Synthesis and Evaluation of Novel [1,2,4]Triazolo[1,5-c]quinazoline Derivatives as Antibacterial Agents

Article abstract of DOI:10.1002/jhet.2979

A series of new 2-aryl-5-methyl-[1,2,4]triazolo[1,5-c]quinazoline derivatives (5a–5g) have been synthesized by the reaction of 3-amino-2-methylquinazolin-4-(3H)-one (3) with aromatic nitriles in potassium tert-butoxide under reflux conditions. 3-Amino-2-methylquinazolin-4-(3H)-one (3) was synthesized by the reaction 2-methyl-4H-benzo[d][1,3]oxazin-4-one (2) with hydrazine hydrate. The chemical structure of products was confirmed by IR, ¹H, ¹³C NMR and elemental analysis. These compounds were screened for antibacterial [Staphylococcus aureus (ATCC 25923), Bacillus cereus (ATCC 11778), Micrococcus luteus (ATCC 9341), Escherichia coli (ATCC 25922), and Pseudomonas aeruginosa (ATCC 27853)] activities, using the zone inhibition method.

Full text of DOI:10.1002/jhet.2979

Month 2017
Synthesis and Evaluation of Novel [1,2,4]Triazolo[1,5-c]quinazoline
1
Derivatives as Antibacterial Agents
a
*
Masoud Mohammadi Zeydi,
Naser Montazeri,b and Mahdi Fouladib
aDepartment of Organic Chemistry, Faculty of Sciences, University of Guilan, Rasht, Iran
bDepartment of Chemistry, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
*
E-mail: zedi.65@gmail.com
Received May 26, 2017
DOI 10.1002/jhet.2979
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A series of new 2-aryl-5-methyl-[1,2,4]triazolo[1,5-c]quinazoline derivatives (5a–5g) have been synthe-
sized by the reaction of 3-amino-2-methylquinazolin-4-(3H)-one (3) with aromatic nitriles in potassium
tert-butoxide under reflux conditions. 3-Amino-2-methylquinazolin-4-(3H)-one (3) was synthesized by the
reaction 2-methyl-4H-benzo[d][1,3]oxazin-4-one (2) with hydrazine hydrate. The chemical structure of
1
products was confirmed by IR, H, 13C NMR and elemental analysis. These compounds were screened
for antibacterial [Staphylococcus aureus (ATCC 25923), Bacillus cereus (ATCC 11778), Micrococcus luteus
(ATCC 9341), Escherichia coli (ATCC 25922), and Pseudomonas aeruginosa (ATCC 27853)] activities,
using the zone inhibition method.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
toward adenosine receptors [26]. Additionally, triazolo-
quinazolines,
which
originated
from
N-
Among the heterocyclic nitrogen-containing compounds,
quinazoline and their derivatives constitute an important
class of compounds with a various pharmacological and
therapeutic properties such as antimalarial [1], anticancer
[2–5], antitumor [6], antimicrobial [7,8], antihypertensive
[9,10], anticonvulsant [11,12], anti-inflammatory [13],
anticholinesterase [14], anti-diabetic [15], cellular
phosphorylation inhibition [16], dihydrofolate reductase
inhibition [17,18], and kinase inhibitory activities [19–21].
In addition, a number of compounds with a quinazoline
core are used as efficient drugs. Among them are erlotinib,
gefitinib, and lapatinib for the treatment of different types
of tumors, trimetrexate for the treatment of Pneumocystis
carinii pneumonia, and prazosin for the treatment of
hypertension [22,23] (Fig. 1).
Conversely, triazolo-quinazolines display diverse
pharmacological and biological activities such as
antihypertensive [7], anti-inflammatory [24], and
phosphodiesterase 10A (PDE10A) inhibitors activities
[25]. Some of the 1,2,4-triazolo[1,5-a]quinazolines have
been proven as excellent agents for controlling the plant
growth diseases caused by fungal pathogens, and some
chlorinated derivatives have shown an interesting affinity
cyanoimidocarbonates, have been described as potent
protein kinase inhibitors [27]. As a part of our current
studies in synthesis of tris-pyrazolines [28], bis-coumarines
[29], triazepanes [30], and thiazolidine derivatives [31]
here, we reported synthesis of novel triazolo-quinazolines
and evaluation of their antibacterial activities.
RESULTS AND DISCUSSION
It was well known that the quinazoline moiety plays an
important role in promoting the antibacterial properties of
molecules. Therefore, study on the interesting
pharmacological features of quinazolines has encouraged
us to synthesize new triazolo-quinazoline derivatives
5a–5g. Here, novel 2-aryl-5-methyl-[1,2,4]triazolo[1,5-c]
quinazoline derivatives 5a–5g were synthesized through
the reaction of 3-amino-2-methylquinazolin-4-(3H)-one
(3) with aromatic nitriles 4a–4g in the presence of bulky
base potassium tert-butoxide under reflux conditions. 3-
Amino-2-methylquinazolin-4-(3H)-one (3) was prepared
through the reaction 2-methyl-4H-benzo[d][1,3]oxazin-4-
one (2) and hydrazine hydrate under microwave
© 2017 Wiley Periodicals, Inc.

2
M. M. Zeydi, N. Montazeri, and M. Fouladi
Vol 000
Figure 1. Selected drugs with a quinazoline core. [Color figure can be viewed at wileyonlinelibrary.com]
irradiation in absolute EtOH. It is remarkable that the
reaction was completed in 27 h reflux in conventional
methods. Alternatively, was completed efficiently, in
15 min, 94% yields under microwave condition. The total
route for the synthesis of triazolo[1,5-c]quinazoline
derivatives is illustrated in Scheme 1.
Addition of aromatic nitriles to 3-amino-2-
methylquinazolin-4-(3H)-one is a regioselective reaction
proceed via addition of the NH2 of compound 3 to the
carbon of nitrile group of 4, and subsequent
intramolecular cyclization of N─H to the carbonyl group
of the amid 3 and elimination of water produce the
corresponding triazolo-quinazolines (Scheme 1).
and spectral analysis. The Fourier transform infrared
(FTIR) spectra of the compound 5a reveal the presence
of two band at 1523 and 1600 cmÀ1 for the C═N group.
1
The H NMR spectrum of 5a in CDCl3 showed methyl
protons as singlet at 2.91 ppm that confirms the
formation of the quinazolines moiety. Aromatic protons
appear in the expected area (7.35–8.39 ppm). As well, in
the 13C NMR spectrum of 5a, the methyl carbon
appeared at 43.6 and three C═N resonate at δ 142.5,
153.5, and 169.5 ppm, respectively (according to the
reference [32]).
The new triazolo-quinazolines 5a–5g were evaluated for
their in vitro antibacterial activity against three Gram-
positive and two Gram-negative bacteria [Staphylococcus
aureus (S. aureus) ATCC 25923, Bacillus cereus
(B. cereus) ATCC 11778, and Micrococcus luteus
(M. luteus) ATCC 9341] and Gram-negative bacteria
[Escherichia coli (E. coli) ATCC 25922 and Pseudomonas
aeruginosa (P. aeruginosa) ATCC 27853] using the zone
inhibition method [33]. Dimethyl sulfoxide (DMSO) was
used as a negative control and showed no activity against
aforementioned bacterial strains. Penicillin was used as
positive control and showed antibacterial activity against
all bacterial strains. The antibacterial activity of
quinazolines 5a–5g was evaluated at a concentration of
1000 μg/mL in DMSO. The experiments were performed
in triplicate. The findings are reported as mean standard
deviation in millimeter and presented in Table 1. All the
synthesized compounds possessed suitable antibacterial
activity against Gram-positive and Gram-negative
bacteria. Compound 5f showed surprising activity against
P. aeruginosa and S. aureus, while compound 5c showed
good activity against B. cereus.
The structures of all synthesized triazolo-quinazolines
5a–5g were assigned on the basis of their physical data
Scheme 1. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Novel Quinazolines as Antibacterial Agents
3
Table 1
Antimicrobial activity of triazolo-quinazolines 5a–5f.
Antimicrobial activity (zone of inhibition in millimeters)
Gram-positive
Gram-negative
Pseudomonas aeruginosa
Entry
Compound
Staphylococcus aureus
Bacillus subtilis
Micrococcus luteus
Escherichia coli
1
2
3
4
5
6
7
14
15
5a
5b
5c
5d
5e
5f
5g
DMSO
Penicillin
18
13
20
10
14
24
22
—
48
16
11
29
15
20
17
8
22
18
19
11
24
20
10
—
49
20
10
14
8
12
19
21
—
21
26
12
15
17
22
27
21
—
47
—
33
CONCLUSIONS
oven (RAGA’S Electromagnetic System). The reaction
was monitored by TLC (CHCl3:MeOH 3:1). After
completion of reaction, the mixture was allowed to cool
at r.t. Separated solid product was recrystallized from
H2O to obtain the pure product. Yield% 94, m.p.
(79–81).
In conclusion, we reported an efficient protocol for
synthesis of 2-aryl-5-methyl-[1,2,4]triazolo[1,5-c]
quinazoline derivatives (5a–5g) in good yields from
reaction of 3-amino-2-methylquinazolin-4-(3H)-one (3)
with aromatic nitriles 4 in potassium tert-butoxide under
reflux conditions. The chemical structure of synthesized
compound was characterized by FTIR, 1H, 13C NMR
spectroscopy, and elemental analysis. The antibacterial
activities of triazolo[1,5-c]quinazolines were estimated
versus five bacterial strains, including S. aureus,
B. cereus, M. luteus, E. coli, and P. aeruginosa. The
triazolo[1,5-c]quinazoline derivatives showed good
antibacterial activity against Gram-positive bacteria
(S. aureus and M. luteus) as well as Gram-negative
bacteria (E. coli and P. aeruginosa).
Synthesis of 3-amino-2-methylquinazolin-4-(3H)-one (3)
[34]. To a mixture of compound 2 (5 mmol, 0.8 g) in
absolute EtOH (15 mL), NH2NH2 hydrate (99%) (2 mL)
was added; the mixture was irradiated under microwave
at 650 W for 30 min in a scientific oven. The reaction
was monitored by TLC (CHCl3:MeOH 3:1); after
completion the reaction, the mixture was cooled and the
precipitate was filtered and recrystallized from H2O.
Yield% 79, m.p. (148–150).
Synthesis
of
2-aryl-5-methyl-[1,2,4]triazolo[1,5-c]
quinazoline
(5a–5g).
3-Amino-2-methylquinazolin-
4(3H)-one 3 (1 mmol, 0.175 g) and aromatic nitriles 4
(1 mmol) were dissolved in potassium tert-butoxide
(10 mL) and refluxed for 48 h. The progress of the
reaction was monitored by TLC (CHCl3:MeOH 5:2).
After completion of the reaction, the reaction mixture
was poured into cold water and neutralize with dilute 1N
HCl. Finally, the product was filtered, washed with water,
dried, and recrystallized from EtOH 90% to recover the
products in good yield with high purity.
EXPERIMENTAL
All materials, reagents, and biological cultures were
obtained from commercial suppliers Merck, Sdfine,
Quelab, and were used without further purification. All
reactions were monitored by silica gel-coated thin-layer
chromatography (TLC) plates (60 F254 Merck). FTIR
spectra were recorded on
a
Shimadzu IR-470
3-Amino-2-methyl-4(3H)-quinazolinone (3).
Yellow to
brick red crystals; yield: 80%; m.p. 148–150°C; FTIR
(KBr): 3448, 3252 (NH2); 1586 (C═N) cmÀ1
spectrophotometer in anhydrous KBr. The 1H and 13C
NMR spectra were recorded at r.t. on a Bruker Avance
400 MHz and 100 MHz spectrometer using DMSO-d6 and
CDCl3 as solvents. Elemental analyses were carried out on
a Carlo–ErbaEA1110CNNO-Sanalyzer. All melting points
were determined with a Mettler Fp5 apparatus and were
uncorrected.
.
5-Methyl-2-phenyl[1,2,4]triazolo[1,5-c]quinazoline (5a).
Yellow crystals; yield: 72%; m.p. 230–232°C; FTIR
(KBr): 3130 (C─H); 1600, 1523 (C═N) cmÀ1; H NMR
1
(CDCl3, δ, ppm): 2.91 (s, 3H, CH3), 7.35 (m, 3H, Ar-H),
7.50 (t, 1H, J = 7.6 Hz, Ar-H), 7.63 (t, 1H, J = 7.2 Hz,
Ar-H), 7.80 (d, 1H, J = 8.4 Hz, Ar-H), 8.19 (d, 2H,
J = 7.6 Hz, Ar-H), 8.39 (d, 1H, J = 7.6 Hz, Ar-H); 13C
NMR (100 MHz, CDCl3, δ, ppm): 169.5, 153.5, 150.1,
142.5, 134.7, 130.5, 129.3, 127.3, 126.9, 126.3, 126.2,
Synthesis of 2-methyl-4H-benzo[d][1,3]oxazin-4-one (2)
[34].
A mixture of 2-aminobenzoic acid (10 mmol,
1.37 g) and acetic anhydride (10 mL) was irradiated
under microwave at 650 W for 15 min in a scientific
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

4
M. M. Zeydi, N. Montazeri, and M. Fouladi
Vol 000
122.0, 119.5, 21.5. Anal. Calcd for C16H12N4: C, 73.83; H,
4.65; N, 21.52. Found: C, 73.85; H, 4.61; N, 21.56.
5-Methyl-2-(3-methylphenyl)[1,2,4]triazolo[1,5-c]
Ar-H), 7.85 (d, 2H, J = 8.4 Hz, Ar-H), 7.99 (d, H,
J = 8.4 Hz, Ar-H), 11.54 (s, 1H, OH); 13C NMR (CDCl3,
δ, ppm): 170.0, 159.4, 158.5, 155.8, 149.7, 132.0, 130.3,
127.1, 126.1, 125.1, 122.4, 116.7, 116.4, 21.7. Anal.
Calcd for C16H12N4O: C, 69.55; H, 4.38; N, 20.28.
quinazoline (5b). Yellow crystals; yield: 65%; m.p. 256–
1
258°C; FTIR (KBr): 3067 (C─H); 1608 (C═N) cmÀ1; H
NMR (CDCl3, δ, ppm): 2.51 (s, 3H, CH3), 3.11 (s, 3H,
CH3), 7.34 (d, 1H, J = 7.2 Hz, Ar-H), 7.44 (t, 1H,
J = 7.6 Hz, Ar-H), 7.71 (t, 1H, J = 7.6 Hz, Ar-H), 7.83
(t, 1H, J = 7.6 Hz, Ar-H), 8.01 (d, 1H, J = 7.2 Hz, Ar-
H), 8.21 (m, 2H, Ar-H), 8.60 (d, 1H, J = 7.6 Hz, Ar-H);
13C NMR (CDCl3, δ, ppm): 164.2, 151.4, 147.6, 142.7,
138.5, 131.8, 131.2, 130.1, 128.7, 128.1, 127.9, 127.8,
124.7, 123.7, 117.3, 21.4, 20.0. Anal. Calcd for
C17H14N4: C, 74.43; H, 5.14; N, 20.42. Found: C, 74.47;
Found: C, 69.51; H, 4.43; N, 20.22
2-(4-Methoxyphenyl)-5-methyl-[1,2,4]triazolo[1,5-c]
quinazoline (5g). Yellow crystals; yield: 84%; m.p. 186–
188°C; IR (KBr): 3135 (C─H); 1644, 1605, 1549, 1435
(C═N, C═C); 1268 (C─O) cmÀ1; H NMR (DMSO-d6,
1
δ, ppm): 2.90 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 6.94 (d,
2H, J = 8.00 Hz, Ar-H), 7.44–7.58 (m, 2H, Ar-H), 7.70–
7.81 (m, 1H, Ar-H), 7.86–8.04 (m, 3H, Ar-H); 13C NMR
(CDCl3, δ, ppm): 168.9, 159.0, 157.9, 155.5, 149.7,
132.0, 129.7, 128.6, 127.5, 124.2, 122.1, 116.4, 114.3,
48.9, 21.5. Anal. Calcd for C17H14N4O: C, 70.33; H,
4.86; N, 19.30. Found: C, 70.37; H, 4.82; N, 19.24.
H, 5.10; N, 20.46.
5-Methyl-2-(4-methylphenyl)[1,2,4]triazolo[1,5-c]
quinazoline (5c). Yellow crystals; yield: 70%; m.p. 243–
245°C; FTIR (KBr): 3053 (C─H); 1623, 1565 (C═N)
Determination
of
antimicrobial
activity.
The
cmÀ1 1H NMR (CDCl3, δ, ppm): 2.70 (s, 3H, CH3),
;
antibacterial activity of triazolo-quinazolines 5a–5g was
measured biologically using the agar well-diffusion
method. Then Mueller–Hinton agar (Merck) plates were
readied similar to manufacturers’ instructions in order
to compare the antibacterial activities of products. The
sterile Mueller–Hinton agar plates were inoculated with
the bacteria; 0.001 g of test samples was dissolved in
1 mL DMSO to obtain a stock solution; 0.1 mL of
each sample was dropped into each labeled well
aseptically. The inculcated plates were then incubated
for 24 h at 37°C. DMSO was used as a negative
control and penicillin as a positive control. After
incubation time, antimicrobial activity was estimated by
measuring the zone of inhibition against the test
organisms and compared with that of the standard. The
results of our tests were presented as the inhibition
zones, given in millimeters (mm). The experiment was
carried out in repetitive and the average zone of
inhibition was estimate.
3.12 (s, 3H, CH3), 7.57 (d, 2H, J = 5.6 Hz, Ar-H), 7.71
(t, 1H, J = 7.6 Hz, Ar-H), 7.84 (t, 1H, J = 7.2 Hz, Ar-H),
8.01 (d, 1H, J = 7.2 Hz, Ar-H), 8.41 (d, 2H, J = 7.6 Hz,
Ar-H), 8.60 (d, 1H, J = 7.2 Hz, Ar-H); 13C NMR
(CDCl3, δ, ppm): 164.2, 151.7, 147.6, 142.7, 131.9,
130.4, 130.3, 128.7, 127.9, 127.8, 127.6, 123.8, 118.7,
22.0, 20.0. Anal. Calcd for C17H14N4: C, 74.43; H, 5.14;
N, 20.42. Found: C, 74.40; H, 5.19; N, 20.36.
2-(3-Chlorophenyl)-5-methyl[1,2,4]triazolo[1,5-c]
quinazoline (5d). Yellow crystals; yield: 87%; m.p. 302–
305°C; IR (KBr): 3114 (C─H); 1623, 1578, 1445 (C═N,
C═C) cmÀ1 1H NMR (CDCl3, δ, ppm): 2.82 (s, 3H,
;
CH3), 7.44 (d, 1H, J = 8.00 Hz, Ar-H), 7.51–7.55 (m,
3H, Ar-H), 7.78 (d, 1H, J = 6.8 Hz, Ar-H), 7.93 (s, 1H,
Ar-H), 7.27–8.41 (m, 2H, Ar-H); 13C NMR (CDCl3, δ,
ppm): 163.0, 160.1, 157.4, 151.9, 148.9, 132.4, 130.0,
129.1, 128.7, 127.7, 127.4, 126.8, 126.5, 122.8, 116.1,
21.6. Anal. Calcd for C16H11ClN4: C, 65.20; H, 3.76; N,
19.01. Found: C, 65.17; H, 3.72; N, 19.06.
2-(4-Chlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-c]
quinazoline (5e). Yellow crystals; yield: 81%; m.p. 233–
Acknowledgments. The authors are grateful to the Research
Council of University of Guilan for financial support of this work.
335°C; IR (KBr): 3097 (C─H); 1596, 1539, 1481 (C═N,
1
C═C) cmÀ1; H NMR (DMSO-d6, δ, ppm): 2.52 (s, 3H,
CH3), 7.22 (d, 2H, J = 8.4 Hz, Ar-H), 7.30 (d, 1H,
J = 8.4 Hz, Ar-H), 7.81–7.92 (m, 2H, Ar-H), 8.64 (d, 2H,
J = 8.4 Hz, Ar-H), 8.81 (d, 1H, J = 8.4 Hz, Ar-H); 13C
NMR (CDCl3, δ, ppm): 168.9, 160.9, 155.7, 138.5,
134.4, 131.8, 129.5, 129.3, 128.9, 127.8, 126.7, 121.6,
116.1, 21.5. Anal. Calcd for C16H11ClN4: C, 65.20; H,
3.76; N, 19.01. Found: C, 65.26; H, 3.71; N, 19.05.
4-(5-Methyl-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)phenol
(5f). Yellow crystals; yield: 85%; m.p. 210–213°C; IR
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet