Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-diamines

Article abstract of DOI:10.1007/s00706-017-1981-1

Abstract: Some new bis(azolylamino)- and bis(azolylmethylamino)quinazolines were prepared from 2,4-dichloroquinazoline and azolyl amines under ultrasonication and tested for their antimicrobial activity. The chloro-, bromo-, and nitro-substituted bis(thia

Full text of DOI:10.1007/s00706-017-1981-1

Monatsh Chem
DOI 10.1007/s00706-017-1981-1
ORIGINAL PAPER
Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-
diamines
Tamatam Rekha1 Suram Durgamma1 Adivireddy Padmaja1 Venkatapuram Padmavathi1
•
•
•
Received: 16 November 2016 / Accepted: 10 April 2017
Ó Springer-Verlag Wien 2017
Abstract Some new bis(azolylamino)- and bis(azolyl-
methylamino)quinazolines were prepared from 2,4-
dichloroquinazoline and azolyl amines under ultrasonica-
tion and tested for their antimicrobial activity. The chloro-,
bromo-, and nitro-substituted bis(thiazolylamino)quinazo-
lines displayed excellent antibacterial activity against
Bacillus subtilis whereas unsubstituted, chloro-, bromo-,
and nitro-substituted bis(imidazolylamino)quinazolines
exhibited excellent antifungal activity against Aspergillus
niger.
Introduction
Quinazolines are privileged motifs present in a wide range
of bioactive molecules and considered as attractive targets
for medicinal chemists. Several antitumor drugs e.g.,
erlotinib [1] and gefitinib [2] have quinazoline moiety.
Some of the derivatives of quinazoline also exhibit
antimicrobial [3, 4], antimalarial [5], anti-inflammatory
[6–8], antidiabetic [9], and anticancer activities [10–12].
Azoles having both electron donating (O/S/N) and electron
withdrawing groups (C=N) gained importance syntheti-
cally and biologically. Oxazoles have excellent biological
activities e.g., leucamide A and its analogues are used as
anticancer agents [13]. Many thiazole derivatives have
been reported in the drug development for the treatment of
allergies [14], inflammation [15], bacterial infection [16],
schizophrenia [17], and HIV infections [18]. Commonly
used antifungal agents such as fluconazole, itraconazole,
miconazole, and voriconazole possess imidazole moiety.
Thus, the clinical efficacy of these aromatic heterocycles
encouraged the chemists to construct a variety of novel
molecules with different pharmacophoric units. Recently
we have reported some pyrimidine/quinazoline benzazoles
and studied their antimicrobial and cytotoxic properties
[19, 20].
Graphical abstract
Keywords Quinazoline Á Oxazole Á Thiazole Á Imidazole Á
Antimicrobial activity
Ultrasound irradiation has emerged as a powerful tech-
nique for the promotion of organic reactions. The use of
ultrasound in chemical reactions in solution provides
specific activation based on acoustic cavitation. Thus, the
rapid vibration causes cavitation, the formation and violent
collapse of microscopic bubbles. The collapse of thousands
of cavitation bubbles releases tremendous energy in the
cavitation field. Hence this approach is more convenient
and is easily controlled when compared with the traditional
methods. The advantages of using ultrasound as an energy
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-1981-1) contains supplementary
material, which is available to authorized users.
& Venkatapuram Padmavathi
vkpuram2001@yahoo.com
1
Department of Chemistry, Sri Venkateswara University,
Tirupati, Andhra Pradesh 517 502, India
123

T. Rekha et al.
source to promote organic reactions include shorter reac-
tion times and higher yields when compared with
conventional thermal heating methods [21–23]. In fact, the
synthesis of different heterocycles by applying ultrasound
conditions was reported [24–27]. The beneficial effects of
ultrasonic irradiation and our interest to develop and to
improve the methodologies in chemical processes espe-
cially where classical methods require prolonged reaction
times prompted to develop potential heterocycles—
bis(azolyl)quinazoline-2,4-diamines under ultrasonication
and study their antimicrobial activity.
quinazoline-2,4-diamines 12 and N2,N4-bis(4-aryl-1H-imi-
dazol-2-ylmethyl)quinazoline-2,4-diamines 13 were also
prepared by performing the reaction of 1 with 9 and 10,
respectively (Scheme 2). The 1H NMR spectra of 11a, 12a,
and 13a exhibited two singlets at 4.35, 4.28, 4.29 and 4.39,
4.33, 4.34 ppm for methylene protons. A broad singlet was
also observed at 9.40, 9.50, 9.18 ppm due to two NH
protons. In addition to these, compound 13a showed
another broad singlet at 11.25 ppm due to two NH protons
of imidazole. The signals of NH disappeared when D2O
0
was added. The signal corresponding to C5 -H was
appeared at downfield region and merged with aromatic
protons. The structures of all the compounds were further
ascertained by IR, 13C NMR, mass and elemental analyses.
Results and discussion
Chemistry
Antibacterial activity
The synthetic intermediate 2,4-dichloroquinazoline (1) was
prepared by the reaction of anthranilic acid with urea fol-
lowed by chlorination with POCl3 in the presence of N,N-
dimethylaniline [28]. The compounds 4-aryloxazol-2-ami-
nes 2, 4-arylthiazol-2-amines 3, 4-aryl-1H-imidazol-2-
amines 4, (4-aryloxazol-2-yl)methanamines 8, (4-arylthia-
zol-2-yl)methanamines 9, and (4-aryl-1H-imidazol-2-
yl)methanamines 10 were prepared as per the literature
precedents [29–32]. The regioselective substitution of
chlorine at C-4 of quinazoline was reported with appro-
priate amine at room temperature [33]. Moreover, the
reaction of 2,4-dichloroquinazoline with cyclic amines was
also reported under acidic conditions [34]. On the other
hand, nucleophilic substitution of chlorine at C-2 of
quinazoline was carried out at higher temperatures either in
2-propanol or in THF [33]. In fact, we have succeeded to
prepare bis nucleophilic substituted products in the pres-
ence of conc. HCl in 2-propanol under ultrasonication for
30–45 min. Thus, amino linked heterocycles, N2,N4-bis(4-
aryloxazol-2-yl)quinazoline-2,4-diamines 5, N2,N4-bis(4-
arylthiazol-2-yl)quinazoline-2,4-diamines 6, and N2,N4-
The compounds 5–7 and 11–13 were evaluated for
antibacterial activity at two concentrations 50 and 100 lg/
well. The results showed in Table 1 and Fig. 1 indicated
that Gram-positive bacteria were more susceptible towards
the tested compounds than Gram-negative bacteria. The
bis(azolyl)quinazolines linked by amino group (5–7)
exhibited higher activity than those linked by amino-
methane moiety (11–13). Further it was observed that the
compounds having bis(thiazolyl)quinazolines (6, 12)
exhibited higher activity than the respective bis(oxazolyl)-
(5, 11) and bis(imidazolyl)quinazolines (7, 13). Amongst
the latter compounds 7, 13 exhibited more activity than 5,
11. The effect of substituents on the activity indicated that
unsubstituted, chloro-, bromo-, and nitro-substituted com-
pounds displayed higher activity than those having methyl
and N,N-dimethyl substituents. This may be due to ?I
effect of methyl and ?M effect of N,N-dimethyl sub-
stituents on the aromatic ring. On the other hand bromo-
substituted compounds showed slightly lower activity than
chloro-substituted ones. In the literature it was also
reported that quinazolines in combination with other
heterocycles exhibited remarkable in vitro antimicrobial
potency and the presence of electron withdrawing groups
like chloro, bromo, fluoro, and nitro substituents on the
aromatic ring increased the activity [35–37]. In fact, 6c and
6f showed activity against Bacillus subtilis greater than the
standard drug chloramphenicol at all tested concentrations
while 6d exhibited similar activity to the standard drug. On
the other hand, the compounds 5e, 11b, 11e, 12e, and 13e
displayed no activity.
bis(4-aryl-1H-imidazol-2-yl)quinazoline-2,4-diamines 7
were prepared by the reaction 1 with 2, 3, and 4 sonicated
in an ultrasonic bath at 46 kHz frequency (Scheme 1). In
1
the H NMR spectra of 5a, 6a, and 7a a broad singlet was
observed at d = 9.45, 9.54, 9.25 ppm due to two NH
protons. A singlet due to C5’-H was appeared at much
downfield region and merged with aromatic protons.
Besides, compound 7a displayed another broad singlet at
11.32 ppm due to two NH protons of imidazole. The sig-
nals of highly acidic protons disappeared on deuteration.
In a much similar way, N2,N4-bis((4-aryloxazol-2-
yl)methyl)quinazoline-2,4-diamines 11 were prepared by
the reaction of 1 with 8 in the presence of conc. HCl in
2-propanol under ultrasonication for 60–90 min. Adopting
similar methodology, N2,N4-bis(4-arylthiazol-2-ylmethyl)-
Antifungal activity
The compounds 5–7 and 11–13 were also screened for anti-
fungal activity against Aspergillus niger and Penicillium
chrysogenum at two concentrations 50 and 100 lg/well and the
123

Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-diamines
Scheme 1
Scheme 2
results are presented in Table 2 and Fig. 2. All the tested
compounds showed greater activity on A. niger than on P.
chrysogenum. The bis(azolylamino)quinazolines 5–7 dis-
played slightly higher activity than bis(azolylmethylamino)-
quinazolines 11–13. The imidazolylquinazolines (7, 13) dis-
played greater activity than thiazolyl- (6, 12) and
oxazolylquinazolines (5, 11). Amongst the latter compounds 6
and 12 showed higher activity than 5 and 11. The presence of
electron withdrawing chloro, bromo, and nitro substituents on
the aromatic ring increases the activity. In fact, the compounds
7a, 7c, 7d, and7f displayed greater activity onA. niger than the
standard drug ketoconazole at all tested concentrations. On the
other hand, the compounds 5e, 6e, 11b, 11e, and 12e exhibited
no activity.
The compounds that exhibited higher antimicrobial
activity are further assayed for MIC, MBC and MFC and
the results are depicted in Table 3. MIC is the lowest
concentration of an antimicrobial that will inhibit the vis-
ible growth of a microorganism (but it is not sure that the
microorganisms are completely killed). The MBC/MFC is
the lowest concentration of antibiotic required to kill a
particular bacterium/fungus. The MBC/MFC involves an
123

T. Rekha et al.
Table 1 The in vitro antibacterial activity of compounds 5–7 and 11–13
Compound
Zone of inhibition/mm
Gram-positive bacteria
S. aureus
Gram-negative bacteria
B. subtilis
P. aeruginosa
K. pneumoniae
50 lg/well 100 lg/well
50 lg/well
100 lg/well
50 lg/well
100 lg/well
50 lg/well
100 lg/well
5a
10
9
2
12
10
14
13
–
1
3
2
3
13
10
14
12
–
3
1
2
1
15
12
16
15
–
2
1
1
2
9
3
2
10
9
1
11
9
2
12
11
13
12
–
1
1
2
1
5b
4
8
1
3
5c
12
10
–
1
2
10
8
1
12
11
–
2
1
12
10
–
1
2
5d
2
5e
–
5f
14
25
17
27
29
8
1
3
2
2
3
15
28
21
30
31
10
32
25
20
28
25
9
3
2
1
3
2
3
1
2
2
3
3
16
33
20
36
34
9
2
1
3
1
2
19
36
23
39
38
12
42
27
21
31
30
10
34
13
–
1
2
3
2
2
1
2
1
3
1
2
2
2
1
11
21
13
22
20
7
3
1
3
2
1
14
23
15
25
24
9
1
3
1
1
2
13
25
14
27
26
8
2
3
2
2
1
16
28
16
29
27
9
1
2
1
3
3
6a
6b
6c
6d
6e
1
2
2
2
1
1
6f
28
22
16
24
22
7
2
4
3
2
1
38
26
20
29
28
8
2
3
2
1
2
24
16
12
19
17
–
1
1
3
3
2
27
19
14
22
21
–
2
3
2
1
3
30
19
13
22
20
–
1
1
1
3
2
33
21
15
25
23
–
2
1
2
3
1
7a
7b
7c
7d
7e
1
1
1
2
7f
27
9
1
3
29
11
–
2
3
31
11
–
2
1
21
8
2
25
10
–
1
1
23
9
3
1
27
11
–
1
1
11a
1
1
1
11b
–
–
–
11c
10
8
12
11
–
2
1
12
10
–
3
2
14
13
–
2
1
9
4
2
11
11
–
1
2
10
9
12
11
–
1
2
11d
2
8
11e
–
–
–
11f
11
23
14
27
25
–
2
2
1
2
3
14
26
17
29
28
–
1
1
2
1
2
13
28
18
31
30
–
2
3
3
1
2
16
30
20
33
32
–
3
3
1
2
1
11
17
12
20
18
–
1
3
3
2
1
13
21
13
22
21
–
2
3
1
2
2
13
20
13
23
22
–
1
2
1
3
1
15
23
14
27
25
–
2
3
1
2
2
12a
12b
12c
12d
12e
12f
29
20
12
21
19
–
1
2
1
3
1
32
22
14
23
20
–
2
1
1
1
2
33
21
15
24
21
–
2
4
1
2
2
36
24
17
26
24
–
1
1
2
1
3
21
13
11
14
12
–
3
1
3
1
1
24
17
12
18
15
–
2
3
2
3
2
26
16
12
17
16
–
1
1
2
1
2
29
19
14
20
19
–
2
1
2
1
1
13a
13b
13c
13d
13e
13f
23
33
–
1
1
26
35
–
2
3
25
34
–
3
2
28
38
–
2
1
17
27
–
1
2
19
30
–
2
1
19
40
–
1
3
22
42
–
2
2
Chloramphenicol
Control (DMSO)
additional set of steps performed once the MIC is deter-
mined. The antimicrobials are usually regarded as
bactericidal/fungicidal if the MBC/MFC is not greater than
four times the MIC [38]. The compounds 6c, 6d, and 6f
displayed low MIC values against B. subtilis and the MBC
is 2 9 MIC. However, the compounds 7a, 7c, 7d, and 7f
exhibited low MIC values on A. niger and the MFC is
2 9 MIC.
123

Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-diamines
45
40
35
30
25
20
15
10
5
S. aureus 50 µg/well
S. aureus 100 µg/well
B. subtilis 50 µg/well
B. subtilis 100 µg/well
P. aeruginosa 50 µg/well
P. aeruginosa 100 µg/well
K. pneumoniae 50 µg/well
K. pneumoniae 100 µg/well
0
Tested compounds
Fig. 1 The in vitro antibacterial activity of compounds 5–7 and 11–13
F254 0.25 mm) and components were visualized by
observation under UV light (254 and 365 nm). The syn-
Conclusion
thetic
intermediates
2,4-dichloroquinazoline
(1),
Some new bis(azolylamino)- and bis(azolylmethyl-
amino)quinazolines were prepared from 2,4-dichloro-
quinazoline and azolyl amines under ultrasonication and
4-aryloxazol-2-amines 2, 4-arylthiazol-2-amines 3, 4-aryl-
1H-imidazol-2-amines 4, (4-aryloxazol-2-yl)methanamines
8, (4-arylthiazol-2-yl)methanamines 9, and (4-aryl-1H-im-
idazol-2-yl)methanamines 10 were prepared as per the
literature precedents [28–32].
tested
for
their
antimicrobial
activity.
The
bis(azolyl)quinazolines linked by amino group (5–7)
exhibited higher activity than those linked by aminomethane
moiety. The chloro-, bromo-, and nitro-substituted bis(thia-
zolylamino)quinazolines 6c, 6d, and 6f exhibited excellent
antibacterial activity against B. subtilis with MIC value 6.25
and MBC is 2 9 MIC. However, unsubstituted, chloro-,
bromo-, and nitro-substituted bis(imidazolylamino)
quinazolines 7a, 7c, 7d, and 7f showed excellent antifungal
activity against A. niger with MIC value 6.25 and MBC is
2 9 MIC.
General procedure for the synthesis of N2,N4-bis(4-aryl-
oxazol-2-yl)quinazoline-2,4-diamines 5a–5f, N2,N4-bis(4-
arylthiazol-2-yl)quinazoline-2,4-diamines
N2,N4-bis(4-aryl-1H-imidazol-2-yl)quinazoline-2,4-diami-
6a–6f, and
nes 7a–7f
A solution of 2,4-dichloroquinazoline (1, 1.0 mmol),
4-aryloxazol-2-amine 2/4-arylthiazol-2-amine 3/4-aryl-
1H-imidazol-2-amine
4 (2.5 mmol) and conc. HCl
(2.0 mmol) in 5 cm3 2-propanol was sonicated at room
temperature for 30–45 min in an ultrasonic bath working at
46 kHz (constant frequency). After completion of the
reaction (monitored by TLC), the separated solid was
filtered, dried, and recrystallized from 2-propanol.
Experimental
Melting points were determined in open capillaries on a
Mel-Temp apparatus. The purity of the compounds was
checked by TLC (silica gel H, BDH, ethyl acetate/hexane,
1:3). The IR spectra were recorded on a Thermo Nicolet IR
200 FT-IR spectrometer as KBr pellets and the
N2,N4-Bis(4-phenyloxazol-2-yl)quinazoline-2,4-diamine
(5a, C26H18N6O2)
1
White crystals; yield 0.73 g (66%); m.p.: 123–125 °C; H
wavenumbers were given in cm-1. The H NMR spectra
1
NMR (400 MHz, DMSO-d6): d = 7.25–7.81 (m, 16H, Ar–
H, C5 -H), 9.45 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
0
were recorded in DMSO-d6 on a Bruker spectrometer
operating at 400 MHz. The 13C NMR spectra were recor-
ded in DMSO-d6 on a Bruker spectrometer operating at
100 MHz. All chemical shifts are reported in d/ppm using
TMS as an internal standard. The high-resolution mass
spectra were recorded on micromass Q-TOF micromass
spectrometer using electrospray ionization. The micro-
DMSO-d6): d = 137.5, 140.6, 159.2, 173.9, 183.4, 114.5,
116.1, 123.8, 125.3, 127.4, 129.0, 131.6, 132.9, 136.0,
ꢀ
151.4 ppm; IR (KBr): m = 3297 (NH), 1649 (C=C), 1567
(C=N) cm-1; HRMS: m/z = 469.4515 ([M?Na], calcd),
469.4507 (found).
N2,N4-Bis[4-(4-methylphenyl)oxazol-2-yl]quinazoline-2,4-
analyses were performed on
a Perkin-Elmer 240C
diamine (5b, C28H22N6O2)
elemental analyzer. Ultrasonication was performed in a
Bandelin Sonorex RK 102H ultrasonic bath operating at a
frequency of 46 kHz. The progress of the reaction was
monitored by TLC using silica gel plates (silica gel 60
1
White crystals; yield 0.80 g (68%); m.p.: 115–117 °C; H
NMR (400 MHz, DMSO-d6): d = 2.34 (s, 6H, Ar–CH3),
0
7.19–7.90 (m, 14H, Ar–H, C5 -H), 9.50 (bs, 2H, NH) ppm;
123

T. Rekha et al.
Table 2 The in vitro antifungal
activity of compounds 5–7 and
11–13
Compound
Zone of inhibition/mm
A. niger
P. chrysogenum
50 lg/well
100 lg/well
50 lg/well
100 lg/well
5a
12
9
3
14
10
17
15
–
1
2
3
1
–
–
9
2
1
5b
1
8
5c
14
13
–
2
2
9
1
2
10
9
3
5d
8
2
5e
–
–
5f
16
27
20
30
30
–
1
2
2
2
1
19
29
23
32
31
–
2
2
1
3
3
12
18
13
21
20
–
1
3
2
3
2
14
21
14
25
23
–
2
3
1
2
2
6a
6b
6c
6d
6e
6f
32
34
22
36
35
13
38
14
–
2
2
2
1
2
1
2
3
34
37
24
38
37
15
42
17
–
1
1
1
3
1
1
2
1
24
24
14
25
24
9
2
3
1
3
2
28
26
16
28
26
10
31
11
–
1
3
2
1
2
2
1
2
7a
7b
7c
7d
7e
2
1
7f
27
10
–
2
1
11a
11b
11c
16
14
–
3
1
19
16
–
3
2
11
9
1
12
11
–
3
2
11d
11e
–
11f
17
23
19
25
22
–
2
3
1
2
1
19
25
22
26
24
–
1
2
1
3
2
13
15
12
16
16
–
2
3
1
2
1
14
18
13
20
18
–
2
2
1
3
2
12a
12b
12c
12d
12e
12f
26
24
19
27
25
10
30
33
–
2
1
2
3
2
1
2
1
29
26
21
30
28
12
32
36
–
3
2
2
2
1
1
1
2
19
20
13
23
20
–
1
3
1
2
2
23
22
15
26
24
11
29
38
–
2
2
1
3
2
1
2
1
13a
13b
13c
13d
13e
13f
25
36
–
1
3
Ketoconazole
Control (DMSO)
– no activity, standard deviation
13C NMR (100 MHz, DMSO-d6): d = 24.9, 137.2, 141.1,
159.6, 173.5, 182.9, 117.7, 121.3, 122.6, 124.2, 128.0,
N2,N4-Bis[4-(4-chlorophenyl)oxazol-2-yl]quinazoline-2,4-
diamine (5c, C26H16Cl2N6O2)
1
ꢀ
130.9, 133.5, 135.8, 139.3, 149.5 ppm; IR (KBr): m = 3288
White crystals; yield 0.92 g (72%); m.p.: 136–138 °C; H
(NH), 1645 (C=C), 1570 (C=N) cm-1
;
HRMS:
NMR (400 MHz, DMSO-d6): d = 7.33–7.82 (m, 14H, Ar–
H, C5 -H), 9.48 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
0
m/z = 497.5031 ([M?Na], calcd), 497.5036 (found).
123

Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-diamines
45
40
35
30
25
20
15
10
5
A. niger 50 µg/well
A. niger 100 µg/well
P. chrysogenum 50 µg/well
P. chrysogenum 100 µg/well
0
Tested compounds
Fig. 2 The in vitro antifungal activity of compounds 5–7 and 11–13
Table 3 MIC, MBC, and MFC of compounds 6a, 6c, 7a, and 7c
Compound
Minimum inhibitory concentration
MIC (MBC/MFC) lg
S. aureus
B. subtilis
P. aeruginosa
K. pneumoniae
A. niger
P. chrysogenum
6a
12.5 (50)
12.5 (50)
12.5 (50)
12.5 (50)
100 ([200)
100 ([200)
100 ([200)
100 ([200)
100 ([200)
12.5 (50)
200 (–)
12.5(50)
6.25(12.5)
6.25(12.5)
6.25(12.5)
50 (200)
50 (200)
50 (200)
50 (200)
50 (200)
50 (200)
50 (200)
50 (200)
6.25
100 ([200)
50 (200)
50 (200)
25 (100)
100 ([200)
100 ([200)
200 (–)
100 ([200)
100 ([200)
100 ([200)
100 ([200)
200 (–)
50 (200)
25 (100)
25 (100)
25 (100)
6.25 (12.5)
6.25 (12.5)
6.25 (12.5)
6.25(12.5)
100 ([200)
50 (200)
25 (100)
12.5 (50)
–
100 ([200)
100 ([200)
100 ([200)
100 ([200)
100 ([200)
100 ([200)
100 ([200)
50 (200)
6c
6d
6f
7a
7c
200 (–)
7d
200 (–)
7f
100 ([200)
100 ([200)
100 ([200)
100 ([200)
200 (–)
200 (–)
12c
200 (–)
100 ([200)
100 ([200)
100 ([200)
100 ([200)
–
12f
100 ([200)
200 (–)
13c
13f
100 ([200)
6.25
200 (–)
Chloramphenicol
Ketoconazole
6.25
12.5
–
–
–
–
6.25
12.5
– no activity
DMSO-d6): d = 136.3, 140.8, 156.9, 174.2, 182.7, 117.2,
118.7, 121.5, 124.8, 127.3, 130.8, 133.4, 134.9, 140.2,
(C=N) cm-1; HRMS: m/z = 627.2351 ([M?Na], calcd),
627.2345 (found).
ꢀ
148.6 ppm; IR (KBr): m = 3293 (NH), 1658 (C=C), 1563
N2,N4-Bis[4-[4-(dimethylamino)phenyl]oxazol-2-yl]quina-
(C=N) cm-1; HRMS: m/z = 538.3400 ([M?Na], calcd),
zoline-2,4-diamine (5e, C30H28N8O2)
538.3391 (found).
1
White crystals; yield 0.86 g (65%); m.p.: 130–132 °C; H
N2,N4-Bis[4-(4-bromophenyl)oxazol-2-yl]quinazoline-2,4-
NMR (400 MHz, DMSO-d6): d = 3.12 (s, 12H, N(CH3)2),
0
diamine (5d, C26H16Br2N6O2)
7.40–7.95 (m, 14H, Ar–H, C5 -H), 9.41 (bs, 2H, NH) ppm;
1
White crystals; yield 0.96 g (64%); m.p.: 144–146 °C; H
13C NMR (100 MHz, DMSO-d6): d = 42.8, 137.9, 141.5,
155.3, 173.5, 183.8, 119.2, 120.5, 123.5, 124.7, 128.1,
NMR (400 MHz, DMSO-d6): d = 7.28–7.78 (m, 14H, Ar–
H, C5 -H), 9.43 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
132.2, 134.0, 136.3, 139.4, 150.6 ppm; IR (KBr): m = 3282
0
ꢀ
DMSO-d6): d = 136.1, 139.7, 155.4, 173.6, 181.5, 117.0,
118.9, 121.3, 124.6, 127.2, 129.1, 133.7, 134.8, 137.9,
(NH), 1640 (C=C), 1558 (C=N) cm-1; HRMS: m/
z = 555.5255 ([M?Na], calcd), 555.5862 (found).
ꢀ
148.3 ppm; IR (KBr): m = 3296 (NH), 1654 (C=C), 1565
123

T. Rekha et al.
N2,N4-Bis[4-(4-nitrophenyl)oxazol-2-yl]quinazoline-2,4-
N2,N4-Bis[4-[4-(dimethylamino)phenyl]thiazol-2-yl]quina-
diamine (5f, C26H16N8O6)
zoline-2,4-diamine (6e, C30H28N8S2)
1
1
White crystals; yield 0.92 g (69%); m.p.: 158–160 °C; H
NMR (400 MHz, DMSO-d6): d = 7.47–7.92 (m, 14H, Ar–
White crystals; yield 0.93 g (66%); m.p.: 167–169 °C; H
NMR (400 MHz, DMSO-d6): d = 3.06 (s, 12H, N(CH3)2),
H, C5 -H), 9.46 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
7.27–7.81 (m, 14H, Ar–H, C5 -H), 9.57 (bs, 2H, NH) ppm;
0
0
DMSO-d6): d = 137.8, 141.9, 159.1, 174.3, 183.6, 119.5,
121.7, 123.9, 125.8, 128.4, 132.0, 134.2, 136.5, 140.1,
13C NMR (100 MHz, DMSO-d6): d = 43.6, 115.7, 148.8,
161.3, 173.1, 183.6, 118.6, 119.3, 120.8, 121.6, 122.7,
ꢀ
ꢀ
150.7 ppm; IR (KBr): m = 3298 (NH), 1662 (C=C), 1574
126.9, 129.4, 134.7, 149.6, 150.4 ppm; IR (KBr): m = 3301
(C=N) cm-1; HRMS: m/z = 559.4391 ([M?Na], calcd),
(NH), 1648 (C=C), 1582 (C=N) cm-1; HRMS: m/
z = 587.7167 ([M?Na], calcd), 587.7163 (found).
559.4399 (found).
N2,N4-Bis(4-phenylthiazol-2-yl)quinazoline-2,4-diamine
N2,N4-Bis[4-(4-nitrophenyl)thiazol-2-yl]quinazoline-2,4-
(6a, C26H18N6S2)
diamine (6f, C26H16N8O4S2)
1
1
White crystals; yield 0.75 g (63%); m.p.: 157–159 °C; H
White crystals; yield 0.88 g (62%); m.p.: 197–199 °C; H
NMR (400 MHz, DMSO-d6): d = 7.22–7.72 (m, 16H, Ar–
NMR (400 MHz, DMSO-d6): d = 7.31–7.76 (m, 14H, Ar–
H, C5 -H), 9.54 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
H, C5 -H), 9.53 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
0
0
DMSO-d6): d = 114.8, 148.3, 161.7, 173.0, 184.3, 117.2,
118.7, 121.5, 124.8, 127.3, 130.8, 133.4, 134.9, 140.2,
DMSO-d6): d = 115.9, 148.6, 161.8, 173.5, 184.2, 119.4,
120.9, 124.7, 125.3, 129.6, 130.5, 133.1, 134.8, 140.5,
ꢀ
ꢀ
148.6 ppm; IR (KBr): m = 3309 (NH), 1651 (C=C), 1575
151.2 ppm; IR (KBr): m = 3320 (NH), 1663 (C=C), 1584
(C=N) cm-1; HRMS: m/z = 501.5810 ([M?Na], calcd),
(C=N) cm-1; HRMS: m/z = 591.5705 ([M?Na], calcd),
501.5802 (found).
591.5701 (found).
N2,N4-Bis[4-(4-methylphenyl)thiazol-2-yl]quinazoline-2,4-
diamine (6b, C28H22N6S2)
N2,N4-Bis(4-phenyl-1H-imidazol-2-yl)quinazoline-2,4-di-
amine (7a, C26H20N8)
1
White crystals; yield 0.84 g (67%); m.p.: 162–164 °C;
White crystals; yield 0.73 g (66%); m.p.: 210–212 °C; H
1H NMR (400 MHz, DMSO-d6): d = 2.31 (s, 6H, Ar–
NMR (400 MHz, DMSO-d6): d = 7.43–8.15 (m, 16H, Ar–
0
0
CH3), 7.09–7.65 (m, 14H, Ar–H, C5 -H), 9.50 (bs, 2H,
H, C5 -H), 9.25 (bs, 2H, NH), 11.32 (bs, 2H, imidazole-
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 24.3,
115.2, 147.6, 161.1, 173.2, 184.7, 118.3, 120.8, 124.6,
127.1, 129.5, 130.9, 132.4, 134.0, 136.8, 150.1 ppm; IR
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 129.1,
138.6, 142.3, 172.5, 183.1, 115.7, 116.2, 124.5, 126.0,
128.8, 129.4, 132.1, 133.9, 136.0, 145.6 ppm; IR (KBr):
-1
(KBr): m = 3306 (NH), 1660 (C=C), 1571 (C=N) cm
HRMS: m/z = 529.6343 ([M?Na], calcd), 529.6338
;
m = 3285 (NH), 1643 (C=C), 1560 (C=N) cm-1; HRMS:
ꢀ
ꢀ
m/z = 467.4816 ([M?Na], calcd), 467.4808 (found).
(found).
N2,N4-Bis[4-(4-methylphenyl)-1H-imidazol-2-yl]quinazo-
N2,N4-Bis[4-(4-chlorophenyl)thiazol-2-yl]quinazoline-2,4-
line-2,4-diamine (7b, C28H24N8)
1
diamine (6c, C26H16Cl2N6S2)
White crystals; yield 0.76 g (65%); m.p.: 196–198 °C; H
1
White crystals; yield 0.87 g (64%); m.p.: 176–178 °C; H
NMR (400 MHz, DMSO-d6): d = 2.30 (s, 6H, Ar–CH3),
0
NMR (400 MHz, DMSO-d6): d = 7.16–7.70 (m, 14H, Ar–
7.20–7.98 (m, 14H, Ar–H, C5 -H), 9.29 (bs, 2H, NH), 11.29
H, C5 -H), 9.49 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
(bs, 2H, imidazole-NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 24.0, 130.5, 139.0, 142.7, 172.8, 182.7,
114.4, 116.8, 122.8, 125.3, 126.9, 128.1, 134.7, 136.0,
0
DMSO-d6): d = 114.5, 147.1, 160.5, 173.9, 182.1, 119.2,
120.5, 121.9, 125.4, 127.2, 129.7, 130.1, 132.8, 135.2,
ꢀ
ꢀ
151.3 ppm; IR (KBr): m = 3315 (NH), 1656 (C=C), 1578
137.4, 148.9 ppm; IR (KBr): m = 3277 (NH), 1638 (C=C),
(C=N) cm-1; HRMS: m/z = 570.4712 ([M?Na], calcd),
1565 (C=N) cm-1; HRMS: m/z = 495.5335 ([M?Na],
570.4705 (found).
calcd), 495.5339 (found).
N2,N4-Bis[4-(4-bromophenyl)thiazol-2-yl]quinazoline-2,4-
N2,N4-Bis[4-(4-chlorophenyl)-1H-imidazol-2-yl]quinazo-
diamine (6d, C26H16Br2N6S2)
line-2,4-diamine (7c, C26H18Cl2N8)
1
1
White crystals; yield 1.08 g (68%); m.p.: 183–185 °C; H
White crystals; yield 0.87 g (68%); m.p.: 220–222 °C; H
NMR (400 MHz, DMSO-d6): d = 7.13–7.69 (m, 14H, Ar–
NMR (400 MHz, DMSO-d6): d = 7.29–7.60 (m, 14H, Ar–
H, C5 -H), 9.47 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
H, C5 -H), 9.23 (bs, 2H, NH), 11.35 (bs, 2H, imidazole-
0
0
DMSO-d6): d = 114.3, 147.5, 160.7, 173.8, 182.4, 118.2,
120.1, 121.6, 124.5, 127.9, 129.8, 130.2, 132.4, 135.7,
148.3 ppm; IR (KBr): mꢀ = 3318 (NH), 1659 (C=C), 1580
(C=N) cm-1; HRMS: m/z = 659.3738 ([M?Na], calcd),
659.3731 (found).
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 129.1,
138.4, 143.6, 173.1, 183.5, 115.8, 118.4, 121.3, 127.0,
128.9, 130.2, 131.5, 133.8, 135.6, 146.5 ppm; IR (KBr):
m = 3271 (NH), 1647 (C=C), 1556 (C=N) cm-1; HRMS:
ꢀ
m/z = 536.3705 ([M?Na], calcd), 536.3700 (found).
123

Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-diamines
N2,N4-Bis[4-(4-bromophenyl)-1H-imidazol-2-yl]quinazo-
2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 52.3,
54.4, 140.8, 143.2, 149.6, 162.1, 182.7, 114.7, 120.3,
122.0, 123.2, 126.5, 132.7, 135.5, 138.1, 139.3, 147.8 ppm;
line-2,4-diamine (7d, C26H18Br2N8)
1
White crystals; yield 0.91 g (61%); m.p.: 226–228 °C; H
NMR (400 MHz, DMSO-d6): d = 7.19–7.73 (m, 14H, Ar–
IR (KBr): mꢀ = 3262 (NH), 1626 (C=C), 1514 (C=N) cm-1
;
0
H, C5 -H), 9.27 (bs, 2H, NH), 11.31 (bs, 2H, imidazole-
HRMS: m/z = 497.5049 ([M?Na], calcd), 497.5040
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 129.4,
138.2, 142.8, 172.6, 182.9, 115.5, 116.1, 121.7, 125.2,
126.3, 128.4, 131.6, 133.5, 136.1, 146.0 ppm; IR (KBr):
(found).
N2,N4-Bis[4-(4-methylphenyl)oxazol-2-ylmethyl]quinazo-
line-2,4-diamine (11b, C30H26N6O2)
m = 3274 (NH), 1646 (C=C), 1559 (C=N) cm-1; HRMS:
ꢀ
m/z = 625.2659 ([M?Na], calcd), 625.2655 (found).
1
White crystals; yield 0.87 g (70%); m.p.: 119–121 °C; H
NMR (400 MHz, DMSO-d6): d = 2.36 (s, 6H, Ar–CH3),
4.30 (s, 2H, CH2), 4.35 (s, 2H, CH2), 7.30–7.88 (m, 14H,
Ar–H, C5 -H), 9.44 (bs, 2H, NH) ppm; 13C NMR
N2,N4-Bis[4-[4-(dimethylamino)phenyl]-1H-imidazol-2-
0
yl]quinazoline-2,4-diamine (7e, C30H30N10)
1
White crystals; yield 0.92 g (70%); m.p.: 216–218 °C; H
(100 MHz, DMSO-d6): d = 25.2, 51.6, 53.5, 139.1,
145.8, 149.2, 161.6, 183.0, 113.5, 119.1, 121.8, 124.3,
125.4, 126.5, 128.7, 133.9, 135.0, 150.4 ppm; IR (KBr):
NMR (400 MHz, DMSO-d6): d = 2.91 (s, 12H, N(CH3)2),
0
7.41–8.11 (m, 14H, Ar–H, C5 -H), 9.21 (bs, 2H, NH), 11.37
(bs, 2H, imidazole-NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 43.9, 131.6, 140.7, 143.1, 172.4, 183.8,
116.4, 118.7, 120.2, 123.6, 126.4, 129.7, 132.0, 134.7,
m = 3260 (NH), 1639 (C=C), 1536 (C=N) cm-1; HRMS:
ꢀ
m/z = 525.5562 ([M?Na], calcd), 525.5554 (found).
N2,N4-Bis[4-(4-chlorophenyl)oxazol-2-ylmethyl]quinazo-
ꢀ
137.2, 149.0 ppm; IR (KBr): m = 3283 (NH), 1636 (C=C),
line-2,4-diamine (11c, C28H20Cl2N6O2)
1551 (C=N) cm-1; HRMS: m/z = 553.6160 ([M?Na],
1
White crystals; yield 0.93 g (69%); m.p.: 129–131 °C; H
NMR (400 MHz, DMSO-d6): d = 4.29 (s, 2H, CH2), 4.33 (s,
calcd), 553.6151 (found).
N2,N4-Bis[4-(4-nitrophenyl)-1H-imidazol-2-yl]quinazo-
2H, CH2), 7.24–7.69 (m, 14H, Ar–H, C5 -H), 9.47 (bs, 2H,
0
line-2,4-diamine (7f, C26H18N10O4)
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 53.2, 54.9,
137.6, 146.3, 150.4, 161.9, 182.2, 115.2, 117.7, 122.5, 124.0,
125.3, 128.8, 131.4, 132.9, 142.2, 151.6 ppm; IR (KBr):
1
White crystals; yield 0.92 g (69%); m.p.: 235–237 °C; H
NMR (400 MHz, DMSO-d6): d = 7.48–8.17 (m, 14H, Ar–
H, C5 -H), 9.32 (bs, 2H, NH), 11.39 (bs, 2H, imidazole-
m = 3251 (NH), 1642 (C=C), 1540 (C=N) cm-1; HRMS: m/
0
ꢀ
z = 566.3932 ([M?Na], calcd), 566.3939 (found).
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 130.3,
139.4, 143.7, 173.2, 183.1, 116.6, 118.5, 122.9, 127.3,
128.4, 130.7, 134.8, 136.2, 137.6, 149.1 ppm; IR (KBr):
N2,N4-Bis[4-(4-bromophenyl)oxazol-2-ylmethyl]quinazo-
line-2,4-diamine (11d, C28H20Br2N6O2)
m = 3286 (NH), 1649 (C=C), 1568 (C=N) cm-1; HRMS:
ꢀ
m/z = 557.4702 ([M?Na], calcd), 557.4711 (found).
1
White crystals; yield 1.01 g (64%); m.p.: 143–145 °C; H
NMR (400 MHz, DMSO-d6): d = 4.27 (s, 2H, CH2), 4.31
General procedure for the synthesis of N2,N4-bis(4-aryl- (s, 2H, CH2), 7.21–7.62 (m, 14H, Ar–H, C5 -H), 9.43 (bs,
0
oxazol-2-ylmethyl)quinazoline-2,4-diamines
11a–11f, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 51.4,
N2,N4-bis(4-arylthiazol-2-ylmethyl)quinazoline-2,4-diami-
nes 12a–12f, and N2,N4-bis(4-aryl-1H-imidazol-2-
ylmethyl)quinazoline-2,4-diamines 13a–13f
53.6, 137.8, 143.0, 149.5, 161.7, 180.3, 114.9, 117.6,
121.1, 123.4, 125.8, 128.2, 131.9, 133.0, 139.7, 147.5 ppm;
-1
ꢀ
IR (KBr): m = 3254 (NH), 1645 (C=C), 1542 (C=N) cm
HRMS: m/z = 655.2949 ([M?Na], calcd), 655.2943
;
The compounds 2,4-dichloroquinazoline (1, 1.0 mmol), (4-
aryloxazol-2-yl)methanamine 8/(4-arylthiazol-2-yl)methan- (found).
amine
9/(4-aryl-1H-imidazol-2-yl)methanamine
10
N2,N4-Bis[4-[4-(dimethylamino)phenyl]oxazol-2-yl-
(2.5 mmol), conc. HCl (2.0 mmol), and 5 cm3 2-propanol
were sonicated at room temperature for 60–90 min. After
completion of the reaction (monitored by TLC), the
separated solid was filtered, dried, and recrystallized from
2-propanol.
methyl]quinazoline-2,4-diamine (11e, C32H32N8O2)
1
White crystals; yield 1.00 g (72%); m.p.: 123–125 °C; H
NMR (400 MHz, DMSO-d6): d = 2.96 (s, 12H, N(CH3)2),
4.32 (s, 2H, CH2), 4.37 (s, 2H, CH2), 7.35–7.89 (m, 14H,
Ar–H, C5 -H), 9.39 (bs, 2H, NH) ppm; 13C NMR
0
N2,N4-Bis(4-phenyloxazol-2-ylmethyl)quinazoline-2,4-di-
(100 MHz, DMSO-d6): d = 42.1, 52.7, 54.3, 138.2,
145.1, 149.6, 162.3, 180.9, 116.2, 120.5, 123.5, 124.7,
128.1, 132.2, 134.0, 136.3, 139.4, 150.6 ppm; IR (KBr):
amine (11a, C28H22N6O2)
1
White crystals; yield 0.79 g (67%); m.p.: 133–135 °C; H
NMR (400 MHz, DMSO-d6): d = 4.35 (s, 2H, CH2), 4.39
0
(s, 2H, CH2), 7.11–7.72 (m, 16H, Ar–H, C5 -H), 9.40 (bs,
m = 3246 (NH), 1635 (C=C), 1532 (C=N) cm-1; HRMS:
ꢀ
m/z = 583.6386 ([M?Na], calcd), 583.6391 (found).
123

T. Rekha et al.
N2,N4-Bis[4-(4-nitrophenyl)oxazol-2-ylmethyl]quinazo-
55.6, 116.2, 153.4, 162.9, 169.8, 182.5, 115.7, 118.6,
line-2,4-diamine (11f, C28H20N8O6)
120.9, 123.2, 128.0, 131.4, 134.9, 136.1, 138.0, 147.3 ppm;
-1
ꢀ
IR (KBr): m = 3271 (NH), 1642 (C=C), 1553 (C=N) cm ;
HRMS: m/z = 687.4219 ([M?Na], calcd), 687.4212
1
White crystals; yield 0.95 g (68%); m.p.: 161–163 °C; H
NMR (400 MHz, DMSO-d6): d = 4.38 (s, 2H, CH2), 4.36
0
(s, 2H, CH2), 7.37–7.93 (m, 14H, Ar–H, C5 -H), 9.48 (bs,
(found).
2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 52.1,
54.7, 139.3, 145.6, 150.8, 162.4, 182.5, 116.9, 119.0,
N2,N4-Bis[4-[4-(dimethylamino)phenyl]thiazol-2-yl-
methyl]quinazoline-2,4-diamine (12e, C32H32N8S2)
123.6, 124.1, 128.7, 132.3, 134.2, 136.8, 142.5, 150.9 ppm;
-1
1
White crystals; yield 1.08 g (73%); m.p.: 152–154 °C; H
ꢀ
IR (KBr): m = 3263 (NH), 1649 (C=C), 1547 (C=N) cm
HRMS: m/z = 587.4950 ([M?Na], calcd), 587.4943
;
NMR (400 MHz, DMSO-d6): d = 2.89 (s, 12H, N(CH3)2),
4.34 (s, 2H, CH2), 4.38 (s, 2H, CH2), 7.41–8.03 (m, 14H,
(found).
Ar–H, C5 -H), 9.40 (bs, 2H, NH) ppm; 13C NMR
0
N2,N4-Bis(4-phenylthiazol-2-ylmethyl)quinazoline-2,4-di-
(100 MHz, DMSO-d6): d = 42.5, 55.4, 57.1, 118.7,
156.3, 160.7, 162.1, 182.6, 117.4, 119.5, 122.0, 123.1,
125.6, 127.9, 131.3, 135.4, 146.2, 149.8 ppm; IR (KBr):
amine (12a, C28H22N6S2)
1
White crystals; yield 0.88 g (70%); m.p.: 141–143 °C; H
m = 3258 (NH), 1629 (C=C), 1547 (C=N) cm-1; HRMS:
ꢀ
m/z = 615.7699 ([M?Na], calcd), 615.7691 (found).
NMR (400 MHz, DMSO-d6): d = 4.28 (s, 2H, CH2), 4.33
0
(s, 2H, CH2), 7.32–7.86 (m, 16H, Ar–H, C5 -H), 9.50 (bs,
2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 54.2,
56.5, 115.5, 153.7, 162.7, 170.1, 182.4, 115.1, 118.4,
N2,N4-Bis[4-(4-nitrophenyl)thiazol-2-ylmethyl]quinazo-
line-2,4-diamine (12f, C28H20N8O4S2)
119.5, 125.0, 130.6, 133.8, 135.9, 137.0, 143.2, 152.6 ppm;
-1
1
White crystals; yield 0.92 g (62%); m.p.: 188–190 °C; H
ꢀ
IR (KBr): m = 3367 (NH), 1632 (C=C), 1580 (C=N) cm
HRMS: m/z = 529.6356 ([M?Na], calcd), 529.6349
;
NMR (400 MHz, DMSO-d6): d = 4.37 (s, 2H, CH2), 4.39
(s, 2H, CH2), 7.46–8.12 (m, 14H, Ar–H, C5-H), 9.49 (bs,
2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 55.1,
57.3, 118.9, 155.7, 163.6, 170.4, 182.8, 117.2, 119.0,
(found).
N2,N4-Bis[4-(4-methylphenyl)thiazol-2-ylmethyl]quinazo-
line-2,4-diamine (12b, C30H26N6S2)
122.3, 125.5, 130.1, 133.6, 135.4, 137.2, 146.7, 152.8 ppm;
-1
1
ꢀ
IR (KBr): m = 3276 (NH), 1643 (C=C), 1558 (C=N) cm ;
HRMS: m/z = 619.6160 ([M?Na], calcd), 619.6167
White crystals; yield 0.90 g (68%); m.p.: 137–139 °C; H
NMR (400 MHz, DMSO-d6): d = 2.35 (s, 6H, Ar–CH3),
4.26 (s, 2H, CH2), 4.30 (s, 2H, CH2), 7.18–7.75 (m, 14H,
(found).
Ar–H, C5 -H), 9.42 (bs, 2H, NH) ppm; 13C NMR
0
N2,N4-Bis(4-phenyl-1H-imidazol-2-ylmethyl)quinazoline-
(100 MHz, DMSO-d6): d = 24.5, 54.6, 55.9, 116.9,
155.2, 163.0, 169.5, 182.1, 117.7, 119.5, 122.6, 124.1,
128.5, 131.9, 134.7, 136.3, 139.5, 149.2 ppm; IR (KBr):
2,4-diamine (13a, C28H24N8)
1
White crystals; yield 0.83 g (71%); m.p.: 200–202 °C; H
NMR (400 MHz, DMSO-d6): d = 4.29 (s, 2H, CH2), 4.34
m = 3275 (NH), 1637 (C=C), 1541 (C=N) cm-1; HRMS:
ꢀ
m/z = 557.6874 ([M?Na], calcd), 557.6880 (found).
0
(s, 2H, CH2), 7.11–7.71 (m, 16H, Ar–H, C5 -H), 9.18 (bs,
2H, NH), 11.25 (bs, 2H, imidazole-NH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 44.6, 46.2, 127.4, 139.5,
141.9, 161.7, 181.3, 115.6, 116.2, 119.5, 123.0, 126.4,
N2,N4-Bis[4-(4-chlorophenyl)thiazol-2-ylmethyl]quinazo-
line-2,4-diamine (12c, C28H20Cl2N6S2)
1
ꢀ
White crystals; yield 1.03 g (72%); m.p.: 165–167 °C; H
127.9, 130.7, 133.5, 135.7, 151.9 ppm; IR (KBr): m = 3354
NMR (400 MHz, DMSO-d6): d = 4.33 (s, 2H, CH2), 4.35
(s, 2H, CH2), 7.25–7.80 (m, 14H, Ar–H, C5-H), 9.47 (bs,
2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 54.5,
56.3, 117.5, 155.9, 160.3, 162.5, 182.9, 118.2, 119.7,
(NH), 1631 (C=C), 1581 (C=N) cm-1; HRMS: m/
z = 495.5352 ([M?Na], calcd), 495.5341 (found).
N2,N4-Bis[4-(4-methylphenyl)-1H-imidazol-2-yl-
methyl]quinazoline-2,4-diamine (13b, C30H28N8)
120.3, 123.4, 125.2, 126.6, 129.1, 135.7, 138.5, 147.0 ppm;
-1
1
White crystals; yield 0.86 g (69%); m.p.: 179–181 °C; H
ꢀ
IR (KBr): m = 3269 (NH), 1640 (C=C), 1550 (C=N) cm
HRMS: m/z = 598.5244 ([M?Na], calcd), 598.5236
;
NMR (400 MHz, DMSO-d6): d = 2.38 (s, 6H, Ar–CH3),
4.33 (s, 2H, CH2), 4.38 (s, 2H, CH2), 7.19–7.74 (m, 14H,
(found).
0
Ar–H, C5 -H), 9.22 (bs, 2H, NH), 11.21 (bs, 2H, imidazole-
N2,N4-Bis[4-(4-bromophenyl)thiazol-2-ylmethyl]quinazo-
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 23.6,
44.8, 45.9, 128.9, 138.9, 141.5, 160.5, 180.6, 116.1, 119.6,
line-2,4-diamine (12d, C28H20Br2N6S2)
1
White crystals; yield 1.14 g (69%); m.p.: 174–176 °C; H
121.0, 127.8, 130.5, 133.9, 134.2, 137.8, 140.0, 148.5 ppm;
-1
ꢀ
IR (KBr): m = 3254 (NH), 1621 (C=C), 1527 (C=N) cm ;
HRMS: m/z = 523.5867 ([M?Na], calcd), 523.5873
NMR (400 MHz, DMSO-d6): d = 4.31 (s, 2H, CH2), 4.34
(s, 2H, CH2), 7.23–7.79 (m, 14H, Ar–H, C5-H), 9.45 (bs,
2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 54.3,
(found).
123

Synthesis and antimicrobial activity of bis(azolyl)quinazoline-2,4-diamines
N2,N4-Bis[4-(4-chlorophenyl)-1H-imidazol-2-yl-
Cells
methyl]quinazoline-2,4-diamine (13c, C28H22Cl2N8)
1
White crystals; yield 0.91 g (68%); m.p.: 214–216 °C; H
NMR (400 MHz, DMSO-d6): d = 4.28 (s, 2H, CH2), 4.32
Bacterial strains Staphylococcus aureus, B. subtilis (Gram-
positive bacteria), Pseudomonas aeruginosa, Klebsiella
pneumoniae (Gram-negative bacteria), and fungi A. niger,
P. chrysogenum were obtained from the Department of
Microbiology, S.V. University, Tirupati.
0
(s, 2H, CH2), 7.28–7.80 (m, 14H, Ar–H, C5 -H), 9.14 (bs,
2H, NH) 11.23 (bs, 2H, imidazole-NH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 44.1, 46.2, 129.5, 137.2,
140.3, 160.9, 181.0, 116.2, 118.7, 120.5, 125.3, 127.6,
ꢀ
128.9, 132.7, 135.3, 139.4, 152.9 ppm; IR (KBr): m = 3249
Antibacterial and antifungal assays
(NH), 1632 (C=C), 1539 (C=N) cm-1; HRMS: m/
z = 564.4237 ([M?Na], calcd), 564.4241 (found).
The in vitro antimicrobial studies were carried out by agar
well diffusion method against test organisms [39, 40].
Nutrient broth (NB) plates were swabbed with 24-h old
broth culture (100 mm3) of test bacteria. Using the sterile
cork borer, wells (6 mm) were made into each petri plate.
The compounds (5 mg/cm3) were dissolved in DMSO and
from this 10 and 20 mm3 (50 and 100 lg/well) were added
into the wells using sterile pipettes. Simultaneously the
standard antibiotics, chloramphenicol for antibacterial
activity and ketoconazole for antifungal activity were tes-
ted as positive control against the pathogens. The samples
dissolved in DMSO which showed no zone of inhibition
acts as negative control. The plates were incubated at
37 °C for 24 h for bacteria and at 28 °C for 48 h for fungi.
After appropriate incubation, the diameter of zone of
inhibition of each well was measured. Duplicates were
maintained and the average values were calculated for
eventual antibacterial activity. Broth dilution test was used
to determine minimum inhibitory concentration (MIC) of
the above mentioned samples [41, 42]. Freshly prepared
nutrient broth was used as diluents. The 24 h old culture of
the test bacteria S. aureus, B. subtilis, P. aeruginosa, and K.
pneumoniae and the test fungi A. niger and P. chrysogenum
were diluted 100 folds in nutrient broth (100 mm3 bacterial
cultures in 10 cm3 NB). The stock solution of the synthe-
sized compounds was prepared in DMSO by dissolving
5 mg of the compound in 1 cm3 of DMSO. Increasing
concentrations of the test samples (1.25, 2.5, 5, 10, 20,
40 mm3 of stock solution contains 6.25, 12.5, 25, 50, 100,
200 lg of the compounds) were added to the test tubes
containing the bacterial and fungal cultures. All the tubes
were incubated at 37 °C for 24 h for bacteria and at 28 °C
for 48 h for fungi. The tubes were examined for visible
turbidity and using NB as control. Control without test
samples and with solvent was assayed simultaneously.
The lowest concentration that inhibited visible growth of
the tested organisms was recorded as MIC. To determine
the minimum bactericidal concentration (MBC) [43] and
minimum fungicidal concentration (MFC) [44] for each set
of test tubes in the MIC determination, a loopful of broth
was collected from those tubes which did not show any
growth and inoculated on sterile nutrient broth (for
N2,N4-Bis[4-(4-bromophenyl)-1H-imidazol-2-yl-
methyl]quinazoline-2,4-diamine (13d, C28H22Br2N8)
White crystals; yield 1.10 g (70%); m.p.: 219–221 °C;
1H NMR (400 MHz, DMSO-d6): d = 4.25 (s, 2H, CH2),
0
4.30 (s, 2H, CH2), 7.26–7.76 (m, 14H, Ar–H, C5 -H),
9.13 (bs, 2H, NH) 11.19 (bs, 2H, imidazole-NH) ppm;
13C NMR (100 MHz, DMSO-d6): d = 44.3, 45.7, 127.2,
138.6, 140.8, 160.1, 180.5, 115.4, 116.9, 119.3, 123.7,
126.6, 129.8, 132.0, 135.5, 139.2, 148.3 ppm; IR (KBr):
ꢀ
m = 3252 (NH), 1635 (C=C), 1542 (C=N) cm-1
;
HRMS: m/z = 653.3387 ([M?Na], calcd), 653.3399
(found).
N2,N4-Bis[4-[4-(dimethylamino)phenyl]-1H-imidazol-2-yl-
methyl]quinazoline-2,4-diamine (13e, C32H34N10)
1
White crystals; yield 1.01 g (73%); m.p.: 207–209 °C; H
NMR (400 MHz, DMSO-d6): d = 2.84 (s, 12H, N(CH3)2),
4.34 (s, 2H, CH2), 4.37 (s, 2H, CH2), 7.35–7.92 (m, 14H,
0
Ar–H, C5 -H), 9.11 (bs, 2H, NH), 11.20 (bs, 2H, imidazole-
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 41.4,
44.9, 46.5, 128.7, 138.0, 140.9, 161.2, 181.8, 117.3, 118.8,
120.7, 124.6, 125.9, 129.2, 131.8, 137.1, 140.6, 150.7 ppm;
-1
ꢀ
IR (KBr): m = 3237 (NH), 1627 (C=C), 1535 (C=N) cm
HRMS: m/z = 581.6691 ([M?Na], calcd), 581.6683
;
(found).
N2,N4-Bis[4-(4-nitrophenyl)-1H-imidazol-2-yl-
methyl]quinazoline-2,4-diamine (13f, C28H22N10O4)
1
White crystals; yield 0.92 g (66%); m.p.: 232–234 °C; H
NMR (400 MHz, DMSO-d6): d = 4.35 (s, 2H, CH2), 4.38
0
(s, 2H, CH2), 7.39–7.81 (m, 14H, Ar–H, C5 -H), 9.25 (bs,
2H, NH) 11.27 (bs, 2H, imidazole-NH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 44.5, 46.9, 129.3, 139.6,
141.7, 161.8, 181.4, 117.0, 119.5, 121.2, 124.1, 127.8,
ꢀ
133.6, 134.3, 137.0, 140.9, 151.7 ppm; IR (KBr): m = 3257
(NH), 1639 (C=C), 1546 (C=N) cm-1; HRMS: m/
z = 585.5238 ([M?Na], calcd), 585.5231 (found).
Antimicrobial activity
The compounds 5–7 and 11–13 were dissolved at two
concentrations of 50 and 100 lg/cm3.
123

T. Rekha et al.
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bacteria) and PDA (for fungi) by streaking. Plates inocu-
lated with bacteria and fungi were incubated at 37 °C for
24 h and at 28 °C for 48 h, respectively. After incubation,
the lowest concentration was noted as MBC (for bacteria)
or MFC (for fungi) at which no visible growth was
observed.
Acknowledgements The authors are grateful to BRNS (Board of
Research in Nuclear Sciences) Trombay, Mumbai-400085 for finan-
cial assistance under major research project. One of the authors, S.
Durgamma is thankful to University Grants Commission (UGC), New
Delhi for the sanction of UGC-BSR fellowship.
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