Synthesis and antimicrobial activities of some novel substituted 2-imidazolyl-N-(4-oxo-quinazolin-3(4H)-yl)-acetamides

Article abstract of DOI:10.1248/cpb.55.1615

Several substituted-quinazolin-3(4H)-ones 8-11ad were synthesized by condensation of 2-chloro-N-(4-oxosubstituted-quinazolin-3(4H)-yl)-acetamides with various substituted imidazoles through one pot reaction. Elemental analysis, IR, 1H-NMR and mass spectral data confirmed the structure of the newly synthesized compounds. Synthesized quinazolin-4-one derivatives were investigated for their antitubercular, antibacterial and antifungal activities. Some of the tested compounds showed good antitubercular activity. None of the synthesized compounds showed significant antibacterial and antifungal activity.

Full text of DOI:10.1248/cpb.55.1615

November 2007
Chem. Pharm. Bull. 55(11) 1615—1619 (2007)
1615
Synthesis and Antimicrobial Activities of Some Novel Substituted
2-Imidazolyl-N-(4-oxo-quinazolin-3(4H)-yl)-acetamides
Nulgulmnalli Manjunathiah RAGHAVENDRA, ,a Parameshwaran THAMPI,a
*
b
Purvarga Mattada GURUBASAVARAJASWAMY,a and Dharmarajan SRIRAM
a Medicinal Chemistry Research Laboratory, Acharya and B.M. Reddy College of Pharmacy; Bangalore, Karnataka
560090, India: and b Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and
Science; Pilani, Rajasthan 333031, India. Received July 24, 2007; accepted September 3, 2007
Several substituted-quinazolin-3(4H)-ones 8—11ad were synthesized by condensation of 2-chloro-N-(4-oxo-
substituted-quinazolin-3(4H)-yl)-acetamides with various substituted imidazoles through one pot reaction. Ele-
1
mental analysis, IR, H-NMR and mass spectral data confirmed the structure of the newly synthesized com-
pounds. Synthesized quinazolin-4-one derivatives were investigated for their antitubercular, antibacterial and
antifungal activities. Some of the tested compounds showed good antitubercular activity. None of the synthesized
compounds showed significant antibacterial and antifungal activity.
Key words quinazolin-4-one; imidazolyl quinazolin-4-one; antitubercular activity; imidazole
Quinazolin-4-one ring system has been consistently re- acetamides 6, 7ab. Similarly the 1H-NMR spectra of 2-
warded as a promising molecule because of its broad spec- chloro-N-(4-oxo-substituted-quinazolin-3(4H)-yl)-ace-
trum pharmacological activities like antitubercular,1) antibac- tamides 6, 7ab showed characteristic diastereotopic two dou-
terial,2) antifungal,3) anticancer,4,5) anti-HIV,6) anthelmintic,7) blets at d 4.1—4.4 due to CꢁOCH2Cl protons. Presence of
anti-inflammatory8) and antihypertensive activities.9) Imida- singlet at d 6.6—7.3 due to imidazole protons established
zoles are one of the oldest and potent heterocyclic com- that all the 2-chloro-N-(4-oxo-substituted-quinazolin-3(4H)-
pounds having antimicrobial activities.10,11) Structure activity yl)-acetamides had converted into 2-(1H-substituted-imida-
relationship studies of quinazolinone ring system revealed in zol-1-yl)-N-(4-oxo-substituted-quinazolin-3(4H)-yl)-acet-
1
various literatures12—14) suggest position 2, 6 and 8 are very amides and 8—11ad. The H-NMR, MS, IR and elemental
much important for structure activity studies and position 3 analysis supported the structure of title compounds.
should be attached to different heterocyclic rings for better
chemotherapeutic activity.
Antitubercular Activity Compounds were evaluated for
their in vitro antimycobacterial activity by agar dilution
As these two heterocycles are present in biologically active method18) against Mycobacterium tuberculosis H37Rv and M.
compounds, we were interested in preparing compounds con- smegmatis in duplicate. The agar dilution method was per-
taining them. In view of these observations, we report herein formed using Middlebrook 7H10 medium supplemented
the reactions of imidazoles with 2-chloro-N-(4-oxo-substi- with Middlebrook OADC medium (Hi-Media). After solidifi-
tuted-quinazolin-3(4H)-yl)-acetamides to give appropriate 2- cation of the agar, the plates were inoculated with 0.1 ml of
(1H-substituted-imidazol-1-yl)-N-(4-oxo-substituted-quina- 10ꢀ4 dilutions of a McFarland 1.0 concentration of a suspen-
zolin-3(4H)-yl)-acetamides 8—11ad and their antimicrobial sion of organism. The inoculated plates were then incubated
activities.
at 37 °C for 4 weeks. The minimum inhibitory concentration
(MIC) was considered to be the lowest concentration that
completely inhibited growth on agar plates, disregarding a
Chemistry
In Chart 1, o-aminobenzoic acid was brominated at 15 °C
in presence of glacial acetic acid to form 2-amino-3,5-dibro-
mobenzoic acid 1. Different anthranilic acids on treatment
with benzoyl chloride/acid anhydrides yields substituted-4H-
3,1-benzoxazin-4-one 2, 3ab, which on condensation with
hydrazine hydrate gives 3-amino-substituted-quinazolin-
4(3H)-one 4ab,15,16) 5a17) and 5b. These 3-amino-quinazolin-
4(3H)-ones 4, 5ab were reacted with chloroacetyl chloride in
toluene to form 2-chloro-N-(4-oxo-substituted-quinazolin-
3(4H)-yl)-acetamides 6, 7ab (compound 7a was reported as
an intermediate for various quinazolin-4-one derivatives as
anthelmintic agents,7) which were later treated with imida-
zole derivatives in presence of anhydrous potassium carbon-
ate to yield 2-(1H-substituted-imidazol-1-yl)-N-(4-oxo-sub-
stituted-quinazolin-3(4H)-yl)-acetamides 8—11ad. The in-
frared spectra of the 3-amino-quinazolin-4(3H)-ones 4, 5ab
showed characteristic absorption bands at 3200—3300 cmꢀ1,
was attributed to NH2, which were disappeared by the forma-
Chart 1. Synthesis of 2-(1H-Substituted-imidazol-1-yl)-N-(4-oxo-substi-
tion of 2-chloro-N-(4-oxo-substituted-quinazolin-3(4H)-yl)- tuted-quinazolin-3(4H)-yl)-acetamides 8—11ad
∗ To whom correspondence should be addressed. e-mail: nmraghu76@yahoo.co.in
© 2007 Pharmaceutical Society of Japan

1616
Vol. 55, No. 11
single colony or a faint haze caused by the inoculums. In ately active compounds towards various bacteria is recorded
vitro antimycobacterial activity of tested compounds are re- in Table 2.
ported in Table 1.
Antibacterial and Antifungal Activity The antibacter- Results and Discussion
ial and antifungal activity of title compounds was determined
In vitro antitubercular screening reveals that some of the
in vitro by using paper disc method.19) The agar media for tested compounds are promising candidates having good ac-
each microorganism were prepared as per by Institute of tivity against M. tuberculosis H37Rv and M. smegmatis.
Microbial Technology, Chandigarh, India. The zone of Compounds 8b, 9b and 11c showed good antitubercular
inhibition (ZI) in mm was measured. The concentration activities comparable to standard antitubercular agents (Table
(100 mg/ml) of test compounds were prepared by dissolving 1). Compound 9b exhibited the highest degree of antituber-
the compounds in dimethyl sulfoxide (DMSO). Under identi- cular activity than ciprofloxacin against M. tuberculosis
cal conditions, ciprofloxacin and griseofulvin were tested as H37Rv. Rest of the compounds does not show any significant
standard drug (100 mg/ml) for bacteria and fungi respec- antitubercular activity as compared with standard agents.
tively. Antibacterial and antifungal activity shown by moder-
The results of the antibacterial and antifungal effect of the
Table 1. In Vitro Antimycobacterial Activity of Compounds 8—11ad
MIC in (mg/ml)
M. tuberculosis
MIC in (mg/ml)
M. smegmatis
Compounds
X
R
R1
8a
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
10d
11a
11b
11c
11d
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
C3H7
C3H7
C3H7
C3H7
Imidazolyl
ꢂ12.5
1.56
6.25
12.5
ꢂ12.5
0.4
ꢂ12.5
12.5
12.5
6.25
6.25
12.5
ꢂ12.5
6.25
1.56
6.25
1.56
0.39
0.05
0.2
50
6.25
25
25
25
0.78
50
25
50
50
25
50
50
50
25
25
ꢃ0.78
0.78
6.25
1.56
2-Methyl imidazolyl
2-Methyl benzimidazolyl
Benzimidazolyl
H
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Imidazolyl
2-Methyl imidazolyl
2-Methyl benzimidazolyl
Benzimidazolyl
Imidazolyl
2-Methyl imidazolyl
2-Methyl benzimidazolyl
Benzimidazolyl
Imidazolyl
2-Methyl imidazolyl
2-Methyl benzimidazolyl
Benzimidazolyl
Ciprofloxacin
Gatifloxacin
Isoniazid
Rifampicin
Table 2. Antibacterial and Antifungal Activity of Compounds 8—11ada)
Compoundsb)
B. subtilis
P. aeruginosa
K. pneumoniae
A. oryzae
C. albicans
C. tropicalis
8a
8b
8c
9a
9b
—
11.5ꢄ0.50c)
11ꢄ0.00
—
9ꢄ0.00
8ꢄ0.00
8.5ꢄ0.50
8ꢄ0.00
8ꢄ1.00
11ꢄ0.00
11ꢄ0.00
6.5ꢄ0.50
9ꢄ0.00
8ꢄ0.00
—
—
7ꢄ0.00
8ꢄ0.00
—
—
—
—
—
—
—
—
—
10ꢄ0.00
—
11ꢄ0.50
—
12.5ꢄ0.50
11.5ꢄ0.50
10ꢄ0.00
—
—
—
—
—
—
—
—
34ꢄ0.50
—
—
—
—
—
—
9c
9d
9ꢄ0.00
8ꢄ0.00
—
12ꢄ1.00
—
9ꢄ0.00
8.5ꢄ0.50
8.5ꢄ0.50
12ꢄ0.00
42ꢄ0.50
10.5ꢄ0.50
9ꢄ0.00
8ꢄ0.00
—
—
—
10ꢄ0.00
8.5ꢄ0.50
9.5ꢄ0.50
41ꢄ0.50
9ꢄ0.00
—
—
—
—
9.5ꢄ0.50
—
—
33ꢄ0.50
10a
10b
10c
10d
11b
11c
11d
Standardd)
—
—
—
—
—
—
—
—
43ꢄ0.50
31ꢄ0.50
a) Zone of inhibition in mm at concentration of 100 mg/ml (inactive, —; mild, ꢃ10; moderate, 10—20; good, 20—30; potent, 30—45 mm), all the compounds were inactive
against S. aureus and A. awamori. b) Compounds 8d and 11a were found to be inactive against all tested microorganisms. c) Standard error. d) Ciprofloxacin for bacteria
and griseofulvin for fungi.

November 2007
1617
ies on a Thermonik melting point apparatus, Mumbai, India and are uncor-
newly synthesized compounds are reported as MIC against
Staphylococcus aureus (S. aureus) (MTCC 3160), Bacillus
subtilis (B. subtilis) (MTCC 441) (gram-positive bacteria),
Pseudomonas aeruginosa (P. aeruginosa) (MTCC 424),
Klebsiella pneumoniae (K. pneumoniae) (MTCC 3384)
(gram-negative bacteria) and four fungi Aspergillus awamori
(A. awamori) (MTCC 2879), Aspergillus oryzae (A. oryzae)
(MTCC 1122), Candida albicans (C. albicans) (MTCC 183)
and Candida tropicalis (C. tropicalis) (MTCC 461). Com-
pounds 8bc, 10b and 11d exhibit moderate activity against B.
subtilis. Compounds 9ac were moderately active against C.
albicans (Table 2); 9c was found to have similar activity
against P. aeruginosa and K. pneumoniae also. Compounds
8ac, 9d and 11b showed moderate activity against C. tropi-
rected. The IR spectra (KBr, gMax, cmꢀ1) were run on Shimadzu-8400
1
FTIR spectrophotometer. H-NMR (d ppm, CDCl3/DMSO-d6) spectra were
recorded using Brucker WM-400 spectrometer with TMS as internal stan-
dard. Mass spectra were recorded on Micromass Q-TOF and Shimadzu
LCMS 2010A Mass spectrometer. Elemental analyses were performed on
Thermo Finnigan FLASH EA 1122 CHNS Analyzer and were within
ꢄ0.4% of theoretical values.
Synthesis of Substituted-4H-3,1-benzoxazin-4-one (2, 3)ab These
compounds were synthesized by methods reported earlier.20—22)
General Method for the Synthesis of 2,6,8-Substituted-3-amino-4-oxo-
quinazolin-3(4H)-one (4, 5ab) Respective benzoxazin-4-ones (2, 3ab)
(1.0 mmol) was refluxed with hydrazine hydrate (50 ml) for 3 h with occa-
sional shaking. The reaction mixture was cooled to room temperature. The
crystals formed were filtered, washed with water and dried. The products
thus formed was recrystallized from ethyl acetate and used in the next step.
3-Amino-2-phenyl-quinazolin-4(3H)-one (4a) Yield 40%; mp 172 °C;
calis, P. aeruginosa and K. pneumoniae respectively. Com- IR (KBr) n cmꢀ1: 3307, 3215, 3062, 1662, 1564, 1471, 1338. 1H-NMR
(DMSO-d6) d: 8.15—8.25 (1H, d, Jꢁ7.0 Hz), 7.8—8.1 (3H, m), 7.71—7.73
(1H, d, Jꢁ8.0 Hz), 7.55—7.6 (1H, t, Jꢁ5.6 Hz), 7.45—7.5 (3H, d,
Jꢁ6.73 Hz), 5.2 (2H, s).
3-Amino-6,8-dibromo-2-phenyl-quinazolin-4(3H)-one (4b) Yield
65%; mp 235 °C; IR (KBr) n cmꢀ1: 3311, 3274, 3082, 1670, 1568, 694. 1H-
NMR (DMSO-d6) d: 8.4 (1H, s), 8.2—8.3 (1H, s), 7.8—7.9 (2H, d,
Jꢁ6.4 Hz), 7.4—7.6 (3H, m), 5.72—5.75 (2H, s).
pounds 8ac, 9ab and 10c were mild in activity against P.
aeruginosa. 8bc, 9d, 10a and 11cd were mild in activity
against K. pneumoniae. Compounds 9cd, 10d and 11bc
showed mild activity against B. subtilis. As noted, against A.
oryzae compounds 9d and 11b exhibit mild activity. How-
ever, the activities of the tested compounds are much less
than those of standard antifungal and antibacterial agents
used.
Structure activity relationship studies of the title com-
pounds for antitubercular activity against M. tuberculosis in-
dicates compound 9b (MIC, 0.4 mg/ml) having phenyl group
at position 2 of the quinazolinone ring is more active than
propyl derivative compound 11b (MIC, 6.25 mg/ml) and
methyl derivative compound 10b (MIC, 6.25 mg/ml). Methyl
substituted azoles attached to acetamido side chain at posi-
tion 3 of quinazolinone proves more beneficial than unsubsti-
tuted azoles as compound 8b (MIC, 1.56 mg/ml), 11c (MIC,
1.56 mg/ml) are more active than compound 8a (MIC,
3-Amino-6,8-dibromo-2-methyl-quinazolin-4(3H)-one (5a) Yield
65%; mp 225 °C; IR (KBr) n cmꢀ1: 3305, 3247, 3076, 2952, 2862, 1664,
1
1542, 1448, 694. H-NMR (CDCl3) d: 8.4 (1H, s), 8.2—8.3 (1H, s), 5.8—
5.9 (2H, s), 2.6 (3H, s).
3-Amino-6,8-dibromo-2-propyl-quinazolin-4(3H)-one (5b) Yield
60%; mp 182 °C; IR (KBr) n cmꢀ1: 3313, 3211, 3086, 2978, 2861, 2817,
1666, 1606, 1589, 792, 692. 1H-NMR (DMSO-d6) d: 8.34 (1H, s), 8.1—8.2
(1H, s), 5.8 (2H, s), 2.9—3.1 (4H, m), 1.2—1.4 (3H, t, Jꢁ7.3 Hz).
General Method for the Synthesis of 2-Chloro-N-(2,6,8-substituted-4-
oxo-quinazolin-3(4H)-yl)-acetamide (6, 7)ab 2,6,8-Substituted-3-amino-
4-oxoquinazolin-3(4H)-one (4, 5)ab (1.8 mmol) was dissolved in 50 ml of
dry toluene and cooled to 15 °C. To this chloroacetyl chloride (2 mmol,
2.3 ml) was added drop wise with stirring. The temperature was brought
slowly to room temperature and then refluxed for 4 h. Excess toluene was
distilled off; precipitate obtained was filtered, washed several times with dry
ꢂ12.5 mg/ml) and 11a (MIC, ꢂ12.5 mg/ml) respectively. Re- benzene, dried and recrystallized from aqueous dioxan. The completion of
the reaction was monitored on silica gel 60 F254 precoated TLC plates by
placement of hydrogen by bromine at position 6 and 8 of the
quinazolinone ring as in compound 9b (MIC, 0.4 mg/ml) fa-
vors antitubercular activity than non halogen derivative com-
using ethyl acetate, petroleum ether and methanol (1 : 1 : 0.3) as the eluent
and observed in UV light.
2-Chloro-N-(4-oxo-2-phenyl-quinazolin-3(4H)-yl)-acetamide (6a)
Yield 55%; mp 148 °C; IR (KBr) n cmꢀ1: 3205, 3010, 2935, 1690, 1568,
1475, 1328, 775. 1H-NMR (DMSO-d6) d: 11.5 (1H, s), 8.1—8.2 (2H, d,
Jꢁ6.7 Hz), 7.89—7.90 (1H, t, Jꢁ7.0 Hz), 7.75—7.77 (1H, d, Jꢁ7.9 Hz),
7.48—7.54 (5H, m), 4.08—4.18 (2H, q, Jꢁ13.6 Hz).
pound 8b (MIC, 1.56 mg/ml).
Structured activity relationship studies for antibacterial
and antifungal studies reveals that the presence of bromine at
position 6 and 8 of the quinazolinone ring favors antifungal
activity as compound 9a (ZI, 12.5 mm) is more active than
compound 8a (ZI, 0 mm) against C. albicans; based on the
same structural features compound 9c (ZI, 11 mm) is more
active than 8c (ZI, 8.5 mm) against P. aeruginosa. On the
other hand, in case of C. tropicalis it is the presence of
bromine atom at position 6 and 8 of quinazolinone ring de-
creases activity as compound 9c (ZI, 0 mm) is inactive com-
pared to moderately active compound 8c (ZI, 11 mm). As
noted, methyl substituted azole moiety of 8b (ZI, 11.5 mm)
increased activity against B. subtilis relative to 8a (ZI, 0 mm)
that has unsubstituted azole; similarly compound 10b (ZI,
12 mm) is more active than compound 10a (ZI, 0 mm).
In summary, in view of these observations, we conclude
that this series could be developed as a novel class of antimy-
cobacterial agents. However, further structural evaluation is
required to identify the potent molecule among the series.
2-Chloro-N-(6,8-dibromo-4-oxo-2-phenyl-quinazolin-3(4H)-yl)-ac-
etamide (6b) Yield 58%; mp 238 °C; IR (KBr) n cmꢀ1: 3230, 3070, 2943,
1710, 1542, 1488, 700, 694. 1H-NMR (DMSO-d6) d: 11.6—11.8 (1H, s),
8.4—8.5 (1H, s), 8.2—8.3 (1H, s), 7.4—7.7 (5H, m), 4.05—4.20 (2H, q,
Jꢁ13.7 Hz).
2-Chloro-N-(6,8-dibromo-2-methyl-4-oxo-quinazolin-3(4H)-yl)-ac-
etamide (7a) Yield 60%; mp 188 °C; IR (KBr) n cmꢀ1: 3188, 3010, 2962,
1
2856, 1685, 1583, 1438, 756, 663. H-NMR (CDCl3) d: 8.35—8.4 (1H, s),
8.15—8.2 (1H, s), 4.3—4.5 (2H, q, Jꢁ13.6 Hz), 2.35—2.4 (3H, s).
2-Chloro-N-(6,8-dibromo-4-oxo-2-propyl-quinazolin-3(4H)-yl)-ac-
etamide (7b) Yield 75%; mp 192 °C; IR (KBr) n cmꢀ1: 3301, 3070, 2939,
1683, 1585, 1442, 788, 756, 696. 1H-NMR (CDCl3) d: 11.5 (1H, b), 8.45
(1H, s), 8.3 (1H, s), 4.3—4.5 (2H, q, Jꢁ13.7 Hz), 2.58—2.88 (4H, m), 1.1—
1.3 (3H, t, Jꢁ7.2 Hz).
General Method for the Synthesis of 2-(Substituted-imidazol-1-yl)-N-
(2,6,8-substituted-4-oxo-quinazolin-3(4H)-yl)-acetamide
(8, 10, 11)ad
2-Chloro-N-(2,6,8-substituted-4-oxo-quinazolin-3(4H)-yl)-acetamide
(6a, 7ab) (0.6 mmol) was dissolved in 50 ml of dry toluene, to this freshly
dried anhydrous potassium carbonate (0.65 mmol, 0.9 g) and substituted imi-
dazole (0.67 mmol) were added and refluxed for 4—5 h. Excess toluene was
distilled off; precipitate obtained was washed with petroleum ether, hot
water, dried and recrystallized from aqueous dioxan. The completion of the
Experimental
All the chemicals were purchased from Merck and used without purifica- reaction was monitored on silica gel 60 F254 precoated TLC plates by using
tion. Analytical TLC was performed on Silica Gel F254 plates (Merck) with ethyl acetate, petroleum ether and methanol (1 : 1 : 0.3) as the eluent and ob-
visualization by UV light. Melting points were determined in open capillar-
served in UV light.

1618
2-(1H-Imidazol-1-yl)-N-(4-oxo-2-phenyl-quinazolin-3(4H)-yl)-ac-
Vol. 55, No. 11
benzimidazol-1-yl)-acetamide (11c) Yield 60%; mp 249 °C; IR (KBr) n
cmꢀ1: 3128, 3080, 2983, 2937, 2850, 1714, 1585, 1444, 1359, 786, 713. 1H-
NMR (CDCl3) d: 8.35—8.4 (1H, s), 8.20 (1H, s), 7.1—8.1 (4H, m), 5.2—
5.3 (2H, q, Jꢁ17.3 Hz), 3.4 (1H, b), 2.54—2.8 (4H, m), 2.58—2.6 (3H, s),
1.15—1.25 (3H, t, Jꢁ7.2 Hz). MS m/z: 533 (Mꢅ). Anal. Calcd for
C21H19Br2N5O2: C, 47.30; H, 3.59; N, 13.13. Found: C, 47.23; H, 3.65; N,
13.15.
etamide (8a) Yield 35%; mp 248 °C; IR (KBr) n cmꢀ1: 3422, 3000, 2926,
2856, 1679, 1560, 1467, 1338. 1H-NMR (CDCl3) d: 11.5 (1H, s), 8.1—8.25
(2H, d, Jꢁ7.8 Hz), 7.9—8.0 (1H, t, Jꢁ8.8 Hz), 7.7—7.8 (1H, d, Jꢁ8.1 Hz),
7.5—7.67 (5H, m), 7.4 (1H, s), 6.85 (1H, s), 6.75 (1H, s), 4.8—4.95 (1H, d,
Jꢁ16.3 Hz), 4.6—4.75 (1H, d, Jꢁ16.3 Hz). MS m/z: 345 (Mꢅ). Anal. Calcd
for C19H15N5O2: C, 66.08; H, 4.38; N, 20.28. Found: C, 66.37; H, 4.32; N,
20.20.
2-(1H-Benzimidazol-1-yl)-N-(6,8-dibromo-4-oxo-2-propyl-quinazolin-
3(4H)-yl)-acetamide (11d) Yield 70%; mp 262 °C; IR (KBr) n cmꢀ1
:
2-(2-Methyl-1H-imidazol-1-yl)-N-(4-oxo-2-phenyl-quinazolin-3(4H)-
yl)-acetamide (8b) Yield 55%; mp 269 °C; IR (KBr) n cmꢀ1: 3420, 3010,
2952, 2869, 2848, 1708, 1566, 1471, 1338. 1H-NMR (DMSO-d6) d: 11.5
(1H, s), 8.1—8.3 (2H, d, Jꢁ7.5 Hz), 7.9—8.0 (1H, t, Jꢁ7.1 Hz), 7.7—7.8
(1H, d, Jꢁ8.0 Hz), 7.4—7.7 (5H, m), 6.85 (1H, s), 6.65 (1H, s), 4.75—4.85
(1H, d, Jꢁ17.0 Hz), 4.5—4.6 (1H, d, Jꢁ17.0 Hz), 1.90 (3H, s). MS m/z:
360.1 (Mꢅꢅ1). Anal. Calcd for C20H17N5O2: C, 66.84; H, 4.77; N, 19.49.
Found: C, 66.55; H, 4.52; N, 19.20.
1
3534, 3068, 2983, 2912, 2875, 1722, 1542, 1444, 1359, 745, 692. H-NMR
(DMSO-d6) d: 9.8 (1H, s), 8.24 (1H, s), 7.95—8.15 (5H, m), 7.7 (1H, s),
5.3—5.55 (2H, q, Jꢁ16.0 Hz), 2.5—2.8 (4H, m), 1.1—1.2 (3H, t,
Jꢁ7.4 Hz). MS m/z: 519 (Mꢅ). Anal. Calcd for C20H17Br2N5O2: C, 46.27; H,
3.30; N, 13.49. Found: C, 46.38; H, 3.24; N, 13.36.
General Method for the Synthesis of 2-(Substituted-imidazol-1-yl)-N-
(2,6,8-substituted-4-oxo-quinazolin-3(4H)-yl)-acetamide
(9ad) 2-
2-(2-Methyl-1H-benzimidazol-1-yl)-N-(4-oxo-2-phenyl-quinazolin-
Chloro-N-(6,8-dibromo-4-oxo-2-phenyl-quinazolin-3(4H)-yl)-acetamide
(6b), (0.6 mmol) was dissolved in 50 ml of dry dioxan, to this freshly dried
anhydrous potassium carbonate (0.65 mmol, 0.9 g) and different imidazoles
(0.67 mmol) were added and refluxed for 4 h. Excess dioxan was distilled
off; precipitate obtained was washed with hot water, dried and recrystallized
from aqueous dioxan. The completion of the reaction was monitored on sil-
ica gel 60 F254 precoated TLC plates by using ethyl acetate, petroleum ether
and methanol (1 : 1 : 0.3) as the eluent and observed in UV light.
3(4H)-yl)-acetamide (8c) Yield 40%; mp 287 °C; IR (KBr) n cmꢀ1: 3450,
1
3045, 2972, 2889, 2848, 1722, 1604, 1469, 1346. H-NMR (DMSO-d6) d:
11.62—11.64 (1H, s), 8.2—8.25 (2H, d, Jꢁ6.9 Hz), 7.9—7.95 (1H, t,
Jꢁ7.1 Hz), 7.5—7.8 (1H, d, Jꢁ8.0 Hz), 7.4—7.67 (5H, m), 7.02—7.16 (4H,
m), 4.75—4.90 (1H, d, Jꢁ17.6 Hz), 5.0—5.15 (1H, d, Jꢁ17.6 Hz), 2.25
(3H, s). MS m/z: 410.1 (Mꢅꢅ1). Anal. Calcd for C24H19N5O2: C, 70.40; H,
4.68; N, 17.10. Found C, 70.44; H, 4.68; N, 17.09.
2-(1H-Benzimidazol-1-yl)-N-(4-oxo-2-phenyl-quinazolin-3(4H)-yl)-ac-
etamide (8d) Yield 60%; mp 242 °C; IR (KBr) n cmꢀ1: 3500, 3030, 2849,
1658, 1568, 1469, 1346. 1H-NMR (CDCl3) d: 11.5—11.6 (1H, s), 8.15—
8.25 (1H, d, Jꢁ7.8 Hz), 7.9—8.0 (1H, t, Jꢁ7.8 Hz), 7.75—7.85 (1H, d,
Jꢁ8.0 Hz), 7.4—7.7 (10H, m), 4.1—4.2 (2H, dd, Jꢁ13.7 Hz). MS m/z: 395
(Mꢅ). Anal. Calcd for C23H17N5O2: C, 69.86; H, 4.33; N, 17.71. Found: C,
69.72; H, 4.51; N, 17.62.
N-(6,8-Dibromo-4-oxo-2-phenyl-quinazolin-3(4H)-yl)-2-(1H-imidazol-
1-yl)-acetamide (9a) Yield 50%; mp 258 °C; IR (KBr) n cmꢀ1: 3522,
1
3064, 2954, 2856, 1685, 1539, 1444, 1319, 775, 702. H-NMR (DMSO-d6)
d: 8.8 (1H, s), 8.28 (1H, s), 8.18 (1H, s), 7.6—7.7 (2H, d, Jꢁ7.0 Hz), 7.3—
7.5 (5H, m), 7.24 (1H, s), 4.5—4.53 (2H, q, Jꢁ14.0 Hz). MS m/z: 503.9
(Mꢅꢅ1). Anal. Calcd for C19H13Br2N5O2: C, 45.36; H, 2.60; N, 13.92.
Found: C, 45.21; H, 2.80; N, 13.63.
N-(6,8-Dibromo-2-methyl-4-oxo-quinazolin-3(4H)-yl)-2-(1H-imidazol-
1-yl)-acetamide (10a) Yield 50%; mp 271 °C; IR (KBr) n cmꢀ1: 3136,
3029, 2952, 2864, 1716, 1585, 1444, 1340, 694. 1H-NMR (CDCl3) d: 8.4
(1H, s), 8.2 (1H, s), 7.8 (1H, s), 7.2 (1H, s), 6.9 (1H, s), 5.2 (1H, s), 5.0—5.1
(2H, dd, Jꢁ16.8 Hz), 2.4 (3H, s). MS m/z: 441.9 (Mꢅꢅ1). Anal. Calcd for
C14H11Br2N5O2: C, 38.12; H, 2.51; N, 15.88. Found: C, 37.9; H, 2.71; N,
15.52.
N-(6,8-Dibromo-4-oxo-2-phenyl-quinazolin-3(4H)-yl)-2-(2-methyl-1H-
imidazol-1-yl)-acetamide (9b) Yield 55%; mp 250 °C; IR (KBr) n cmꢀ1
:
3521, 3068, 2920, 2848, 1668, 1558, 1443, 1340, 775, 700. 1H-NMR
(CDCl3) d: 8.3 (1H, s), 8.18 (1H, s), 7.64—7.67 (2H, d, Jꢁ7.3 Hz), 7.3—
7.55 (5H, m), 4.5—4.8 (2H, q, Jꢁ15.6 Hz), 2.12 (3H, s). MS m/z: 517 (Mꢅ).
Anal. Calcd for C20H15Br2N5O2: C, 46.45; H, 2.92; N, 13.54. Found: C,
46.32; H, 2.72; N, 13.47.
N-(6,8-Dibromo-2-methyl-4-oxo-quinazolin-3(4H)-yl)-2-(2-methyl-1H-
N-(6,8-Dibromo-4-oxo-2-phenyl-quinazolin-3(4H)-yl)-2-(2-methyl-1H-
benzimidazol-1-yl)-acetamide (9c) Yield 55%; mp 250 °C; IR (KBr) n
cmꢀ1: 3510, 3066, 2954, 2848, 1695, 1589, 1404, 1340, 774, 700. 1H-NMR
(DMSO-d6) d: 8.3 (1H, s), 8.18 (1H, s), 7.3—7.7 (9H, m), 4.9—5.2 (2H, q,
Jꢁ15.9 Hz), 2.4 (3H, s). MS m/z: 567 (Mꢅ). Anal. Calcd for C24H17Br2N5O2:
C, 50.82; H, 3.02; N, 12.35. Found: C, 50.73; H, 3.13; N, 12.57.
imidazol-1-yl)-acetamide (10b) Yield 55%; mp 276 °C; IR (KBr) n cmꢀ1
:
3147, 3068, 2941, 2871, 1712, 1541, 1488, 1340, 694. 1H-NMR (DMSO-d6)
d: 8.4 (1H, s), 8.2 (1H, s), 7.0—7.2 (1H, s), 6.7—6.8 (1H, s), 4.9—5.1 (2H,
dd, Jꢁ17.0 Hz), 2.4 (3H, s), 2.25 (3H, s). MS m/z: 455.9 (Mꢅꢅ1). Anal.
Calcd for C15H13Br2N5O2: C, 39.59; H, 2.88; N, 15.39. Found: C, 39.33; H,
3.13; N, 15.14.
2-(1H-Benzimidazol-1-yl)-N-(6,8-dibromo-4-oxo-2-phenyl-quinazolin-
3(4H)-yl)-acetamide (9d) Yield 65%; mp 257 °C; IR (KBr) n cmꢀ1: 3542,
N-(6,8-Dibromo-2-methyl-4-oxo-quinazolin-3(4H)-yl)-2-(2-methyl-1H-
benzimidazol-1-yl)-acetamide (10c) Yield 60%; mp 247 °C; IR (KBr) n
cmꢀ1: 3544, 3070, 2983, 2918, 1716, 1606, 1446, 1311, 692. 1H-NMR
(DMSO-d6) d: 11.6—11.7 (1H, s), 8.4 (1H, s), 8.2 (1H, s), 7.0—7.6 (4H,
m), 5.1—5.4 (2H, dd, Jꢁ17.5 Hz), 2.42 (3H, s), 2.58 (3H, s). MS m/z: 505
(Mꢅ). Anal. Calcd for C19H15Br2N5O2: C, 45.17; H, 2.99; N, 13.86. Found:
C, 45.28; H, 3.03; N, 13.78.
1
3066, 2954, 2856, 1722, 1585, 1541, 1340, 775, 700. H-NMR (DMSO-d6)
d: 9.52 (1H, s), 8.25 (1H, s), 8.16 (1H, s), 7.62—7.64 (2H, d, Jꢁ8.3 Hz),
7.3—7.7 (8H, m), 4.75—4.95 (2H, q, Jꢁ16.1 Hz). MS m/z: 553.9 (Mꢅꢅ1).
Anal. Calcd for C23H15Br2N5O2: C, 49.94; H, 2.73; N, 12.66. Found: C,
49.54; H, 2.80; N, 12.33.
2-(1H-Benzimidazol-1-yl)-N-(6,8-dibromo-2-methyl-4-oxo-quinazolin-
Acknowledgements The authors are thankful to Indian Institute of Sci-
ence, Bangalore, for the spectral analysis. The authors are also thankful to
Sri. Premnath Reddy, Chairman, Acharya Institutes and Dr. Divakar Goli,
Principal, Acharya and B.M. Reddy College of Pharmacy, Bangalore, for
laboratory facilities.
3(4H)-yl)-acetamide (10d) Yield 65%; mp 280 °C; IR (KBr) n cmꢀ1
:
3534, 3010, 2963, 2871, 1728, 1585, 1444, 1338, 692. 1H-NMR (DMSO-d6)
d: 9.9 (1H, s), 8.25 (1H, s), 8.1 (1H, s), 7.6—8.05 (4H, m), 5.35—5.55 (2H,
dd, Jꢁ5.7 Hz), 2.25 (3H, s). MS m/z: 491 (Mꢅ). Anal. Calcd for
C18H13Br2N5O2: C, 44.02; H, 2.67; N, 14.26. Found: C, 44.15; H, 2.78; N,
14.29.
References
N-(6,8-Dibromo-4-oxo-2-propyl-quinazolin-3(4H)-yl)-2-(1H-imidazol-
1-yl)-acetamide (11a) Yield 65%; mp 268 °C; IR (KBr) n cmꢀ1: 3500,
3072, 2985, 2935, 1718, 1608, 1542, 1442, 1363, 788, 696. 1H-NMR
(CDCl3) d: 9.2—9.3 (1H, s), 8.23 (1H, s), 8.09 (1H, s), 7.6—7.8 (3H, s),
4.8—5.1 (2H, s), 2.7—2.9 (4H, m), 1.05—1.35 (3H, t, Jꢁ7.1 Hz). MS m/z:
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Found: C, 40.51; H, 3.07; N, 14.66.
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