Synthesis, analgesic, anti-inflammatory, and in vitro antimicrobial activities of some novel quinazolin-4(3H)-one derivatives

Article abstract of DOI:10.1007/s00044-012-0037-7

With the aim of developing potent analgesic, anti-inflammatory, and antimicrobial agents a series of novel quinazolin-4(3H)-one derivatives were synthesized and characterized by FT-IR, ¹H-NMR, mass spectroscopy and bases of elemental analysis. Tail-flick technique, carrageenan-induced foot paw edema test, and agar streak dilution test were performed for screening analgesic, anti-inflammatory, and in vitro antimicrobial activity, respectively. Moreover, all compounds were examined for its ulcerogenicity. Results revealed that entire series of compounds exhibited mild to good analgesic, anti-inflammatory, and antimicrobial activity with low to moderate ulcer index. The relationship between the functional group variation and the biological activity of the evaluated compounds were discussed. Compound 2-(2-(4-(trifluoromethyl)benzylidene)hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin- 3(4H)-yl) phenyl) acetamide 5e was determined to be the most active compound.

Full text of DOI:10.1007/s00044-012-0037-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:340–350
DOI 10.1007/s00044-012-0037-7
ORIGINAL RESEARCH
Synthesis, analgesic, anti-inflammatory, and in vitro antimicrobial
activities of some novel quinazolin-4(3H)-one derivatives
•
Govindaraj Saravanan Veerachamy Alagarsamy
•
Chinnasamy Rajaram Prakash
Received: 16 November 2011 / Accepted: 17 March 2012 / Published online: 31 March 2012
ꢀ Springer Science+Business Media, LLC 2012
Abstract With the aim of developing potent analgesic,
anti-inflammatory, and antimicrobial agents a series of novel
quinazolin-4(3H)-one derivatives were synthesized and
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) represent
a heterogeneous family of pharmacologically active com-
pounds used to alleviate acute and chronic inflammation,
pain, and fever. In the past decade, numerous advances
have taken place in the understanding of pathogenesis and
as a result, significant progress has been made and is still
being made in the development of novel NSAIDs (Bhan-
dari et al., 2009). The most important mechanism of
NSAIDs is closely related to their ability to inhibit both
isoforms of the enzyme cyclooxygenase (COX) also known
as prostaglandin H2 (PGH2) synthase i.e., COX-1 and
COX-2 because it catalyzes the conversion of arachidonic
acid to PGH2 (Dannhardt and Kiefer, 2001). The consti-
tutive COX-1 isoform is mainly responsible for the syn-
thesis of prostaglandins which exert cytoprotective effect
in the gastrointestinal tract and control renal function in the
kidneys; while the inducible COX-2 is selectively activated
by pro-inflammatory stimuli and facilitates the release of
prostaglandins involved in the inflammatory process
(Sondhi et al., 2002). However, long term clinical usages
of NSAIDs are associated with significant side effects such
as severe gastrointestinal ulceration, bleeding, in tolerance
and nephrotoxicity (Bertolini et al., 2002; Sherif et al.,
2009). Therefore, investigation of new NSAIDs is still a
major challenge and production of safer and more active
NSAIDs are needed.
1
characterized by FT-IR, H-NMR, mass spectroscopy and
bases of elemental analysis. Tail-flick technique, carra-
geenan-induced foot paw edema test, and agar streak dilution
test were performed for screening analgesic, anti-inflam-
matory, and in vitro antimicrobial activity, respectively.
Moreover, all compounds were examined for its ulceroge-
nicity. Results revealed that entire series of compounds
exhibited mild to good analgesic, anti-inflammatory, and
antimicrobial activity with low to moderate ulcer index. The
relationship between the functional group variation and
the biological activity of the evaluated compounds
were discussed. Compound 2-(2-(4-(trifluoromethyl)ben-
zylidene)hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin-3
(4H)-yl) phenyl) acetamide 5e was determined to be the most
active compound.
Keywords Quinazolin-4(3H)-one Á Analgesic Á
Anti-inflammatory Á Antimicrobial activity
G. Saravanan (&)
Medicinal Chemistry Research Laboratory, Bapatla College
of Pharmacy, Jawaharlal Nehru Technological University,
Hyderabad, Andhra Pradesh, India
e-mail: sarachem1981@gmail.com
Concomitant use of several drugs to treat inflammatory
conditions that might be associated with some microbial
infections may cause serious health problems, especially in
patients with impaired liver or kidney functions. In addi-
tion, from pharmacoeconomic viewpoint, and seeking
better patient compliance, the discovery of an analgesic,
anti-inflammatory, and antimicrobial agent with potential
V. Alagarsamy
Medicinal Chemistry Research Laboratory, M.N.R. College
of Pharmacy, Sangareddy, Andhra Pradesh, India
C. R. Prakash
Department of Medicinal Chemistry, DCRM Pharmacy College,
Inkollu, Andhra Pradesh, India
123

Med Chem Res (2013) 22:340–350
341
activity with fewer adverse effects is a priority of the
current global research, and consequently has occupied
prime interest in recent years. Unfortunately, none of the
drugs possesses these three activities in a single compo-
nent. Therefore, our aim is to find a compound having all
these three (analgesic, anti-inflammatory, and antimicro-
bial) activities. While searching for such a compound, we
have found that quinazoline ring is one of the moieties on
which studies have been concentrated.
and acetic anhydride (10.2 mL, 0.1 mol) was refluxed on
gentle flame for 1 h. The excess of acetic anhydride was
distilled off under reduced pressure and the residue was
dissolved in petroleum ether and kept aside for 1 h. The
light brown solid 1 which obtained was filtered and dried
(Alagarsamy et al., 2003). Yield: 71 % m.p. 181–183 ꢁC.
IR: (KBr cm-1) 3096 (Ar–CH), 2882 (CH3–CH), 1712
(C=O), 1055 (C–O–C). 1H-NMR (CDCl3, 300 MHz) d
ppm: 6.92–7.40 (4H, m, Ar–CH), 2.38 (3H, s, CH3). ESI–
MS: MS: m/z 161. Anal. Cald for C9H7NO2: C, 67.07; H,
4.38; N, 8.69. Found: C, 67.16; H, 4.40; N, 8.66.
Quinazolines and condensed quinazolines have received
the attention of medicinal chemist due to their wide spectrum
of biological activity as many, such as analgesic, anti-
inflammatory (Alagarsamy et al., 2005), antimicrobial
(Mohamed et al., 2010), anticonvulsant (Kumar et al., 2011),
anticancer (Abdel Gawad et al., 2010), antitubercular (Pattan
et al., 2006), antiviral (Dinakaran et al., 2003), and antihel-
mintic activities (Shukla and Shukla, 1989).
Synthesis of 3-(4-aminophenyl)-2-methyl-quinazolin-
4(3H)-one (2)
2-Methyl-4H-benzo-(1,3)-oxazin-4-one 1 (1.61 g, 0.01
mol) and p-phenylenediamine (1.08 g, 0.01 mol) was dis-
solved in 50 mL of anhydrous pyridine and heated on sand
bath for 6 h. The resulting solution was cooled in ice bath and
treated with 100 mL of dilute hydrochloric acid. The product
thus separated 2 was filtered, washed with water, and crys-
tallized from ethanol. Yield: 73 % m.p. 226–228 ꢁC. IR:
(KBr cm-1) 3380 (NH), 3068 (Ar–CH), 2954 (CH3–CH),
1730 (C=O). 1H-NMR (CDCl3, 300 MHz) d ppm: 6.92–7.97
(8H, m, Ar–CH), 5.76 (2H, s, NH2), 2.63 (3H, s, CH3). ESI–
MS: MS: m/z 251. Anal. Cald for C15H13N3O: C, 71.70; H,
5.21; N, 16.72. Found: C, 71.92; H, 5.19; N, 16.67.
Being involved in a research program aiming at finding
out new structure leads that would act as potent analgesic,
anti-inflammatory, and antimicrobial agents, it was of
interest to synthesize a novel series of quinazolin-4(3H)-one
derivatives as atrial to obtain safer and potent analgesic, anti-
inflammatory, and antimicrobial agents. The ulcerogenic
activity of the compounds was also determined.
Materials and methods
Chemistry
Synthesis of 2-chloro-N-(4-(2-methyl-4-oxoquinazolin-
3(4H)-yl)phenyl)acetamide (3)
All solvents used were of laboratory grade and were
obtained from SD fine chemicals (Mumbai, India), and
Merck (Mumbai, India). Ciprofloxacin and Ketoconazole
are received as gift samples from Dr. Reddy’s laboratories,
Hyderabad, India. Melting points were determined in open
glass capillary tubes and are uncorrected. Compounds were
routinely checked for their purity on Silica gel G (Merck)
Thin layer chromatography (TLC) plates; iodine chamber
and UV lamp were used for visualization of TLC spots.
The IR spectra were recorded in KBr pellets on (BIO-RAD
FTS) FT-IR spectrophotometer. 1H-NMR spectra were
recorded on Bruker DPX-300 NMR spectrometer in CDCl3
using tetramethylsilane (TMS) as an internal standard. The
chemical shifts are reported in ppm scale. Mass spectra
were obtained on a JEOL-SX-102 instrument using elec-
tron impact ionization. Elemental analyses were performed
on a Perkin Elmer model 240C analyzer and were within
0.4 % of the theoretical values.
3-(4-Aminophenyl)-2-methyl-quinazolin-4(3H)-one 2 (2.51 g,
0.01 mol) was dissolved in glacial acetic acid (50 mL)
containing 50 mL of saturated solution of sodium acetate.
The mixture was warmed to dissolve the substance com-
pletely. The solution was cooled in ice bath with stirring. A
solution of chloroacetyl chloride (0.012 mol) was added drop
wise to the above stirred solution so that the vigorous reaction
did not take place. After half an hour the product separated is
filtered. The product was washed with water and recrystal-
lised using alcohol. Yield: 70 % m.p. 172–174 ꢁC. IR: (KBr
cm-1) 3456 (NH), 3081 (Ar–CH), 2937 (CH3–CH), 1746
(C=O quinazoline), 1662(C=Oamide), 772(C–Cl). 1H-NMR
(CDCl3, 300 MHz) d ppm: 9.92 (1H, s, CONH), 6.95–8.01
(8H, m, Ar–CH), 4.38 (2H, s, CH2), 2.56 (3H, s, CH3). ESI–
MS: MS: m/z 329 (M ?2). Anal. Cald for C17H14ClN3O2: C,
62.30; H, 4.31; N, 12.82. Found: C, 62.11; H, 4.32; N, 12.86.
Synthesis of 2-hydrazinyl-N-(4-(2-methyl-4-oxoquinazolin-
3(4H)-yl)phenyl)acetamide (4)
Synthesis of 2-methyl-4H-benzo-(1,3)-oxazin-4-one (1)
For the synthesis of 2-methyl-4H-benzo-(1,3)-oxazin-4-one
derivative, a mixture of anthranilic acid (1.37 g, 0.01 mol)
Equimolar quantity of 2-chloro-N-(4-(2-methyl-4-oxoqui-
nazolin-3(4H)-yl)phenyl)acetamide 3 (3.27 g, 0.01 mol)
123

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Med Chem Res (2013) 22:340–350
2-(2-(4-Methylbenzylidene)hydrazinyl)-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide (5c)
and hydrazine hydrate (0.05 g, 0.01 mol) in 30 mL ethanol
was refluxed for 10 h on a water bath. Cool the resulting
solution, filtered, dried, and recrystallised from ethanol.
Yield: 77 % m.p. 215–217 ꢁC. IR: (KBr cm-1) 3428 (NH),
3075 (Ar–CH), 2952 (CH3–CH), 1723 (C=O quinazoline),
IR: (KBr cm-1) 3462 (NH), 3055 (Ar–CH), 2988 (CH3–
CH), 1751 (C=O quinazoline), 1666 (C=O amide), 1547
(CH=N). 1H-NMR (CDCl3, 300 MHz) d ppm: 9.90 (1H, s,
CONH), 8.46 (1H, s, CH=N), 6.84–8.01 (12H, m, Ar–CH),
4.49 (2H, s, CH2), 3.81 (1H, s, CH2NH), 2.92 (3H, s, CH3
benzylidene), 2.38 (3H, s, CH3). ESI–MS: MS: m/z 425.
1
1650 (C=O amide). H-NMR (CDCl3, 300 MHz) d ppm:
9.85 (1H, s, CONH), 7.07–8.19 (8H, m, Ar–CH), 5.62 (2H,
s, NH2), 4.51 (1H, s, CH2NH), 4.06 (2H, d, CH2), 2.39 (3H,
s, CH3). ESI–MS: MS: m/z 323. Anal. Cald for
C17H17N5O2: C, 63.15; H, 5.30; N, 21.66. Found: C, 62.99;
H, 5.32; N, 21.73.
2-(2-(4-Chlorobenzylidene)hydrazinyl)-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide (5d)
General procedure for the synthesis of 5a–5j
IR: (KBr cm-1) 3443 (NH), 3028 (Ar–CH), 2946 (CH3–
CH), 1734 (C=O quinazoline), 1642 (C=O amide), 1530
(CH=N), 775 (C–Cl). 1H-NMR (CDCl3, 300 MHz) d ppm:
9.71 (1H, s, CONH), 8.65 (1H, s, CH=N), 7.12–8.08 (12H,
m, Ar–CH), 4.62 (2H, s, CH2), 3.94 (1H, s, CH2NH), 2.47
(3H, s, CH3). ESI–MS: MS: m/z 447 (M ? 2).
Title compound 5a–5j was synthesized by adding appro-
priate aromatic/heterocyclic aldehydes (0.01 mol) in
fraction with the well stirred mixture of 2-hydrazinyl-N-
(4-(2-methyl-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide 4
(3.23 g, 0.01 mol) in 50 mL ethanol and 2–3 drops of
glacial acetic acid. The pH was maintained to 5–6. The
reaction mixture was then refluxed for a period of 4–6 h
and kept aside for about 2 h. The products were separated
by filtration, washed, and vacuum dried. Finally the prod-
ucts were recrystallized using ethanol to get pure form. The
method used for the preparation and isolation of the com-
pounds gave materials of good purity, as evidenced by their
spectral analyses and by TLC. The title compounds are
found to be soluble in chloroform, dimethyl sulfoxide, and
dimethylformamide. The physicochemical properties of the
synthesized compounds are given in Table 1.
2-(2-(4-(Trifluoromethyl)benzylidene)hydrazinyl)-N-(4-(2-
methyl-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide (5e)
IR: (KBr cm-1) 3435 (NH), 3046 (Ar–CH), 2961 (CH3–
CH), 1738 (C=O quinazoline), 1650 (C=O amide), 1515
(CH=N), 1137 (C–F). 1H-NMR (CDCl3, 300 MHz) d ppm:
9.85 (1H, s, CONH), 8.33 (1H, s, CH=N), 7.04–8.19 (12H,
m, Ar–CH), 4.38 (2H, s, CH2), 3.72 (1H, s, CH2NH), 2.56
(3H, s, CH3). ESI–MS: MS: m/z 479.
2-(2-(4-Methoxybenzylidene)hydrazinyl)-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide (5f)
2-(2-Benzylidenehydrazinyl)-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide (5a)
IR: (KBr cm-1) 3468 (NH), 3032 (Ar–CH), 2950 (CH3–
CH), 1755 (C=O quinazoline), 1679 (C=O amide), 1524
IR: (KBr cm-1) 3454 (NH), 3037 (Ar–CH), 2973 (CH3–
CH), 1720 (C=O quinazoline), 1645 (C=O amide), 1531
(CH=N). 1H-NMR (CDCl3, 300 MHz) d ppm: 9.94 (1H, s,
CONH), 8.51 (1H, s, CH=N), 7.03–8.17 (13H, m, Ar–CH),
4.26 (2H, s, CH2), 3.74 (1H, s, CH2NH), 2.50 (3H, s, CH3).
ESI–MS: MS: m/z 411.
1
(CH=N), 1061 (C–O–C). H-NMR (CDCl3, 300 MHz) d
ppm: 9.93 (1H, s, CONH), 8.77 (1H, s, CH=N), 6.90–7.92
(12H, m, Ar–CH), 4.70 (2H, s, CH2), 3.75 (1H, s, CH2NH),
3.44 (3H, s, OCH3), 2.31 (3H, s, CH3). ESI–MS: MS:
m/z 441.
2-(2-(4-Nitrobenzylidene)hydrazinyl)-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide (5g)
2-(2-(4-Fluorobenzylidene)hydrazinyl)-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide (5b)
IR: (KBr cm-1) 3450 (NH), 3074 (Ar–CH), 2989 (CH3–
CH), 1722 (C=O quinazoline), 1647 (C=O amide), 1542
(CH=N), 1505 and 1311 (C–NO2). 1H-NMR (CDCl3,
300 MHz) d ppm: 9.89 (1H, s, CONH), 8.62 (1H, s,
CH=N), 7.09–8.20 (12H, m, Ar–CH), 4.55 (2H, s, CH2),
3.98 (1H, s, CH2NH), 2.57 (3H, s, CH3). ESI–MS: MS:
m/z 456.
IR: (KBr cm-1) 3439 (NH), 3063 (Ar–CH), 2955 (CH3–
CH), 1747 (C=O quinazoline), 1674 (C=O amide), 1516
(CH=N), 1122 (C–F). 1H-NMR (CDCl3, 300 MHz) d ppm:
9.87 (1H, s, CONH), 8.70 (1H, s, CH=N), 7.21–8.26 (12H,
m, Ar–CH), 4.53 (2H, s, CH2), 3.92 (1H, s, CH2NH), 2.35
(3H, s, CH3). ESI–MS: MS: m/z 429.
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343
Table 1 Structure and physicochemical properties of synthesized compounds 5a–5j
H
N
N
R
O
N
H
O
N
N
CH3
Compounds
R
m.p. (oC) Yield (%) Molecular formula Log Pa Analysis (%), found (calc.): C; H; N;
5a
232–234
251–253
197–199
208–210
244–246
188–190
262–264
203–205
70
78
75
77
72
79
71
75
C24H21N5O2
C24H20FN5O2
C25H23N5O2
C24H20ClN5O2
C25H20F3N5O2
C25H23N5O3
C24H20N6O4
C24H21N5O3
3.11
3.27
3.60
3.67
4.03
2.98
2.85
2.72
70.31 (70.06); 5.12 (5.14); 16.97 (17.02)
66.95 (67.12); 4.70 (4.69); 16.26 (16.31)
70.81 (70.57); 5.43 (5.45); 16.41 (16.46)
64.87 (64.65); 4.51 (4.52); 15.67 (15.71)
62.40 (62.63); 4.21 (4.20); 14.55 (14.61)
68.22 (68.01); 5.23 (5.25); 15.81 (15.86)
62.96 (63.15); 4.43 (4.42); 18.47 (18.41)
67.66 (67.44); 4.93 (4.95); 16.32 (16.38)
5b
5c
5d
5e
5f
F
CH3
Cl
CF3
OCH3
NO2
OH
5g
5h
123

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Med Chem Res (2013) 22:340–350
Table 1 continued
Compounds
R
m.p. (oC) Yield (%) Molecular formula Log Pa Analysis (%), found (calc.): C; H; N;
5i
276–278
72
C26H22N6O2
2.65
69.16 (69.32); 4.93 (4.92); 18.72 (18.66)
N
H
5j
239–241
76
C23H21N5O3
2.06
66.70 (66.49); 5.07 (5.09); 16.82 (16.86)
CH3
O
a
Log P was calculated with Chem office 2009 software
2-(2-(4-Hydroxybenzylidene)hydrazinyl)-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide (5h)
analysis of variance (ANOVA) was performed to certain
the significance of all the exhibited activities. The test
compounds and the standard drugs were administered in
the form of a suspension (1 % carboxy methyl cellulose as
a vehicle) by oral route of administration for analgesic and
anti-inflammatory but for ulcerogenicity studies by intra-
peritoneally as suspension in 10 % v/v Tween-80. Each
group consisted of six animals. The animals were main-
tained in colony cages at 25 2 ꢁC, relative humidity of
45–55 %, under a 12 h light and dark cycle; were fed
standard animal feed (Olfert et al., 1993). All the animals
were acclimatized for a week before use.
IR: (KBr cm-1) 3530 (Ar–OH), 3426 (NH), 3051 (Ar–CH),
2977 (CH3–CH), 1742 (C=O quinazoline), 1665 (C=O
amide), 1538 (CH=N). 1H-NMR (CDCl3, 300 MHz) d ppm:
9.82 (1H, s, CONH), 8.49 (1H, s, CH=N), 7.05–8.11 (12H,
m, Ar–CH), 5.81 (1H, s, Ar–OH), 4.64 (2H, s, CH2), 3.86
(1H, s, CH2NH), 2.33 (3H, s, CH3). ESI–MS: MS: m/z 427.
2-(2-((1H-Indol-3-yl)methylene)hydrazinyl)-N-(4-(2-
methyl-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide (5i)
IR: (KBr cm-1) 3457 (NH), 3060 (Ar–CH), 2935 (CH3–
CH), 1754 (C=O quinazoline), 1652 (C=O amide), 1526
(CH=N). 1H-NMR (CDCl3, 300 MHz) d ppm: 9.78 (1H, s,
CONH), 9.03 (1H, s, NH indole), 8.31 (1H, s, CH=N),
6.92–7.98 (13H, m, Ar–CH), 6.06 (1H, s, CH2NH), 4.25
(2H, s, CH2), 2.42 (3H, s, CH3). ESI–MS: MS: m/z 450.
Analgesic activity
The analgesic activity was performed by tail-flick tech-
nique using Wistar albino mice (25–35 g) of either sex
selected by random sampling technique (Kulkarni, 1980;
D’Amour and Smith, 1941). Diclofenac sodium at a dose
level of 10 and 20 mg/kg was administered orally as ref-
erence drug for comparison. The test compounds at two
dose levels i.e., 10 and 20 mg/kg were administered orally.
The reaction times were recorded immediately before and
30 min, 1, 2, and 3 h after the treatment and cut-off time
was 10 s. The percent analgesic activity (PAA) was cal-
culated by the following formula. PAA = [T2-T1/10-T1]
9 100; where T1 is the reaction time (s) before treatment,
and T2 is the reaction time (s) after treatment. The observed
results are presented in Table 2.
N-(4-(2-Methyl-4-oxoquinazolin-3(4H)-yl)phenyl)-2-(2-
((5-methylfuran-2-yl)methylene)hydrazinyl)acetamide (5j)
IR: (KBr cm-1) 3431 (NH), 3059 (Ar–CH), 2943 (CH3–CH),
1735 (C=O quinazoline), 1648 (C=O amide), 1534 (CH=N),
1
1072 (C–O–C). H-NMR (CDCl3, 300 MHz) d ppm: 9.95
(1H, s, CONH), 8.58 (1H, s, CH=N), 6.76–7.90 (10H, m, Ar–
CH), 6.12 (1H, s, CH2NH), 4.76 (2H, s, CH2), 2.80 (3H, s,
CH3 furan), 2.37 (3H, s, CH3). ESI–MS: MS: m/z 415.
Biological activities
Anti-inflammatory activity
Pharmacology
Anti-inflammatory activity was evaluated by carrageenan-
induced paw edema test in rats (Winter et al., 1962).
Diclofenac sodium 10 and 20 mg/kg was administered as
standard drug for comparison. The test compounds were
The synthesized compounds were evaluated for analgesic,
anti-inflammatory, and ulcerogenic activities. One-way
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Med Chem Res (2013) 22:340–350
345
Table 2 PAA of the synthesized compounds (tail-flick method)
Compounds
Dose (mg/kg)
PAA
30 min
1 h
2 h
3 h
5a
5b
5c
5d
5e
5f
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
30 1.09*
42 1.23*
32 0.84**
44 1.78*
37 0.70*
48 0.46*
36 1.23***
50 0.84**
40 0.55**
53 1.84*
24 1.61**
35 0.84*
26 1.27*
38 1.48*
23 0.79*
36 1.33*
19 0.88*
30 2.13*
17 0.95*
29 1.29*
35 1.52*
50 0.81**
38 1.52*
54 1.01**
42 1.47**
59 0.92***
45 0.53*
58 1.82***
48 1.42*
63 0.69**
32 1.86*
40 1.29*
31 2.05**
42 0.64*
30 1.38*
43 1.94**
25 2.24*
35 0.81*
24 1.83*
33 0.74*
41 1.33**
57 2.16*
42 1.07*
58 1.53**
47 0.64*
63 1.39**
48 1.47*
64 0.68**
53 0.83***
70 1.22***
35 2.15*
48 0.60**
36 1.13*
49 2.06*
34 1.02**
47 0.51*
29 1.46*
41 1.15*
27 1.06*
38 1.31*
29 0.81*
32 1.45*
31 0.69**
35 1.15*
37 2.03**
41 1.03*
35 1.61*
40 1.27*
39 1.16**
45 0.53**
23 1.72*
28 1.77*
25 0.62*
27 1.25**
20 1.84*
26 0.76*
18 2.51*
20 0.78*
19 1.41*
21 1.76*
5g
5h
5i
5j
Control
4
0.72
5
0.49
6
0.84
3
0.41
Diclofenac
10
20
34 1.18*
44 1.69**
55 1.35**
49 1.06***
64 1.08***
32 0.62*
41 0.87*
47 1.42**
Each value represents the mean SEM (n = 6)
Significance levels * p \ 0.5, ** p \ 0.01, *** p \ 0.001 as compared with the respective control
administered at two dose levels of 10 and 20 mg/kg. The
paw volumes were measured using the mercury displace-
ment technique with the help of plethysmograph immedi-
ately before and 30 min, 1, 2, and 3 h after carrageenan
injection. The percent inhibition of paw edema was cal-
culated according to the following formula, percent inhi-
bition I = 100[1 - (a - x)/(b - y)], where x is the mean
paw volume of rats before the administration of carra-
geenan and test compounds or reference compound (test
group), a is the mean paw volume of rats after the
administration of carrageenan in the test group (drug
treated), b is the mean paw volume of rats after the
administration of carrageenan in the control group, y is the
mean paw volume of rats before the administration of
carrageenan in the control group. All the percent inhibition
results are shown in Table 3.
each of six animals. Control group of animals were
administered only with 10 % v/v Tween-80 suspension
intraperitoneally. One group was administered with aspirin
intraperitoneally in a dose of 200 mg/kg once daily for
3 days. Diclofenac was also administered as standard drug
at 20 mg/kg once daily for 3 days to another group of
animals in the same route. The remaining group of animals
was administered with test compounds intraperitoneally in
a dose of 20 mg/kg. On fourth day, pylorus was ligated as
per previous reported method (Shay et al., 1945). Animals
were fasted for 36 h before the pylorus ligation procedure.
Four hours after the ligation, animals were sacrificed. The
stomach was removed and opened along with the greater
curvature. Ulcer index was determined by earlier reported
method (Ganguly and Bhatnagar, 1973) and presented in
Table 3.
Ulcerogenicity
Antimicrobial activity
Ulceration in rats was induced as reported method (Goyal
et al., 1985). Albino rats of Wistar strain weighing
150–200 g of either sex were divided into various groups
In this study, all the synthesized compounds were screened
for antimicrobial activity by agar streak dilution method.
The antibacterial activity of the compounds were evaluated
123

346
Med Chem Res (2013) 22:340–350
Table 3 Percent anti-inflammatory activity (Carrageenan induced paw edema test in rats) and ulcer index of the synthesized compounds
Compounds
Dose (mg/kg)
Percent protection
30 min
Ulcer index
1 h
2 h
3 h
5a
5b
5c
5d
5e
5f
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
24 1.80**
35 1.46*
26 0.47*
37 1.55*
30 1.14*
41 0.56*
31 1.02***
43 1.30*
35 0.52*
46 1.25*
22 1.81*
31 0.71**
20 1.28*
29 0.73*
21 1.50*
30 0.92**
20 1.71*
28 2.17*
19 0.47*
31 1.24*
29 0.72*
46 1.58**
33 1.97*
49 0.47**
35 0.66**
54 1.51*
37 0.75*
52 1.87*
40 1.14**
57 1.93***
25 1.62*
37 0.52*
26 1.81**
36 1.70*
25 2.13*
39 1.25*
23 0.91**
36 1.87*
25 1.91*
35 0.58*
34 1.56**
51 1.32*
36 0.71**
52 1.42*
41 1.24*
60 0.84***
43 1.18*
59 1.36**
46 1.27***
65 1.18***
29 1.30**
42 1.65*
31 1.65*
40 1.28*
28 1.72**
43 0.51*
29 1.14*
41 1.69*
30 1.36*
39 1.17**
28 1.44*
32 0.71*
29 1.54**
36 1.80**
31 1.41*
39 1.30**
34 1.26*
42 0.43***
39 1.38*
47 1.61**
19 0.47**
30 1.19*
20 0.91*
31 1.54**
22 1.17*
29 1.08*
21 2.15*
32 1.57*
23 1.41*
30 1.15*
0.70 0.27
0.64 0.39
0.61 0.41
0.59 0.35
0.55 0.31
0.86 0.53
0.80 0.68
0.82 0.52
0.72 0.44
0.77 0.56
5g
5h
5i
5j
Control
4
0.28
6
0.63
5
0.41
4
0.75
0.13 0.05
1.61 0.78
Diclofenac
10
20
31 1.28*
40 0.96*
–
36 1.09**
51 1.41*
–
42 1.03***
60 1.73***
–
29 0.51*
43 1.18**
–
Aspirin
1.79 0.62
Each value represents the mean SEM (n = 6)
Significance levels * p \ 0.5, ** p \ 0.01, *** p \ 0.001 as compared with the respective control
against four Gram-positive bacteria Staphylococcus aureus
ATCC 9144, Staphylococcus epidermidis ATCC 155,
Micrococcus luteus ATCC 4698, and Bacillus cereus ATCC
11778 and three Gram-negative bacteria Escherichia coli
ATCC 25922, Pseudomonas aeruginosa ATCC 2853, and
Klebsiella pneumoniae ATCC 11298. The antifungal activ-
ities of the synthesized compounds were evaluated against
two fungi Aspergillus niger ATCC 9029 and Aspergillus
fumigatus ATCC 46645. Bacterial strains were cultured over
night at 37 ꢁC in Mueller–Hinton broth and the yeast was
cultured overnight at 30 ꢁC in YEPDE agar for antibacterial
and antifungal activity tests. Test strains were suspended in
nutrient agar to give a final density of 5 9 10-5 cfu/mL.
of molten sterile agar (nutrient agar for antibacterial
activity and Sabouraud’s dextrose agar medium for anti-
fungal activity). A specified quantity of the medium
(40–50 ꢁC) containing the compound was poured into a
Petri dish to give a depth of 3–4 mm and allowed to
solidify. Suspension of the micro-organism were prepared
to contain approximately 5 9 10-5 cfu/mL and applied to
plates with serially diluted compounds in dimethyl form-
amide to be tested and incubated at 37 ꢁC for 24 and 48 h
for bacteria and fungi, respectively. The MIC was con-
sidered to be the lowest concentration of the test substance
exhibiting no visible growth of bacteria or fungi on the
plate. The observed MIC is presented in Table 4.
Minimum inhibitory concentration (MIC)
Results and discussion
MIC of the compound was determined by agar streak
dilution method (Hawkey and Lewis, 1994). A stock
solution of the synthesized compound (100 lg/mL) in
dimethyl formamide was prepared and graded quantities of
the test compounds were incorporated in specified quantity
Chemistry
In this study, we synthesized a series of novel 2-methyl-
quinazolin-4(3H)-one derivative by substituting different
123

Med Chem Res (2013) 22:340–350
347
Table 4 MIC (in lg/mL) of synthesized compounds
Compounds
S. aureusus S. epidermidis M. luteus B. cereus E. coli P. aeruginosa K. pneumoniae A. niger A. fumigatus
5a
31.25
31.25
31.25
7.81
62.5
31.25
7.81
31.25
15.62
3.9
62.5
31.25
7.81
15.62
3.9
31.25
31.25
62.5
31.25
15.62
5b
15.62
31.25
62.5
5c
125
62.5
125
62.5
31.25
7.81
7.81
31.25
7.81
125
5d
31.25
15.62
15.62
15.62
62.5
7.81
7.81
31.25
31.25
15.62
7.81
15.62
7.81
7.81
15.62
62.5
15.62
62.5
62.5
62.5
–
5e
5f
125
31.25
125
62.5
62.5
7.81
125
31.25
125
62.5
62.5
5g
7.81
15.62
62.5
15.62
15.62
5h
125
125
125
125
125
31.25
125
5i
62.5
62.5
15.62
–
31.25
62.5
7.81
–
31.25
31.25
62.5
7.81
–
62.5
62.5
15.62
–
15.62
31.25
7.81
–
15.62
62.5
3.9
5j
125
Ciprofloxacin
Ketoconazole
7.81
–
–
–
15.62
7.81
2-(2-methylenehydrazinyl)-N-phenylacetamide at 3rd
position of quinazolin-4(3H)-one. Initially, anthranilic acid
and acetic anhydride were used as starting materials to
produce 2-methyl-4H-benzo-(1,3)-oxazin-4-one 1 by sim-
ple acetylation followed by ring closure reaction. Further
this compound were treated with p-phenylenediamine gave
3-(4-aminophenyl)-2-methyl-quinazolin-4(3H)-one 2 with
elimination of water. On stirring with chloroacetyl chloride
in the presence of sodium acetate and glacial acetic acid,
compound 2 gets converted to 2-chloro-N-(4-(2-methyl-4-
oxoquinazolin-3(4H)-yl)phenyl)acetamide 3. In the sub-
sequent step, the compound 3 was treated with hydrazine
hydrate results in 2-hydrazinyl-N-(4-(2-methyl-4-oxoqui-
nazolin-3(4H)-yl)phenyl)acetamide 4. Finally this com-
pound 4 was treated with different aromatic/heterocyclic
aldehydes in the presence of glacial acetic acid, and a
variety of Schiff base derivatives have been isolated
according to the synthetic Scheme 1.
supported by the appearance of singlet for two protons at d
4.38 ppm in its H-NMR spectra which might be assigned
1
to CH2 group of acetamide. 1H-NMR spectra of compound
4 showed a singlet peaks at d 4.51 and d 5.62 ppm corre-
sponds to NH and NH2 of CH2NHNH2, respectively,
confirms its formation. The title compounds 5a–5j showed
absorption bands at 3426–3468, 1720–1755 cm-1, and
weak band at 1515–1547 cm-1, which can be assignable to
NH, C=O of quinazoline, and CH=N (azomethine linkage)
vibrations, respectively. The proton magnetic resonance
spectrums of synthesized compounds were recorded in
CDCl3. The following conclusions can be derived by
comparing the NMR spectra of compounds 5a–5j:
•
•
•
•
•
•
A singlet at d 2.31–2.57 ppm for CH3,
A singlet at d 4.25–4.76 ppm for CH2,
A singlet at d 3.72–6.12 ppm for CH2NH,
A multiplet at d 6.76–8.26 ppm for Ar–CH,
A singlet at d 8.31–8.77 ppm for CH=N,
A singlet at d 9.71–9.95 ppm for CONH.
1
IR, H-NMR, mass spectra and elemental analyses of
the synthesized compounds are in accordance with the
assigned structures. The IR spectra of all synthesized
compounds showed some characteristic peaks indicating
the presence of particular groups. Formation of 2-methyl-
4H-benzo-(1,3)-oxazin-4-one 1 was confirmed by the
presence of absorption peak at 1,712 and 1,055 cm-1 in IR
due to presence of C=O and C–O–C stretching, respec-
tively. The formations of compound 2 were confirmed by
the absence of absorption bands around 1,050 cm-1 cor-
responds to C–O–C stretching and appearance of peak at
3,380 cm-1 in IR corresponds to N–H stretching of NH2.
Appearance of singlet at d 5.76 ppm for two protons in its
1H-NMR spectra which might be assigned to NH2 group
also confirms the formation of 2. IR spectrum of compound
3 shows absorption peak at 1,662 and 772 cm-1 which
might be due to C=O of amide and C–Cl, respectively,
confirms the formation of compound 3. This is further
Biological activities
Analgesic activity
Entire test compounds 5a–5j was tested for their analgesic
activity by tail-flick technique using Wistar albino mice.
The results of analgesic study are summarized in Table 2.
The reports indicate that all the test compounds exhibited
significant activity and graded dose response. Moreover,
this study revealed that test compounds showed moderate
analgesic activity at 30 min of reaction time; the activity
increased at 1 h, further it reached to peak level at 2 h and
past its best in activity was observed at 3 h. Compound 5a
with unsubstituted phenyl derivative showed moderate
analgesic activity compared to standard drug diclofenac
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Med Chem Res (2013) 22:340–350
NH2
O
O
N
COOH
NH2
N
O
p-NH2C6H4NH2
(CH3CO)2O
Pyridine; 6 h
N
CH3
CH3
2
1
Anthranilic acid
CH3COOH
CH3COONa
ClCH2COCl
H
N
O
Cl
R
R
O
N
OCH3
NO2
5f =
5g =
5h =
5a =
N
CH3
3
NH2NH2
10 h
F
5b =
5c =
H
N
NH2
O
N
H
CH3
Cl
OH
O
N
5d =
5e =
N
CH3
5i =
5j =
4
N
H
RCHO
4-6 h
CF3
H
N
N
R
CH3
O
N
H
O
O
N
N
CH3
Title compounds (5a-5j)
Scheme 1 Schematic representation of the synthesized compounds
sodium. With the increased lipophilicity p-fluoro derivative
5b showed an increase in activity. Replacement of fluorine
with methyl or chlorine further increases the lipophilicity
results in enhanced activity which was found to be equi-
potent with reference standard diclofenac. Exchange of
methyl or chlorine with trifluoromethyl further increases
the lipophilicity led to moderate increase in activity which
was found to be more potent than standard drug tested.
Exchange of trifluoromethyl by methoxy or nitro or
hydroxyl results in sharp fall in activity may be due to
decreased lipophilicity. Introduction of heterocyclic moiety
such as indole and furan instead of p-(methoxy/nitro/
hydroxyl)phenyl group further decreases the activity. Com-
pound 2-(2-(4-(trifluoromethyl)benzylidene)hydrazinyl)-
N-(4-(2-methyl-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide
5e was found to be the most active analgesic agent and it is
moderately more potent when compared to the reference
standard diclofenac sodium.
Anti-inflammatory activity
Carrageenan-induced paw edema test was performed to
assess the anti-inflammatory activity of test compounds
using Wistar rats. The anti-inflammatory activity results
(Table 3) showed that all the test compounds protected rats
from carrageenan-induced inflammation reasonably at
30 min of reaction time; the activity increased at 1 h and it
reached to maximum level at 2 h. Declining in activity was
observed at 3 h. The compounds possessing unsubstituted
phenyl ring 5a exhibited moderate anti-inflammatory
activity when compared to the reference standard diclofe-
nac sodium. With increased lipophilicity the compound
123

Med Chem Res (2013) 22:340–350
349
with p-fluoro substituent 5b showed moderately more
activity than 5a. Methyl and chlorine derivative 5c and 5d
showed equipotent activity with reference standard dic-
lofenac sodium. Among all tested compounds trifluoro-
methyl analog 5e exhibited better activity which is more
potent than diclofenac. A deep fall in activity was observed
when trifluoromethyl group 5e was replaced with methoxy
or nitro or hydroxyl group 5f–5h. Unlike analgesic activity
replacement of these p-(methoxy/nitro/hydroxyl)phenyl
group by heterocyclic moiety 5i–5j retains the activity.
lesser activity than standard. All compounds except 5b, 5e,
and 5g showed worse activities than standard against
B. cereus, compounds 5b and 5g showed the same activity
(MIC: 7.81 lg/mL); moreover 5e demonstrated better
activity (MIC: 3.9 lg/mL) than Ciprofloxacin. All the
compounds exhibited lower activity against E. coli (MIC:
31.25–125 lg/mL). Compounds 5b and 5e displayed the
equivalent activity (MIC: 7.81 lg/mL) as standard against
P. aeruginosa. Only compound 5b showed the same activ-
ity (MIC: 3.9 lg/mL) as Ciprofloxacin against K. pneu-
moniae, while rest of test compounds displayed poorer
activity. Against A. niger compound 5e demonstrated bet-
ter activity (MIC: 7.81 lg/mL) than Ketaconazole, while
compounds 5d and 5g exhibited similar activity (MIC:
15.62 lg/mL) as Ketaconazole; remaining compounds
showed inferior activity (MIC: 31.25–125 lg/mL). Com-
pound 5d showed similar activity (MIC: 7.81 lg/mL)
against A. fumigatus while the others have lower activity
(MIC: 15.62–125 lg/mL) than standard.
The current results revealed that most of the synthesized
derivatives exhibited significant antimicrobial activity. The
potent antibacterial and antifungal activity exhibited by
compounds 5b, 5d, 5e, and 5g might be due to the presence
of electron withdrawing substituent like fluoro, chloro,
trifluoromethyl, and nitro group, respectively. While other
compounds, though they contain electron donating sub-
stituents like methyl, methoxy, and hydroxyl groups (5c,
5f, and 5h) exhibited less in vitro antimicrobial activity.
The unsubstituted compounds showed moderate antimi-
crobial activity. The MIC values were determines as the
lowest concentration that totally inhibited visible growth of
the microorganisms. The chemical structure and antimi-
crobial activity relationship of the synthesized compounds
revealed that the compounds having electron withdrawing
moiety exhibited better activity when compared with
compounds having electron releasing moieties. Among
tested compounds, 2-(2-(4-(trifluoromethyl)benzylidene)
hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin-3(4H)-yl)phenyl)
acetamide 5e exhibited better activity against B. cereus and
A. niger; while it displayed equal activity as standard
against S. aureus, M. leutus, and P. aeruginosa.
Ulcerogenicity
Further all the test compounds were examined for its ulc-
erogenicity and the results are summarized in Table 3.
Entire test compounds exhibited less ulcer index compared
to standard diclofenac and aspirin. Results of ulcer index
revealed that the compounds bearing halogen and methyl
substituents 5b–5e showed negligible ulcer index, whereas
replacement of p-(halogen/methyl)phenyl by phenyl/het-
erocyclic moiety leads to slight increases in ulcer index.
Over other test compounds, 5f–5h possessing methoxy or
nitro or hydroxyl group exhibited higher ulcer index. The
test compounds exhibited 34–53 and 31–48 % of the ulcer
index when compared to the reference drug diclofenac
(1.61 0.78) and aspirin (1.79 0.62), respectively.
Among the tested compounds, 2-(2-(4-(trifluoromethyl)
benzylidene)hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin-
3(4H)-yl)phenyl) acetamide 5e exhibited least ulcer index
(0.55 0.31) which is about one-third of the ulcer index
of reference standards. Out of entire tested compounds,
2-(2-(4-methoxybenzylidene)hydrazinyl)-N-(4-(2-methyl-
4-oxoquinazolin-3(4H)-yl) phenyl)acetamide 5f was found
to possess highest ulcer index (0.86 0.53) which is about
51 % of the ulcer index of diclofenac and aspirin.
Antimicrobial activity
All the synthesized compounds were evaluated for their in
vitro antibacterial and antifungal activity by agar streak
dilution method. A comparison of antimicrobial activity of
the synthesized compounds with that of standard drugs was
effectively presented in Table 4. The MICs of Ciproflox-
acin and Ketoconazole were determined in parallel exper-
iments to control the sensitivity of the test organisms. As
seen in Table 4, except 5e (MIC: 15.62 lg/mL) all other
compounds showed lower activities (MIC: 31.25–125
lg/mL) than Ciprofloxacin against S. aureus. Compounds
5b and 5g displayed the equal activity (MIC: 7.81 lg/mL)
against S. epidermidis, whereas rest of series exhibited
lower activity (MIC: 15.62–125 lg/mL). Against M. luteus
compounds 5d and 5e exhibited comparable activity (MIC:
7.81 lg/mL) as Ciprofloxacin, while others demonstrated
Conclusion
In summary, a series of novel quinazolin-4(3H)-one
derivative were synthesized and characterized by FT-IR,
1H-NMR, Mass spectroscopy, and elemental analysis.
These derivatives were evaluated for their analgesic, anti-
inflammatory, ulcerogenicity, and in vitro antimicrobial
activity. In general, halogen substituted compounds par-
ticularly trifluoromethyl analog exhibited potent analgesic
and anti-inflammatory activity with negligible ulcer index.
123

350
Med Chem Res (2013) 22:340–350
D’Amour FE, Smith DL (1941) A method for determining loss of
pain sensation. J Pharmacol Exp Ther 72:74–79
Moreover, electron withdrawing group substituted deriva-
tives showed remarkable antimicrobial properties than elec-
tron releasing group substituted compounds. Among several
tested compounds, 2-(2-(4-(trifluoromethyl) benzylidene)
hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin-3(4H)-yl)
phenyl)acetamide 5e showed better analgesic and anti-
inflammatory activity which is more potent than reference
standard diclofenac. Interestingly this derivative possessed
about 32 % of the ulcer index of reference standards. In
addition, compound 5e also showed some excellent anti-
microbial activity against S. aureus, M. leutus, B. cereus,
P. aeruginosa, and A. niger. Hence, this analog could be
developed as a new class of analgesic, anti-inflammatory,
and antimicrobial agents. However, further structural
modification is planned to enhance these activities with the
low ulcerogenic index.
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