7-chloro-3-(substituted benzylidene/phenyl ethylidene amino)-2- phenylquinazolin-4(3H)-ones: Synthesis, antimicrobial and antitubercular evaluation

Article abstract of DOI:10.1007/s00044-011-9813-z

In this study, a series of 7-chloro-3-(substituted benzylidene/phenyl ethylidene amino)-2-phenyl quinazolin- 4(3H)-ones (1-10) were prepared and evaluated for antitubercular activity against Mycobacterium tuberculosis (MTB). The antitubercular screening results indicated that 7-chloro-3-(4- (dimethylamino)benzylidene amino)-2- phenylquinazolin-4(3H)-one (10) was the most potent one (MIC = 0.78 × 10^-3 μM) and exhibited activity equivalent to the standard compound isoniazid (MIC = 0.80 × 10^-3 μM). Further, the synthesized compounds were tested for their antibacterial activity against Gram positive and Gram negative bacteria. The comparison of antibacterial and antimycobacterial results indicated that different structural requirements are necessary for a compound to be effective against bacterial and mycobacterial targets.

Full text of DOI:10.1007/s00044-011-9813-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2831–2836
DOI 10.1007/s00044-011-9813-z
ORIGINAL RESEARCH
7-chloro-3-(substituted benzylidene/phenyl ethylidene amino)-2-
phenylquinazolin-4(3H)-ones: synthesis, antimicrobial
and antitubercular evaluation
•
Rajarathinam Vijai Anand Balasubramanian Narasimhan
•
•
Ramachandran Vasanthakumari Pradeep Chandran
Koralakundata Narsimha Jayaveera
Received: 12 May 2011 / Accepted: 6 October 2011 / Published online: 30 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract In this study, a series of 7-chloro-3-(substituted
benzylidene/phenyl ethylidene amino)-2-phenyl quinazolin-
4(3H)-ones (1–10) were prepared and evaluated for antitu-
bercular activity against Mycobacterium tuberculosis
(MTB). The antitubercular screening results indicated
that 7-chloro-3-(4-(dimethylamino)benzylidene amino)-2-
phenylquinazolin-4(3H)-one (10) was the most potent one
(MIC = 0.78 9 10-3 lM) and exhibited activity equiva-
lent to the standard compound isoniazid (MIC = 0.80 9
10-3 lM). Further, the synthesized compounds were tested
for their antibacterial activity against Gram positive and
Gram negative bacteria. The comparison of antibacterial and
antimycobacterial results indicated that different structural
requirements are necessary for a compound to be effective
against bacterial and mycobacterial targets.
Introduction
According to WHO global report, there were an estimated
9.2 million new cases of tuberculosis (TB) and 1.5 million
deaths from TB in HIV-negative people. Keeping in view
of above statistics, WHO declared TB as a global health
emergency and aimed at saving 14 million lives between
2006 and 2015 (Abdel-Aziz and Abdel-Rahman, 2010).
First-line drugs for TB control includes streptomycin,
isoniazid, rifampin (RMP), ethambutol, and pyrazinamide,
while second-line treatments are based on use of p-amino
salicylic acid, ethionamide, cycloserine, and macrolide
antibiotics, such as azithromycin and clarithromycin, as
well fluoroquinolones. However, the main problem asso-
ciated with antitubercular drugs is poor compliance with
prolonged treatment, and especially with the regimens used
to treat TB that are badly tolerated, expensive, relatively
ineffective, and must be taken for at least 2 years (Gemma
et al., 2009). Hence, there is a need to develop newer an-
timycobacterial agents acting by novel mode of action with
minimal chances of cross resistance to existing drugs.
Quinazoline nucleus has attracted attention of medicinal
chemists because of their wide spectrum of biological
activities Viz. anticonvulsant (Ochiai and Ishida, 1982),
antiphlogistic (Alagarsamy et al., 2006), muscle-relaxant
(Maggio et al., 2001), antimalarial, antihistamine (Ghorab
et al., 2000), anti-inflammatory (Jantova et al., 2000),
antimicrobial, and antitubercular activities (Kidwai et al.,
2005; Pandeya et al., 1999; Caroll et al., 1994; Farghaly
and Moharram, 1999; Kunes et al., 2000; Pattan et al.,
2006).
Keywords Quinazolinones ꢀ Synthesis ꢀ Antitubercular ꢀ
Antibacterial
R. V. Anand (&)
Department of Pharmaceutical Chemistry,
R.V.S. College of Pharmaceutical Sciences,
Sulur, Coimbatore 641402, India
e-mail: ocranand@yahoo.com
B. Narasimhan
Faculty of Pharmaceutical Sciences,
Maharshi Dayanand University, Rohtak 124001, India
R. V. P. Chandran
Department of Pharmaceutical Chemistry,
Narayana Pharmacy College, Nellore 524002, India
There are two basic approaches to develop a new drug
for tuberculosis: (a) synthesis of analogue, modifications or
derivatives of existing compounds for shortening and
improving TB treatment; and (b) searching for novel
K. N. Jayaveera
Department of Chemistry, Jawaharlal Nehru Technical
University, Ananthapur 515002, India
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Med Chem Res (2012) 21:2831–2836
structures that TB organism has never been presented with
before (Kumar et al., 2010).
(0.01 mol) synthesized above was dissolved in ethanol
(20 ml) and added slowly to an ethanolic solution of cor-
responding aromatic carbonyl compound (0.01 mol). The
reaction mixture was acidified with 5 ml of glacial acetic
acid and refluxed for half an hour. The precipitate obtained
was filtered and washed with the mixture of ether and water
and dried, and recrystallized from 95% ethanol.
By observing the biological potential of quinazolinone
and in continuation of our research on the development of
antitubercular agents (Kumar et al., 2010; Narasimhan
et al., 2011), we have decided to follow the second
approach of drug design, i.e., searching for novel structures
that TB organism has never been presented with before,
and we hereby report the synthesis and antitubercular
evaluation of 7-chloro-3-(substituted benzylidene/phenyl
ethylidene amino)-2-phenylquinazolin-4(3H)-ones (1–10).
1
Compound 1: IR (cm-1): C=O—1660, C=N—1574; H
NMR (d ppm): Ar (13H) 7.5–8.813, CH=N—8.819; MS:
m/z 359.0921 (M?); Anal. Calculated for C21H14ClN3O: C,
70.10; H, 3.92; N, 11.68, Found: C, 70.18; H, 3.98; N,
11.60.
Compound 2: IR (cm-1): C=O—1668, C=N—1588,
NO2—–1515, 1348; 1H NMR (d ppm): 7.59–8.06 (m, 12H,
Ar–H), 8.81 (s, 1H, CH=N); MS: m/z 404.1391 (M?);
Anal. Calculated for C22H13ClN4O3: C, 62.31; H, 3.24; N,
13.84, Found: C, 62.24; H, 3.19; N, 13.78.
Experimental
The melting points were taken in open capillary tubes and
are uncorrected. The IR spectra of the compounds were
recorded in the region, 4000–400 cm-1 using KBr disks on
JASCO 4100 FTIR, and the NMR spectral study was done
using DMSO as solvent on DSX-300/AV-700 transform-
NMR spectrometer. Mass spectra studies were done in
JEOL GC mate. Elemental analysis was performed on a
Perkin-Elmer 2400 C, H, and N analyzer (Perkin Elmer,
Beaconsfield, UK).
Compound 3: IR (cm-1): OH—3500–3100, C=O—
1
1665, C=N—1587; HNMR (d ppm): 7.60–8.84 (m, 12H,
Ar–H), 8.84 (s, 1H, CH=N), 10.59 (s, 1H, OH); MS: m/
z 375.08 (M?); Anal. Calculated for C21H14ClN3O2: C,
67.12; H, 3.75; N, 11.18, Found: C, 67.19; H, 3.75; N,
11.21.
Compound 4: IR (cm-1): OH—3500–3100, C=O—
1672, C=N—1590, CH. Str. 3000–2800; 1H NMR (d ppm):
7.57–8.67 (m, 12H, Ar–H), 8.811 (s, 1H, CH=N), 10.25 (s,
1H, OH); MS: m/z 375.3051 (M?); Anal. Calculated for
C21H14ClN3O2: C, 67.12; H, 3.75; N, 11.18, Found: C,
67.08; H, 3.79; N, 11.23.
General procedure for synthesis of 7-chloro-3-
(substituted benzylidene/phenyl ethylidene amino)-2-
phenylquinazolin-4(3H)-ones (1–10)
2-Amino-4-chlorobenzoic acid (0.1 mol) was dissolved in
30 ml of dry pyridine by slow stirring at room temperature.
This solution was cooled to 0°C, and a solution of a benzoyl
chloride (0.2 mol) in 30 ml of dry pyridine was added
slowly with constant stirring. After this addition, the reaction
mixture was further stirred for half an hour at room tem-
perature and set aside for 1 h. The pasty mass thus obtained
was diluted with 50 ml of water and treated with aqueous
sodium bicarbonate solution. When the effervescence
ceased, the resultant precipitate was filtered and washed with
water, and recrystallized from ethanol. To a cold solution of
7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one (0.05 mol)
(synthesized above) in anhydrous pyridine (20 ml) was
added drop-wise a solution of hydrazine hydrate (0.1 mol)
in anhydrous pyridine (25 ml) with constant stirring. When
the addition was completed, the reaction mixture was stirred
vigorously for 30 min at room temperature and subse-
quently refluxed for 6 h under anhydrous reaction condi-
tions. The reaction mixture was then allowed to cool to
room temperature and poured into ice cold water containing
diluted hydrochloric acid. The precipitated 3-amino-7-
chloro-2-phenylquinazolin-4(3H)-one was filtered, washed
repeatedly with water, dried, and recrystallized from
ethanol. 3-amino-7-chloro-2-phenylquinazolin-4(3H)-one
Compound 5: IR (cm-1): OH—3500–3100, C=O—
1668, C=N—1588, CH. Str.—3000–2800; 1H NMR (d
ppm): 7.57–8.80 (m, 11H, Ar–H), 8.81 (s, 1H, CH=N),
10.23 (s, 1H, OH), 3.82 (s, 1H, OCH3); MS: m/z 405.12
(M?); Anal. Calculated for C22H16ClN3O3: C, 65.11; H,
3.97; N, 10.35, Found: C, 65.16; H, 3.99; N, 10.41.
1
Compound 6: IR (cm-1): C=O—1662, C=N—1571; H
NMR (d ppm): 7.57–8.8 (m, 12H, Ar–H), 8.81 (s, 1H,
CH=N), 3.47 (s,1H, OCH3); MS: m/z 389.0875 (M?);
Anal. Calculated for C22H16ClN3O2: C, 67.78; H, 4.14; N,
10.78, Found: C, 67.72; H, 4.16; N, 10.80.
1
Compound 7: IR (cm-1): C=O—1668, C=N—1574; H
NMR (d ppm): 7.57–8.06 (m, 12H, Ar–H), 8.81 (s, 1H,
CH=N), 2.49 (s,1H, CH3); MS: m/z 373.33 (M?); Anal.
Calculated for C22H16ClN3O: C, 70.68; H, 4.31; N, 11.24,
Found: C, 70.72; H, 4.29; N, 11.30.
Compound 8: IR (cm-1): OH—3500–3100, C=O—
1667, C=N—1575, CH. Str.—3000–2800; 1H NMR (d
ppm): 7.58–8.82 (m, 11H, Ar–H), 8.81 (s, 1H, CH=N),
10.29 (s, 1H, OH), 2.49 (s,1H, CH3); MS: m/z 389.09
(M?); Anal. Calculated for C22H16ClN3O2: C, 67.78; H,
4.14; N, 10.78, Found: C, 67.84; H, 4.14; N, 10.75.
1
Compound 9: IR (cm-1): C=O—1679, C=N—1583; H
NMR (d ppm): 7.59–8.59 (m, 11H, Ar–H), 8.81 (s, 1H,
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Med Chem Res (2012) 21:2831–2836
2833
CH=N), 2.52 (s,1H, CH3); MS: m/z 406.9873 (M?); Anal.
Calculated for C22H15Cl2N3O: C, 64.72; H, 3.70; N, 10.29,
Found: C, 64.77; H, 3.75; N, 10.34.
Compound 10: IR (cm-1): C=O—1661, C=N—1591;
1H NMR (d ppm): 6.76–7.68 (m, 12H, Ar–H), 9.65 (s, 1H,
CH=N), 3.03 (s,6H, N(CH3)2; MS: m/z 402.606 (M?);
Anal. Calculated for C23H19ClN4O: C, 68.57; H, 4.750; N,
13.19, Found: C, 68.56; H, 4.77; N, 13.13.
mixture of Alamar Blue reagent and 10% tween 80 was
added to the plate and incubated for 24 h. A blue color in
the well was interpreted as no bacterial growth, and a
pink color was scored as growth. The MIC (minimal
inhibition concentration) was defined as the lowest drug
concentration, which prevented a color change from blue to
pink.
Antibacterial screening by Kirby–Bauer Method
Antitubercular activity
Diffusion Disk Method (Kirby–Bauer) was used to evalu-
ate the antimicrobial activity of synthesized quinalzolinone
derivatives. Staphylococcus aureus (ATCC 6538), Esche-
richia coli (ATCC 25922), and Pseudomonas aeroginosa
(ATCC 27853) were inoculated in Mueller–Hinton, Mac-
Conkey, and Cetrimide agar, respectively, and incubated
at 37°C for 24 h. After incubation, each culture was diluted
in sterile saline solution (0.9% NaCl) according to 0.5
MacFarland scale, to obtain a bacterial density of 1.0 9
108 cfu/ml approximately. A sample of this suspension was
inoculated homogeneously in petri dishes, and the syn-
thesized compounds were deposited aseptically in disk
forms over the inoculated medium and the petri dishes
were incubated at 37°C for 24 h. After incubation, the zone
of inhibition was measured.
The synthesized compounds were screened for their anti-
tubercular activity against Mycobacterium tuberculosis
H37Rv using micro plate Alamar Blue assay (MABA)
(Table 1). This methodology is a nontoxic one which uses
thermally stable reagent and shows good correlation with
proportional and BACTEC radiometric methods (Reis
et al., 2004). In brief, 200 ml of sterile deionized water was
added to all outer-perimeter wells of sterile 96-well plates
to minimize the evaporation of medium in test wells during
incubation. The 96 plates received 100 ml of the Middle-
brook 7H9 broth. The serial dilution of synthesized com-
pounds was made directly on the plates. Plates were
covered and sealed with parafilm, and incubated at 37°C
for 5 days. Afterward, 25 ml of a freshly prepared 1:1
Table 1 Physicochemical characteristics and antitubercular activity of synthesized 7-chloro-3-(substituted benzylidene/phenyl ethylidene
amino)-2-phenyl quinazolin-4(3H)-ones
R2
R1
O
X
R3
N
N
R4
R5
N
Cl
(1-10)
Comp.
X
R1 R2
R3
R4 R5 Molecular formula Molecular weight % Yield M.P. (°C) Rf valuea MIC (lM 9 10-3
)
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C21H14ClN3O
C21H13ClN4O3
359.81
404.81
375.81
375.81
405.83
389.83
373.83
389.83
408.28
402.88
92
80
89
88
84
94
96
96
82
88
166
164
136
176
139
185
170
160
156
98
0.72
0.62
0.61
0.48
0.41
0.63
0.60
0.51
0.42
0.52
3.47
3.08
1.66
3.32
6.16
6.41
6.68
6.38
H
NO2
OH
H
3
H
H
C
C
21H14ClN3O2
21H14ClN3O2
4
H
OH
H
5
H
OCH3 OH
C22H16ClN3O3
C22H16ClN3O2
C22H16ClN3O
C22H16ClN3O2
C22H15Cl2N3O
C23H19ClN4O
6
H
H
H
H
H
H
H
OCH3
7
CH3
CH3
CH3
H
H
H
8
H
OH
9
H
Cl
12.2
10
H
N(CH3)2
0.78
0.8
Isoniazid
Ethambutol
Ciprofloxacin
a
7.6
6.4
TLC mobile phase : Benzene: chloroform (80:20)
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Med Chem Res (2012) 21:2831–2836
Results and discussion
losis H37Rv using microplate alamar blue assay (MABA)
(Franzblau et al., 1998), and the results are presented in
Table 1. At the commencement of this study, we have
synthesized quinazolinone with an unsubstituted phenyl
ring on the benzylidene portion (1) and tested for its anti-
mycobacterial activity. The promising antitubercular
activity of compound 1 (MIC = 3.47 9 10-3 lM, which is
greater than the reference standards, ethambutol and cip-
rofloxacin) created interest among us to go for further
optimization taking compound 1 as a prototype compound.
It was known from the literature that the presence of
strongly deactivating electron-withdrawing nitro group on
the phenyl ring improved antimycobacterial activity (Sri-
ram et al., 2007). In view of the above, we decided to
introduce electron-withdrawing nitro group into the phenyl
ring, and accordingly synthesized 7-chloro-3-[(4-nitro-
benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one (2).
However, as expected, the electron-withdrawing nitro
group did not improve the antitubercular activity signifi-
cantly (MIC = 3.08 9 10-3 lM). Hence, we have dropped
the idea of introducing electron-withdrawing groups further
and planned to introduce electron-donating groups and
synthesized compounds, 3 and 4 with an electron-donating
hydroxy group at para and ortho positions of phenyl ring.
This idea resulted in significant improvement of antituber-
cular activity of quinazolinone derivatives especially in
case of 7-chloro-3-(4-hydroxybenzylideneamino)-2-phe-
nylquinazolin-4(3H)-one (3) which showed activity at
1.66 9 10-3 lM which was almost two times more potent
than compound 1 (MIC—3.47 9 10-3 lM). However, the
presence of OH group at ortho position did not improve the
antimycobacterial activity significantly. From the above
results, we have decided to introduce an additional electron-
donating group by keeping the hydroxyl group intact at
The synthesis of 7-chloro-3-(substituted benzylidene/ethyl-
idene amino)-2-phenylquinazolin-4(3H)-ones (1–10) was
carried out as outlined in Scheme 1. The reaction of
2-amino-4-chlorobenzoic acid with benzoyl chloride resul-
ted in the formation of 7-chloro-2-phenyl-4H-benzo[d]-
[1,3]oxazin-4-one which on treatment with hydrazine
hydrate yielded 3-amino-7-chloro-2-phenylquinazolin-
4(3H)-one which on reaction with corresponding aromatic
carbonyl compounds yielded the title compounds, 7-chloro-3-
(substituted benzylidene/ethylidene amino)-2-phenylquinaz-
olin-4(3H)-ones (1–10). The physicochemical characteristics
of the synthesized compounds are presented in Table 1. The
synthesized compounds were characterized by IR, 1H-NMR,
and mass spectral as well by elemental analysis studies, and
the results were found to be in agreement with the assigned
molecular structures.
The characteristic absorption peaks were observed for
all relevant groups in the IR spectra of the synthesized
compounds. The absorption peaks around 1600 cm-1
indicated the formation of C=N ring atoms of quinazoline.
Amide C=O stretching vibration was observed near
1640–1690 cm-1. Aromatic and imine protons were
observed at 6.68–8.13 and 8.0–9.5 d ppm, respectively, for
all the synthesized compounds. Molecular ion peak in mass
spectra confirmed the molecular weight of the synthesized
compounds.
Antimycobacterial activity
The antimycobacterial activity of 7-chloro-3-(substituted
benzylidene/ethylidene amino)-2-phenylquinazolin-4(3H)-
ones (1–10) was assessed against Mycobacterium tubercu-
Scheme 1 Synthesis of
7-chloro-3-(substituted
O
O
benzylidene/phenyl ethylidene
amino)-2-phenyl quinazolin-
4(3H)-ones
O
COOH
Pyridine
+
Cl
N
Cl
Cl
NH2
Pyridine NH2NH2
R2
R1
O
x
R2
R1
H2N
O
R3
O
X
N
R3
N
N
R4
R5
N
Cl
R4
R5
N
Cl
(1-10)
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Med Chem Res (2012) 21:2831–2836
2835
para position and accordingly synthesized 7-chloro-3-(4-
hydroxy-3-methoxybenzylideneamino)-2-phenylquinazolin-
4(3H)-one (5). This idea did not give fruitful result as
evidenced by the MIC value of compound 5 (MIC—
6.16 9 10-3 lM) which was almost four times more than
compound 3. The above results confirmed that the presence
of electron-donating group at para position was essential for
antitubercular activity of quinazolinones. Keeping this fact
in mind and in order to know the antimycobacterial spectrum
of the electron-releasing methoxy group, we have synthe-
sized compound 6. This modification also produced the same
result as in case of compound 5, which ruled out the effec-
tiveness of methoxy substituent to bind with the antimyco-
bacterial target. By viewing the structure, we remembered
that there was a possibility to go for alkylation of CH of
benzylidene group, and accordingly we have synthesized
compounds 7–9 with H, OH, and Cl groups attached to the
phenyl ring of benzylidene moiety. This idea of introducing
alkyl group did not give fruitful results as none of these
compounds (7–9) exhibited appreciable antimycobacterial
activity (Table 1). It was observed that alkylation of CH
group significantly decreased the antitubercular activity as
evidenced by the antimycobacterial activity of compound 8
with para hydroxy group, MIC of which was almost four
times more than the MIC of compound 3 with the same
substitution on phenyl ring. The aforementioned results led
us to conclude that the presence of electron-donating group
at para position is a must for antitubercular activity of qui-
nazolinones, and we have planned to search for the better
electron-donating group than the hydroxyl group at para
position of phenyl ring of synthesized quinazolinones.
During the course of this study, we came across the recent
study of Eswaran et al. (Eswaran et al., 2010) who identified
that addition of (3R)-3-amino-N,N-dimethyl-4-(phenyl-
thio)butanamide to positions 3 and 4 of quinoline skeleton
has tremendously enhanced antitubercular activity of qui-
noline-3-carbohydrazones. This motivated us to replace the
para hydroxy group of compound 3 with N,N-dimethylamino
group, and accordingly we synthesized 7-chloro-3-(4-
(dimethylamino) benzylidene amino)-2-phenylquinazolin-
4(3H)-one (10) which showed excellent antitubercular
activity (MIC—0.78 9 10-3 lM) equivalent to standard,
isoniazid (MIC = 0.80 9 10-3 lM).
Table 2 Antibacterial activity of synthesized compounds
Compound
Zone of inhibition (mm)
E. Coli
P. aeruginosa
S. aureus
5
21
22
22
25
05
04
04
18
15
15
15
17
8
9
Ciprofloxacin
From the results of antimycobacterial and antibacterial
studies, the following SAR may be drawn.
1. The presence of electron-withdrawing group on phenyl
ring of benzylidene moiety attached to the 3rd position
of quinazolinone decreases the antimycobacterial
activity whereas the presence of electron-donating
substituent increases the antimycobacterial activity.
This is contrary to the observations of Sriram et al.
(Sriram et al., 2007) and our previous studies (Kumar
et al., 2010; Narasimhan et al., 2011).
2. Among the different electron-donating groups tried,
the methoxy group failed to improve the antitubercular
activity, and hydroxy and dimethyl amino groups
significantly improved the antitubercular activity. This
indicates the fact that electron-donating hydroxy and
dimethyl amino groups may interact with electron
deficient portion of mycobacterial target.
3. The comparison of antitubercular and antimicrobial
activities of the synthesized quinazolinones revealed
that the presence of hydrogen on CH of benzylidene
moiety is essential for hydrogen bonding of the
synthesized compounds with electronegative region
at mycobacterial target whereas this is not true in the
case of antibacterial studies where the alkylated
compounds 8 and 9 have shown appreciable antibac-
terial activity. This indicated that different structural
requirements are necessary for a drug to bind with
mycobacterial and bacterial targets. This is in accor-
dance with the studies of Sortino et al. (2007).
4. It is worthwhile to note that compound 5 containing
electron-donating groups OH and OCH3 has shown
poor antitubercular activity and appreciable antibacte-
rial activity. The appreciable antibacterial activity of
compound 5 may be attributed to the presence of
methoxy group as observed in one of our previous
studies (Sharma et al., 2009), where we found that
presence of electron-donating methoxy group also
improved the antimicrobial activity of imidazole
derivatives against S. aureus, B. subtilis and
C. albicans along with the imidazole derivatives
containing electron-withdrawing substituents. The
above findings are summarized in Fig. 1.
Antibacterial activity
The synthesized quinazolinone derivatives were tested for
their antibacterial activity by Kirby–Bauer Method (Bauer
et al., 1966) using ciprofloxacin as a standard. None of the
synthesized compounds showed appreciable antibacterial
activity except compounds 5, 8, and 9 which demonstrated
activity comparable to ciprofloxacin against E. coli and
S. aureus (Table 2).
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Electron withdrawing groups decrease
the antitubercular activity
derived from 2-methylquinazolinones. Boll Chim Farm 138:
280–289
Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G,
Hernandez A, DegnanMT, Cook MB, Quenzer VK, Ferguson RM,
Gilman RH (1998) Rapid, low-technology MIC determination
with clinical Mycobacterium tuberculosis isolates by using the
microplate alamar blue assay. J Clin Microbiol 36:362–369
Gemma S, Savini L, Altarelli M, Tripaldi P, Chiasserini L, Coccone SS,
Kumar V, Cmodeca C, Campiani G, Novellino E, Clarizio S,
Delogu G, Butini S (2009) Development of antitubercular
compounds based on a 4-quinolylhydrazone scaffold. Further
structure–activity relationship studies. Bioorgan Med Chem
17:6063–6072
R
p-OH, p-N(CH3)2 increase the
antitubercular activity
N
Electron
donating
groups
N
N
X
Cl
O
OCH3 - Decrease antitubercular
activity and improves
antibacterial activity
X=Me
X=H
Essential for antitubercular activity
Essential for antibacterial activity
Ghorab MM, Gawad SMA, El-Gaby MSA (2000) Synthesis and
evaluation of some new fluorinated hydroquinazoline derivatives
as antifungal agents. Farmaco 55:249–255
Jantova S, Greif G, Spirkova K, Stankovsky S, Oravcova M (2000)
Antibacterial effects of trisubstituted quinazoline derivatives.
Folia Microbiol (Praha) 45:133–137
Fig. 1 Structural requirements for the antimycobacterial and anti-
bacterial activity of 7-chloro-3-(substituted benzylidene/phenyl eth-
ylidene amino)-2-phenyl quinazolin-4(3H)-ones
Kidwai M, Saxena S, Khan MKR, Thukral SS (2005) Synthesis of
4-aryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2-one/
thione-5-one derivatives and evaluation as antibacterials. Eur J
Med Chem 40:816–819
Kumar P, Narasimhan B, Yogeeswari P, Sriram D (2010) Synthesis
and antitubercular activities of substituted benzoic acid
N0-(substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-
3-carbonyl)-hydrazides. Eur J Med Chem 45:6085–6089
Kunes J, Bazant J, Pour M, Waisser K, Slosarek M, Janota J (2000)
Quinazoline derivatives with antitubercular activity. Farmaco
55:725–729
Maggio B, Daidone G, Raffa D, Plescia S, Mantione L, Catena CVM,
Mangano NG, Caruso A (2001) Synthesis and pharmacological
study of ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquina-
zolin-3-yl)-1H-pyrazole-4-acetates. Eur J Med Chem 36:737–742
Narasimhan B, Sharma D, Kumar P, Yogeeswari P, Sriram D (2011)
Synthesis, antimicrobial and antimycobacterial evaluation of
[2-(substituted phenyl)-imidazol-1-yl]-pyridin-3-ylmethanones.
J Enzym Inhib Med Ch 26(5):720–727
Conclusion
In conclusion, 7-chloro-3-(substituted benzylidene/phenyl
ethylidene amino)-2-phenylquinazolin-4(3H)-ones (1–10)
were prepared, characterized, and evaluated in vitro for
their antitubercular and antibacterial activities. The anti-
tubercular screening results indicated that 7-chloro-3-(4-
(dimethylamino)benzylidene amino)-2-phenylquinazolin-
4(3H)-one (10) was the most potent one with MIC value of
0.78 9 10-3 lM which is equivalent to isoniazid
(MIC = 0.80 9 10-3 lM). The comparison of antibacte-
rial and antimycobacterial results indicated that different
structural requirements are necessary for a compound to be
effective against bacterial and mycobacterial targets.
Acknowledgments The author RVA is grateful to the Maratha
Mandals NGH Institute, Belgaum and the Management of RVS
College of Pharmaceutical Sciences, Coimbatore for providing nec-
essary facilities to carry out this research study.
Ochiai T, Ishida R (1982) Pharmacological studies on 6-amino-2-
fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinone (afloqualone),
a
new centrally acting muscle relaxant. (II) effects on the spinal
reflex potential and the rigidity. Jpn J Pharmacol 32:427–438
Pandeya SN, Sriram D, Nath G, Clercq ED (1999) Synthesis,
antibacterial, antifungal and anti-HIV evaluation of Schiff and
Mannich bases of isatin derivatives with 3-amino-2-methylmer-
capto quinazolin-4(3H)-one. Pharm Acta Helv 74:11–17
Pattan SR, Reddy VVK, Manvi FV, Desai BG, Bhat AR (2006)
Synthesis of N-3-(4-(4-chlorophenyl thiazole-2-yl)-(2-(amino)-
methyl)-quinazoline-4(3H)-one and their derivatives for antitu-
bercular activity. Indian J Chem 45B:1778–1781
Reis RS, Neves JI, Lourenco SLS, Fonseca LS, Lourenc MCS (2004)
Comparison of flow cytometric and alamar blue tests with the
proportional method for testing susceptibility of Mycobacterium
tuberculosis to rifampin and isoniazid. J Clin Microbiol 42:
2247–2248
Sharma D, Narasimhan B, Kumar P, Narang R, Judge V, Clercq ED,
Balzarini J (2009) Synthesis, antimicrobial and antiviral evalu-
ation of substituted imidazole derivatives. Eur J Med Chem
44:2347–2353
Sortino M, Delgado P, Jaurez S, Quiroga J, Abonia R, Insuasey B,
Nogueras M, Rodero L (2007) Synthesis and antifungal activity
of (Z)-5-arylidenerhodanines. Bioorgan Med Chem 15:484–494
Sriram D, Yogeeswari P, Dhakla P, Senthilkumar P, Banerjee D
(2007) Hydroxythiosemicarbazones: synthesis and in vitro
antitubercular activity. Bioorgan Med Chem 17:1888–1891
References
Abdel-Aziz M, Abdel-Rahman HM (2010) Synthesis and antimyco-
bacterial evaluation of some pyrazine-2-carboxylic acid hydra-
zide derivatives. Eur J Med Chem 45:3384–3388
Alagarsamy V, Giridhar R, Yadav MR (2006) Synthesis and pharma-
cological investigation of novel 1-substituted-4-(4-substituted
phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new class
of H1-antihistamine agents. J Pharm Pharmacol 58:1249–1255
Bauer AW, Kirby WMM, Sherris JC, Truck M (1966) Antibiotic
susceptibility testing by a standardised single disk method. Am J
Clin Path 45:493–496
Caroll SS, Stahlhut M, Greb J, Olsen DB (1994) Inhibition of HIV-1
RT by quinazolinones. 6-chloro-4-(s)cyclopropyl-3,4-dihydro-
4-[(2-pyridyl)ethynyl]-quinazolinone-2(1H)-one. J Bio Sci 269:
32351–32359
Eswaran S, Adhikari AV, Pal NK, Chowdhury IH (2010) Design and
synthesis of some new quinoline-3-carbohydrazone derivatives
as potential antimycobacterial agents. Bioorg Med Chem Lett
20:1040–1044
Farghaly O, Moharram AM (1999) Synthesis and in vitro antifungal
activity of some N,N-disubstituted dithiocarbamic acid esters
123