda S (2005) Synthesis
and antibacterial activity of some schiff bases derived from
4-aminobenzoic acid. J Serb Chem Soc 70:1155–1161
Patel NB, Chaudhari RC (2006) Quinazolin-4(3H)-ones of 2-[(2,6-
dichlorophenyl) amino]phenyl acetic acid with substituted arylac-
etamide and their microbial studies. J Ind Chem Soc 83:838–841
Patel NB, Chaudhari RC (2008) Synthesis and antimicrobial studies
of 4(3H)-quinazolinones. J Saudi Chem Soc 12:251–260
Patel NB, Lilakar JD (2001) Synthesis of new substituted 4(3H)-
quinazolinone and their antibacterial activity. Ind J Heterocycl
Chem 11:85–86
Patel NB, Patel VN (2007a) New 2,3-disubstituted quinazolin-4(3H)-
ones as antimicrobial agents. Ind J Heterocycl Chem 16:247–250
Patel NB, Patel VN (2007b) Synthesis and antimicrobial evaluation of
new (4-oxo-thiazolidinyl)quinazolin-4(3H)ones of 2-[(2,6-dichlo-
rophenyl)amino]phenyl acetic acid. Iranian J Pharm Res 6:251–
258
Saleh MA, Abdel-Megged MF, Abdo MA, Shokr AM (2002)
Synthesis and antiviral evaluation of some new glycosylthiou-
reas containing a quinazolinone nucleus. Nucleosides Nucleo-
tides Nucleic Acids 21:93–106
Sriram D, Yogeeswari P, Devakaram RV (2006) Synthesis, in vitro
and in vivo antimycobacterial activities of diclofenac acid
hydrazones and amides. Bioorg Med Chem 14:3113–3118
Srivastava SK, Yadav R, Srivastava SD (2004) Synthesis of some
new 2-mercaptobenzothiazolyl-2-oxoazetidines as antimicrobial
and anthelmintic agents. J Ind Chem Soc 81:342–343
Suryavanshi JP, Pai NR (2006) Synthesis and antibacterial screening
of n-[naphthol[1,2-b]pyrano[3,4-d]thiazol-8-yl]spiroindoloazeti-
din-2-ones/thiazolidin-4-ones. Ind J Chem 45B:1227–1230
Yuksek H, Kolayli S, Kucuk M, Yuksek MO, Ocak U, Sahinbas E,
Sivrikaya E, Ocak M (2006) Synthesis and antioxidant activities
of some 4-benzylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-one
derivatives. Ind J Chem 45B:715–718
123