6-Substituted indolo[1,2-c]quinazolines as new antimicrobial agents

Article abstract of DOI:10.1002/ardp.200900068

A series of 2-o-arylidineaminophenylindoles and their cyclic derivatives (indolo[1,2-c]quinazolines) were synthesized. The reactions occurred under relatively mild conditions and afforded the desired product in good yields. Molecular structures of the syn

Full text of DOI:10.1002/ardp.200900068

Arch. Pharm. Chem. Life Sci. 2009, 342, 533–540
R. Rohini et al.
533
Full Paper
6-Substituted Indolo[1,2-c]quinazolines as New Antimicrobial
Agents
Rondla Rohini1, Kanne Shanker1, P. Muralidhar Reddy1, 2, Vasam Chandra Sekhar3, and
Vadde Ravinder1
1 Department of Chemistry, Kakatiya University, Warangal, A. P., India
2 Department of Chemistry, National Dong Hwa University, Hualien, Taiwan
3 Department of Chemistry, GITAM University, Visakhapatnam, A. P., India
A series of 2-o-arylidineaminophenylindoles and their cyclic derivatives (indolo[1,2-c]quinazo-
lines) were synthesized. The reactions occurred under relatively mild conditions and afforded
the desired product in good yields. Molecular structures of the synthesized compounds were
1
confirmed by IR, H-NMR, 13C-NMR, MS spectra, and elemental analyses. Furthermore, all the
final products were screened for in-vitro antibacterial activity against three Gram-positive and
three Gram-negative bacteria and also tested for their inhibitory action against three strains of
fungi. Compound IIc showed potent activity against all the bacterial (except S. typhimurium) and
fungal strains. Especially, compounds IIi and IIj which have isoquinolyl and pyridyl substituents
displayed potent antibacterial as well as antifungal activities compared to those of the respective
standard drugs Ampicillin and Ketoconazole.
Keywords: Antibacterial activity / Antifungal activity / Indolo[1,2-c]quinazolines / Synthesis /
Received: March 30, 2009; accepted: April 29, 2009
DOI 10.1002/ardp.200900068
Supporting Information for this article is available from the author or on the WWW under
http://dx.doi.org/10.1002/ardp.200900068
extremely important in chemistry, industry, and medi-
cine. In the latter category, indole derivatives carrying
different substituents are associated with a wide range of
biological activities including anticancer [12–14], anti-
convulsant [15], antimicrobial [16–18], antimalarial
[19, 20], antiprotozoal [21], anti-inflammatory [22, 23],
and antiHIV [24] properties. Moreover, fused indole deriv-
atives such as indolocarbazoles [25, 26], indoloisoquino-
lines [27, 28], indoloquinoxalines [29, 30], indoloquinazo-
lines [31–33] display a number of interesting pharmaco-
logical properties. Based on the importance of these mol-
ecules, our attention was attracted towards the synthesis
of new fused indole derivatives in order to find more
potent biologically active molecules. Hence, we report
here the synthesis and characterization of some novel
indolo[1,2-c]quinazoline compounds which are structur-
ally related to terrestrial or marine alkaloids (e. g. hinck-
dentine A for the indolo[1,2-c]quinazoline ring). In addi-
tion, the antimicrobial activities of all synthesized quina-
Introduction
Nitrogen heterocycles have a central position in organic
as well as in medicinal chemistry, because of the useful
properties of many members of these compounds [1–3].
Over the past years, indole derivatives are one of the most
extensively studied class of heterocyclic compounds, and
have received increasing attention as a source of new and
useful pharmaceuticals and biologically active com-
pounds [4–7]. The indole nucleus is a fundamental con-
stituent of a number of natural and synthetic products
with biological activity. This basic skeleton for example
is present in the tryptamine [8], melatonin [9], hinckden-
tine A [10], neurotransmitter serotonin [11], and many
natural alkaloids (see Fig. 1). Infact, indole derivatives are
Correspondence: Vadde Ravinder, Department of Chemistry, Kakatiya
University, Warangal-506 009, A. P., India.
E-mail: ravichemku@rediffmail.com
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534
R. Rohini et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 533–540
Figure 1. Natural indole alkaloids.
zolines against different bacteria and fungi were eval-
uated. Among the compounds tested, some of these qui-
nazolines were found to be superior compared to the
reference drugs in inhibiting all the bacterial and fungal
strains.
Results and discussion
Chemistry
We have developed a convenient three-step procedure for
the synthesis of 6-substituted indolo[1,2-c]quinazolines
from commercially available materials. The general
route for the preparation of the target fused quinazolines
IIa–IIj was developed as outlined in Scheme 1. The key
indole derivative (A, 2-o-aminophenylindole) was
obtained by Fischer indole cyclization of the phenylhy-
drazone of 2-aminoacetophenone using a mixture of
methane sulfonic acid and phosphorus pentoxide [34].
The condensation reaction between 2-o-aminophenylin-
dole A and the appropriate aromatic aldehydes (in a 1 : 1
ratio) in ethanol afforded the corresponding 2-o-arylidine
amino phenyl indoles Ia–Ij, which on oxidative cycliza-
tion with powdered KMnO4 in acetone furnished the
desired 6-substituted indolo[1,2-c]quinazoline derivatives
in good yields. All intermediates as well as the final fused
quinazoline analogues were analyzed by different spec-
Scheme 1. Synthetic route of 6-substituted indolo[1,2-c]quinazo-
lines.
nylindole) [36]. The formation of the final 6-substituted
indolo[1,2-c]quinazolines was identified by disappear-
ance of m (NH-) absorption band at 3400–3330 cm– 1
present in 2-o-aminophenylindole, and the appearance of
the absorption band at 1360–1380 cm– 1 characteristic
for the indoloquinazoline ring with a tertiary nitrogen
atom (C-N) [37].
Furthermore, the 1H-NMR spectra of compound A
showed signals at d = 6.4 ppm, a singlet for (-NH2), d =
8.48 ppm as a singlet for the (-NH) group, which con-
firmed the structure [34]. Formation of compounds Ia–Ij
from A was confirmed by disappearance of signals at d =
6.4 ppm due to NH2 protons of compound A and appear-
ance of signals around d = 8.16–8.29 ppm that corre-
spond to -CH=N protons. The formation of the title prod-
ucts IIa–IIj is indicated by the disappearance of peaks
due to indolyl -NH and CH=N protons in IR and NMR spec-
tra of all the intermediate azomethines Ia–Ij [37].
The 13C-NMR spectra of all the compounds showed sig-
nals at d = 141.1–171.3 ppm due to -C=N carbon atoms
[38]. The signals in the range of d = 103.5–158.2 ppm
were attributed to the various aromatic ring carbon
atoms.
1
troscopic technique such as IR, H-NMR, 13C-NMR, and
mass spectroscopy, and by elemental analysis.
The IR spectrum of A exhibited an absorption band at
3380–3440 cm– 1 assigned to the -NH2 group, and in the
spectra of the A and azomethine derivatives Ia–Ij two
absorption bands in the regions 3330–3400 cm– 1 and
1540–1560 cm– 1 were assigned to -NH stretching and
bending vibrations of the indolyl ring, respectively [35].
In all the azomethines (Ia–Ij, 2-o-arylidineaminopheny-
lindoles) the characteristic IR peaks for the -CHO and
-NH2 groups at 1680–1695 cm– 1 and 3380–3440 cm– 1
are absent and the characteristic peak for the CH=N
around 1610–1635 cm– 1 is observed, which indicates the
effective condensation of the aldehyde group with the
amino group of the key indole derivative (2-o-aminophe-
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Arch. Pharm. Chem. Life Sci. 2009, 342, 533–540
6-Substituted Indolo[1,2-c]quinazolines
535
Scheme 2. FAB mass fragmentation pattern of 2-indolo[1,2-c]quinazolin-6-ylphenol (IIa).
The final proof for the compounds was obtained by tion was recorded by measuring the diameter of the
recording their ESI-MS spectra, which showed single inhibition zone at the end of a 24-h period for bacteria
peaks suggesting the molecular formulae of the prod- and 72 h for fungi. Each experiment was repeated thrice
ucts. Moreover, the FAB mass spectrum of compound IIa and the average of the three independent determinations
shows a molecular ion peak [M+] at m/z = 310 (87.2%), was recorded. The results are summarized in Table 1. The
which confirms the proposed formula (C21H14N2O). The antimicrobial screening revealed that all the tested com-
mass spectrum shows major fragments at m/z values of pounds IIa–IIj showed moderate to good inhibition
293 (12.6%), 217 (22.8%), 195 (100%), 192 (65.3%), 191 towards all bacterial and fungal strains. The maximum
(72.5%), 115 (52.6%), and 76 (38.4%). The mass fragmenta- inhibition was observed in IIc against all the tested
tion pattern of compound IIa as assigned on the basis of organisms except S. typhimurium. In addition, the most
mass spectra is presented in Scheme 2.
potent activity against all bacterial and fungal strains
was observed in two fused quinazolines (IIi and IIj) com-
paring them with the respective standard drugs ampicil-
lin and ketoconazole.
Pharmacological results
Antimicrobial screening
The in-vitro antimicrobial activity testing was performed
by using the cup-plate method [39]. All the fused quinazo- Determination of the minimum inhibitory concentration
lines prepared herein were screened for their potential (MIC)
antibacterial activity against Staphylococcus aureus, Bacil- The minimum inhibitory concentration of IIc, IIi, and IIj
lus subtilis, Streptococcus pyogenes (Gram-positive) and Sal- against different bacterial and fungal strains was deter-
monella typhimurium, Escherichia coli, Klebsiella pneumonia mined using the liquid dilution method [40]. The mini-
(Gram-negative) bacterial strains. Ampicillin was used as mum inhibitory concentration at which no growth was
a reference standard. All the newly synthesized fused qui- observed was taken as the MIC values (Table 2). Compari-
nazoline compounds were also examined for their anti- son of the MICs (in lg/mL) of active fused quinazolines
fungal activity against the strains Aspergillus niger, Can- and standard drugs against susceptible organisms are
dida albicans, Trichoderma viridae. Ketoconazole was used presented in Fig. 1. It was found that compound IIc had
as standard drug for comparison of the antifungal good inhibitory activity against all tested strains (MIC =
results. Preliminary screening for ten quinazolines was in the range of 2.5–20 lg/mL) and was inactive against S.
performed at fixed concentrations of 1000 lg/mL. Inhibi- typhimurium. Compounds IIi and IIj (MIC range: 2.5–
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Table 1. Zone of inhibition of newly synthesized 6-arylindolo[1,2-c]quinazolines (IIa–IIj) against different bacteria and fungi.
Zone of inhibition (mm)
Gram-positive bacteria
Gram-negative bacteria
Fungi
Compound S. aureus
(1000 lg/mL)
B. subtilis
S. pyogenes S. typhimurium E. coli K. pneumonia A. niger
C. albicans
T. viridae
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
22
21
52
20
19
20
15
14
55
51
48a)
19
20
41
15
18
16
19
12
48
50
39a)
13
16
40
18
14
15
18
10
51
48
35a)
16
14
42
13
16
12
15
13
51
46
45a)
18
20
45
21
18
20
19
9
16
18
50
15
12
15
18
13
55
52
45a)
22
19
50
16
15
16
18
10
52
51
45b)
16
15
46
12
10
12
15
9
9
13
48
14
9
13
9
14
51
48
41b)
50
51
40a)
48
50
40b)
IIj
Standard
a)
Ampicillin.
Ketoconazole.
b)
Table 2. MIC values of potent 6-arylindolo[1,2-c]quinazolines IIc, IIi, and IIj and standard drugs.
Range of concentration (lg/mL)
Gram-positive bacteria
Gram-negative bacteria
Fungi
Compound S. aureus
(2.5–50 lg/mL)
B. subtilis
S. pyogenes S. typhimurium E. coli K. pneumonia A. niger
C. albicans
T. viridae
IIc
IIi
IIj
Standard
5
10
5
20
10
5
15
2.5
10
5
5
2.5
5
10
5
15
5
15
10
5
2.5
2.5
10a)
10
5
10
10
2.5
20a)
25a)
10a)
15a)
10a)
15b)
25b)
20b)
a)
Ampicillin.
Ketoconazole.
b)
Figure 2. Comparison of MIC values (in lg/mL) of indolo[1,2-c]quinazolines and standard drugs
against different bacteria and fungi.
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Arch. Pharm. Chem. Life Sci. 2009, 342, 533–540
6-Substituted Indolo[1,2-c]quinazolines
537
20 lg/mL) showed the highest activity against all the bac- 2-([2-(1H-2-Indolyl)phenyl]iminomethyl)phenol Ia
Yield: 82%; m.p.: 272–2748C; IR: 3425, 3340, 1650, 1590, 1575,
terial and fungal strains even higher than the standard
drugs ampicillin and ketoconazole.
1
1130 cm– 1; H-NMR (400 MHz, CDCl3) d: 6.71 (s, 2H, Ar), 6.86–
7.35 (m, 9H, Ar), 7.49–7.62 (m, 2H, Ar) 8.15 (s, 1H, indolyl-NH),
8.25 (s, 1H, CH=N), 10.18 (s, 1H,–OH); 13C-NMR (67.93 MHz,
CDCl3) d: 114.6, 117.2, 118.4, 123.5, 126.7, 131.5, 132.2, 133.6,
136.5, 141.2, 142,6, 143.8, 146.3, 163.7, 167.5 (21C, Ar-C); MS m/z:
312 [M+]. Anal. calcd. for C21H16N2O: C, 80.75; H, 5.16; N, 8.97.
Found: C, 80.71; H, 5.09; N, 8.95.
A possible explanation for this result is that the anti-
bacterial and antifungal activity of these compounds
may stem from the basic skeleton of the molecules as
well as from the nature of the substituents such as isoqui-
nolyl, pyridyl, and nitro groups.
4-Bromo-2-([2-(1H-2-indolyl)phenyl]iminomethyl)phenol
The authors have declared no conflict of interest.
Ib
Yield: 78%; m.p.: 326–3288C; IR: 3420, 3335, 1630, 1610, 1580,
1
1100 cm– 1; H-NMR (400 MHz, CDCl3) d: 6.75 (s, 2H, Ar), 6.83–
7.38 (m, 8H, Ar), 7.50–7.65 (m, 2H, Ar), 8.20 (s, 1H, CH=N), 8.29 (s,
1H, indolyl-NH), 10.02 (s, 1H,–OH); 13C-NMR (67.93 MHz, CDCl3)
d: 107.4, 114.1, 118.2, 123.5, 126.7, 130.5, 131.2, 132.2, 136.5,
141.1, 142,8, 143.5, 146.3, 154.48, 158.5, 167.2 (21C, Ar-C), MS
m/z: 390 [M+], 392 [M + 2]. Anal. calcd. for C21H15BrN2O: C, 64.47;
H, 3.86; N, 7.16. Found: C, 64.20; H, 3.56; N, 7.09.
Experimental
All solvents used were of analytical grade. The starting material
2-o-aminophenylindole [9] was prepared by following the litera-
ture procedure. TLC analysis was done using pre-coated silica gel
plates, spots were visualized with iodine vapors. Elemental anal-
yses were performed on a Perkin-Elmer 2400 analyzer (Perkin-
Elmer, USA). The IR spectra were recorded in KBr pellets on Per-
kin-Elmer-283 spectrophotometer. 1H-NMR spectra were
acquired at 400 MHz, and 13C-NMR at 67.93 MHz on a Bruker
NMR spectrometer (Bruker Bioscience, USA). FAB mass spectra
were recorded on a Finnigan-MAT 1020 instrument (Thermo
Electron Corporation, Bremen, Germany). An ion trap mass spec-
trometer (Agilent Series LC/MSD Trap SL) equipped with an elec-
trospray ionization (ESI) source was used for MS analyses (Agi-
lent, Palo Alto, CA, USA). Microorganisms like S. aureus, B. subti-
lis, S. pyogenes (Gram-positive), S. typhimurium, E. coli, K. pneumo-
nia (Gram-negative) bacteria and A. niger, C. albicans, T. viridae
fungi were used in the present investigations.
2-([2-(1H-2-Indolyl)phenyl]iminomethyl)-4-nitrophenol Ic
Yield: 80%; m.p.: 257–2598C; IR: 3420, 3340, 1635, 1608,
1590,1525,1345, 1130, 850 cm– 1 1H-NMR (400 MHz, CDCl3) d:
;
6.79 (s, 2H, Ar), 6.85–7.39 (m, 7H, Ar), 7.53–7.62 (m, 2H, Ar) 8.01
(d, 1H, J = 7.7Hz), 8.29 (s, 1H, CH=N), 8.58 (s, 1H, -NH), 10.15 (s,
1H,–OH); 13C-NMR (67.93 MHz, CDCl3) d: 114.1, 118.5, 119.2,
123.1, 124.2, 126.2, 131.2, 132.2, 136.5, 141.1, 143.5, 146.5,
164.6, 170.2 (21C, Ar-C); MS m/z: 357 [M+]. Anal. calcd. for
C21H15N3O3: C, 70.58; H, 4.23; N, 11.76. Found: C, 70.41; H, 4.25;
N, 11.58.
2-([2-(1H-2-Indolyl)phenyl]iminomethyl)-4-
methoxyphenol Id
Yield: 81%; m.p.: 288–2908C; IR: 3425, 3330, 1638, 1605, 1585,
General procedure for the preparation of 2-(o-
aminophenyl)indole A
1
1246, 1128, 1035 cm– 1; H-NMR (400 MHz, CDCl3) d: 3.86 (s, 3H,
OCH3), 6.45 (s, 1H, Ar), 6.72–6.95 (m, 4H, Ar), 7.01–7.36 (m, 4H,
Ar), 7.53–7.62 (m, 3H, Ar), 8.16 (s, 1H, CH=N), 8.25 (s, 1H, -NH),
10.12 (s, 1H,–OH); 13C-NMR (67.93 MHz, CDCl3) d: 56.2, (1C,
-OCH3), 114.4, 121.2, 122.4, 123.5, 126.2, 130.5, 131.1, 132.4,
141.1, 144,3, 146.8, 153.2, 153.6, 167.3 (21C, Ar-C); MS m/z: 342
[M+]. Anal. calcd. for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found:
C, 77.13; H, 5.19; N, 8.20.
The starting material, 2-(o-aminophenyl)indole (A, lit. m.p.:
1468C), was obtained by Fischer indole cyclization of the phenyl-
hydrazone of o-aminoacetophenone using a mixture of methane
sulfonic acid and phosphorus pentoxide at 858C. Reactions were
carried out according to the procedure described by Billimoria
and Cava [34].
Procedure for the preparation of 2-o-
(arylideneamino)phenylindoles Ia–Ij
3-([2-(1H-2-Indolyl)phenyl]iminomethyl)benzoic acid Ie
Yield: 78%; m.p.: 231–2338C; IR: 3535, 3360, 3215, 1685, 1635,
1
1580, 1130 cm– 1; H-NMR (400 MHz, CDCl3) d: 6.77 (s, 2H, Ar),
To a solution of 2-(o-aminophenyl)indole (A, 0.416 g, 2 mmol) in
20–40 mL of ethanol were added the appropriate aldehyde
(2 mmol, viz., 0.244 g of 2-hydroxy-benzaldehyde, 0.402 g of 5-
bromo2-hydroxy-benzaldehyde, 0.334 g of 2-hydroxy-5-nitro-
benzaldehyde, 0.304 g of 2-hydroxy-5-methoxy-benzaldehyde,
0.300 g of 3-formyl-benzoic acid, 0.332 g of 3-formyl-4-hydroxy-
benzoic acid, 0.300 g of 4-hydroxy-3,5-dimethyl-benzaldehyde,
0.332 g of 3,5-dimethoxy-benzaldehyde, 0.314 g of quinoline-2-
carbaldehyde, and 0.214 g of pyridine-3-carbaldehyde in etha-
nol) and a few drops of acetic acid with vigorous stirring. The
resulting solution was heated under reflux for 3 h. After cooling,
the deposited solid product was collected by filtration and
recrystallized from an ethanol / dichloromethane-methanol
mixture.
6.91 (m, 1H, Ar), 7.12 (m, 1H, Ar), 7.29–7.61 (m, 8H, Ar), 8.16 (s,
1H, CH=N), 8.20 (m, 1H, Ar), 8.52 (s, 1H, -NH), 11.31 (s, 1H,
–COOH); 13C-NMR (67.93 MHz, CDCl3) d: 114.0, 114.4, 123.5,
126.2, 128.2, 130.5, 130.8, 132.0, 134.1, 141.1, 143.5, 146.8,
167.1, 170.1 (22C, Ar-C); MS m/z: 340 [M+]. Anal. calcd. for
C22H16N2O2: C, 77.63; H, 4.74; N, 8.23. Found: C, 77.65; H, 4.58; N,
8.21.
4-Hydroxy-3-([2-(1H-2-
indolyl)phenyl]iminomethyl)benzoic acid If
Yield: 79%; m.p.: 305–3078C; IR: 3535, 3425, 3355, 3215,1680,
1640, 1585, 1128 cm– 1; 1H-NMR (400 MHz, CDCl3) d: 6.73 (s, 2H,
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Ar), 6.90–7.08 (m, 2H, Ar), 7.28–7.63 (m, 6H, Ar), 7.95–8.09 (m,
2H, Ar), 8.20 (s, 1H, CH=N), 8.29 (s, 1H, -NH), 10.23 (s, 1H,–OH),
11.39 (s, 1H,–COOH);13C-NMR (67.93 MHz, CDCl3) d: 112.6, 113.5,
114.3, 123.4, 124.5, 126.2, 127.5, 132.8, 136.4, 141.1, 142,3,
144.5, 146.1, 166.2, 166.7, 168.9 (22C, Ar-C); MS m/z: 356 [M+].
Anal. calcd. for C22H16N2O3: C, 74.15; H, 4.53; N, 7.86. Found: C,
74.10; H, 4.39; N, 7.88.
tone was added the appropriate amount (1.5 equiv.) of powdered
KMnO4. The reaction mixture was refluxed under heat (40–
758C) for 30 min. Then, it was filtered hot, and an equal volume
of hot water added to the filtrate. The fused quinazolines IIa–IIj
rapidly separated, they were collected by filtration and recrystal-
ized from dimethylformamide / ethanol.
2-Indolo[1,2-c]quinazolin-6-ylphenol IIa
Yield: 80%; m.p.: 289–2918C; IR: 3425, 1621, 1585, 1529, 1457,
1375, 773, 741, 732 cm– 1; 1H-NMR (400 MHz, DMSO-d6) d: 6.95–
7.03 (m, 2H, Ar), 7.25–7.45 (m, 6H, Ar), 7.61–7.72 (m, 3H, Ar),
7.81–7.91 (m, 2H, Ar), 10.29 (s, 1H,–OH); 13C-NMR (67.93 MHz,
DMSO-d6) d: 112.3, 116.7, 120.3, 121.6, 122.4, 125.8, 129.3, 131.5,
132.7, 139.2, 143.2, 152.5, 159.2, 161.5 (21C, Ar-C); MS m/z: 310
[M+]. Anal. Calcd. for C21H14N2O: C, 81.27; H, 4.55; N, 9.03. Found:
C, 81.28; H, 4.29; N, 9.09.
4-([2-(1H-2-Indolyl)phenyl]iminomethyl)-2,6-
dimethylphenol Ig
Yield: 76%; m.p.: 198–2008C; IR: 3425, 3330, 2958, 1645, 1608,
1575, 1130 cm– 1 1H-NMR (400 MHz, CDCl3) d: 2.32 (s, 6H, Ar-
;
CH3), 6.61 (s, 2H, Ar), 6.76 (s, 2H, Ar), 6.95–7.12 (m, 2H, Ar), 7.28–
7.61 (m, 5H, Ar), 8.25 (s, 1H, CH=N), 8.56 (s, 1H, -NH), 10.09 (s,
1H,–OH); 13C-NMR (67.93 MHz, CDCl3) d: 15.8 (2C, -CH3), 114.5,
123.4, 126.2, 127.4, 128.2, 132.2, 136.3, 141.1, 146.6, 153.8, 171.3
(21C, Ar-C); MS m/z: 340 [M+]. Anal. calcd. for C23H20N2O: C, 81.15;
H, 5.92; N, 8.23. Found: C, 81.02; H, 5.65; N, 8.20.
4-Bromo-2-indolo[1,2-c]quinazolin-6-ylphenol IIb
Yield: 81%; m.p.: 301–3038C; IR: 3425, 1625, 1609, 1524, 1459,
1378, 775, 742, 736 cm– 1; 1H-NMR (400 MHz, DMSO-d6) d: 7.01–
7.03 (m, 2H, Ar), 7.25–7.45 (m, 4H, Ar), 7.51–7.85 (m, 6H, Ar),
10.30 (s, 1H, -OH); 13C-NMR (67.93 MHz, DMSO-d6) d: 112.3, 118.5,
120.1, 121.5, 122.3, 125.8, 130.7, 131.5, 132.5, 133.2, 145.6,
146.5, 152.8, 154.6, 161.3 (21C, Ar-C); MS m/z: 388 [M+], 390 [M +
2]. Anal. calcd. for C21H13BrN2O: C, 64.80; H, 3.37; N, 7.20. Found:
C, 64.79; H, 3.32; N, 7.21.
N-[(E)-1-(3,5-Dimethoxyphenyl)methylidene]-N-[2-(1H-2-
indolyl)phenyl] amine Ih
Yield: 75%; m.p.: 224–2268C; IR: 3345, 1635, 1600, 1580,
1246,1130, 1035 cm– 1; 1H-NMR (400 MHz, CDCl3) d: 3.86 (s, 6H,
-OCH3), 6.51 (m, 1H, Ar), 6.75–6.95 (m, 3H, Ar), 7.08–7.36 (m, 5H,
Ar), 7.51–7.63 (m, 3H, Ar), 8.19 (s, 1H, CH=N), 8.59 (s, 1H, -NH);
13C-NMR (67.93 MHz, CDCl3) d: 55.2 (2C, -OCH3), 103.9, 108.1,
114.0, 114.2, 124.6, 127.3, 131.2, 132.2, 134.3, 141.1, 146.6,
162.3, 168.6 ( 21C, Ar-C); MS m/z: 356 [M+]. Anal. calcd. for
C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.42; H, 5.66; N,
7.78.
2-Indolo[1,2-c]quinazolin-6-yl-4-nitrophenol IIc
Yield: 78%; m.p.: 264–2668C; IR: 3425, 1640, 1605, 1580, 1520,
1459, 1385, 851, 775, 745, 749, 690 cm– 1 1H-NMR (400 MHz,
;
DMSO-d6) d: 7.01–7.25 (m, 3H, Ar), 7.32–7.65 (m, 5H, Ar), 7.71–
7.85 (m, 2H, Ar), 8.09–8.12 (s, 1H, Ar), 8.34 (s, 1H, Ar), 10.32 (s,
1H, -OH); 13C-NMR (67.93 MHz, DMSO-d6) d: 112.6, 118.3, 120.6,
121.7, 124.8, 125.4, 127.8, 130.7, 132.3, 138.4, 143.6, 145.4,
152.1, 163.2, 164.5 (21C, Ar-C); MS m/z: 355 [M+]. Anal. Calcd. for
C21H13N3O3: C, 70.98; H, 3.69; N, 11.82. Found: C, 70.82; H, 3.60;
N, 11.81.
N-[2-(1H-2-Indolyl)phenyl]-N-[(E)-1-(1-
isoquinolyl)methylidene]amine Ii
Yield: 79%; m.p.: 251–2538C; IR: 3340, 1640, 1610, 1580,
1
1130 cm– 1; H-NMR (400 MHz, CDCl3) d: 6.78 (s, 2H, Ar), 7.07–
7.39 (m, 5H, Ar), 7.50–7.79 (m, 6H, Ar), 8.20 (s, 1H, CH=N), 8.28
(m, 1H, Ar), 8.45 (s, 1H, -NH), 8.76 (m, 1H, Ar); 13C-NMR
(67.93 MHz, CDCl3) d: 113.1 114.5, 121.6, 123.4, 125.6, 127.3,
128.8, 132.6, 135.6, 141.2, 146.8, 158.2, 168.5 (24C,Ar-C); MS m/z:
347 [M+]. Anal. calcd. for C24H17N3: C, 82.97; H, 4.93; N, 12.09.
Found: C, 82.86; H, 4.90; N, 12.05.
2-Indolo[1,2-c]quinazolin-6-yl-4-methoxyphenol IId
Yield: 80%; m.p.: 278–2808C; IR: 3425, 1638, 1612, 1575, 1460,
1380, 1245, 1038, 770, 742, 739 cm– 1; 1H-NMR (400 MHz, DMSO-
d6) d: 3.92 (s, 3H, Ar-OCH3), 6.95–7.45 (m, 8H, Ar), 7.60–7.86 (m,
4H, Ar), 10.29 (s, 1H, -OH); 13C-NMR (67.93 MHz, DMSO-d6) d: 56.3
(1C, -OCH3), 112.1, 119.6, 121.7, 122.7, 124.8, 127.8, 130.6, 131.2,
137.2, 143.6, 152.2, 155.6, 160.4 (21C, Ar-C); MS m/z: 340 [M+].
Anal. calcd. for C22H16N2O2: C, 77.63; H, 4.74; N, 8.23. Found: C,
77.64; H, 4.69; N, 8.21%. 14.90.
N-[2-(1H-2-Indolyl)phenyl]-N-[(E)-1-(3-
pyridyl)methylidene]amine Ij
Yield: 75%; m.p.: 232–2348C; IR: 3345, 1640, 1610, 1585,
1130 cm– 1; 1H-NMR (400 MHz, CDCl3) d: 6.75 (s, 2H, Ar), 6.86 (m,
1H, Ar), 7.05-7.45 (m, 4H, Ar), 7.55–7.68 (m, 4H, Ar), 8.25 (s, 1H,
CH=N), 8.65–8.85 (m, 2H, Ar), 8.58 (s, 1H, -NH); 13C-NMR
(67.93 MHz, CDCl3) d: 113.2, 114.1, 121.5, 123.4, 126.3, 128.5,
130.3, 136.5, 141.8, 143,6, 146.5, 151.6, 151.8, 165.5 (20C, Ar-C);
MS m/z: 297 [M+]. Anal. calcd. for C20H15N3: C, 80.78; H, 5.08; N,
14.13. Found: C, 80.75; H, 5.02; N, 14.15.
3-Indolo[1,2-c]quinazolin-6-ylbenzoic acid IIe
Yield: 75%; m.p.: 242–2448C; IR: 3535, 1685, 1625, 1585, 1529,
1
1457, 1379, 773, 741, 732 cm– 1; H-NMR (400 MHz, DMSO-d6) d:
7.02–7.05 (m, 1H, Ar), 7.21–7.43 (m, 4H, Ar), 7.59–7.85 (m, 5H,
Ar), 8.09–8.29 (m, 2H, Ar), 8.53 (s, 1H, Ar), 11.26 (s, 1H, -COOH);
13C-NMR (67.93 MHz, DMSO-d6) d: 111.6, 114.7, 121.9, 122.8,
124.6, 126.3, 129.7, 131.8, 132.5, 142.6, 142.1, 152.1, 157.8, 167.4
(22C, Ar-C); MS m/z: 338 [M+]. Anal. calcd. for C22H14N2O2: C, 78.09;
H, 4.17; N, 8.28. Found: C, 78.01; H, 4.15; N, 8.29.
Procedure for the preparation of 6-arylindolo[1,2-
c]quinazolines IIa–IIj
The target compounds 6-arylindolo[1,2-c]quinazolines IIa–IIj
were prepared from 2-(o-arylideneaminophenyl)indoles Ia–Ij
through a general oxidative cyclisation method [41]. To a stirred
solution of the azomethine compound Ia–Ij in 60–80 mL of ace-
4-Hydroxy-3-indolo[1,2-c]quinazolin-6-ylbenzoic acid IIf
Yield: 76%; m.p.: 327–3298C; IR: 3535, 3425, 1680, 1621, 1585,
1529, 1457, 1380, 773, 740, 738 cm– 1; 1H-NMR (400 MHz, DMSO-
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2009, 342, 533–540
6-Substituted Indolo[1,2-c]quinazolines
539
d6) d: 7.03–7.15 (m, 2H, Ar), 7.20–7.46 (m, 4H, Ar), 7.61–7.82 (m,
4H, Ar), 8.10-8.35 (m, 2H, Ar), 10.15 (s, 1H, -OH), 11.28 (s, 1H,
-COOH); 13C-NMR (67.93 MHz, DMSO-d6) d: 113.4, 117.7, 120.5,
121.2, 122.5, 128.7, 131.3, 135.5, 143.5, 143.2, 153.5, 161.3,
162.8, 165.7 (22C, Ar-C); MS m/z: 354 [M+]. Anal. calcd. for
C22H14N2O3: C, 74.57; H, 3.98; N, 7.91. Found: C, 74.55; H, 3.90; N,
7.87.
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4-Indolo[1,2-c]quinazolin-6-yl-2,6-dimethylphenol IIg
Yield: 75%; m.p.: 215–2178C; IR: 3425, 2958, 1680, 1621, 1585,
1530, 1457, 1378, 773, 741, 739 cm– 1; 1H-NMR (400 MHz, DMSO-
d6) d: 2.35 (s, 6H, -CH3), 7.02–7.05 (m, 1H, Ar), 7.20–7.45 (m, 6H,
Ar), 7.59–7.86 (m, 4H, Ar), 10.15 (s, 1H, -OH); 13C-NMR
(67.93 MHz, DMSO-d6) d: 15.6 (2C, -CH3), 112.8, 114.2, 120.9,
122.4, 124.6, 125.4, 128.7, 133.5, 145.1, 151.1, 152.5, 159.3, (21C,
Ar-C); MS m/z: 338 [M+]. Anal. calcd. for C23H18N2O: C, 81.63; H,
5.36; N, 8.28. Found: C, 81.61; H, 5.32; N, 8.25.
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6-(3,5-Dimethoxyphenyl)indolo[1,2-c]quinazoline IIh
Yield: 76%; m.p.: 238–2408C; IR: 1645, 1609, 1528, 1455, 1246,
1380, 1038, 773, 741, 732 cm– 1; 1H-NMR (400 MHz, DMSO-d6) d:
3.89 (s, 6H, -OCH3), 6.51–6.53 (m, 1H, Ar), 7.03–7.56 (m, 7H, Ar),
7.65–7.88 (m, 4H, Ar); 13C-NMR (67.93 MHz, DMSO-d6) d: 55.4 (2C,
-OCH3), 103.5, 104.7, 112.3, 120.3, 124.3, 126.9, 130.3, 133.4,
141.2, 143.5, 151.2, 155.2, 165.4 (21C, Ar-C); MS m/z: 354 [M+].
Anal. calcd. for C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C,
77.84; H, 5.10; N, 7.86.
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6-(1-Isoquinolyl)indolo[1,2-c]quinazoline IIi
[18] D. Sinha, A. K. Tiwari, S. Singh, G. Shukla, et al., Eur. J. Med.
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Yield: 71%; m.p.: 248–2508C; IR: 1630, 1612, 1585, 1529, 1457,
1380, 773, 741, 730 cm– 1; 1H-NMR (400 MHz, DMSO-d6) d: 7.01–
7.35 (m, 4H, Ar), 7.38–7.91 (m, 9H, Ar), 8.19–8.24 (m, 1H, Ar),
8.74 (dd, J = 6.9, 2.5 Hz, 1H); 13C-NMR (67.93 MHz, DMSO-d6) d:
113.7, 116.4, 120.3, 121.6, 123.2, 126.9, 133.3, 136.2, 138.4,
141.2, 145.4, 152.2, 153.2, 153.8 (24C, Ar-C); MS m/z: 345 [M+].
Anal. calcd. for C24H15N3: C, 83.46; H, 4.38; N, 12.17. Found: C,
83.42; H, 4.36; N, 12.18.
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6-(3-Pyridyl)indolo[1,2-c]quinazoline IIj
Yield: 76%; m.p.: 237–2398C; IR: 1636, 1610, 1580, 1532, 1457,
1380, 775, 742, 732 cm– 1; 1H-NMR (400 MHz, DMSO-d6) d: 7.01–
7.25 (m, J = 8.2 Hz, 3H, Ar), 7.31–7.49 (m, J = 8.4 Hz, 3H, Ar),
7.62–8.12 (m, 5H, Ar), 8.61 (dd, J = 6.9, 2.5 Hz, 1H) 8.97 (s, 1H, Ar);
13C-NMR (67.93 MHz, DMSO-d6) d: 113.4, 118.6, 121.4, 123.3,
126.2, 130.3, 133.5, 137.6, 142.1, 143.7, 149.4, 150.1, 152.5 (20C,
Ar-C); MS m/z: 295 [M+]. Anal. calcd. for C20H13N3: C, 81.34; H, 4.44;
N, 14.23. Found: C, 81.32; H, 4.45; N, 14.19.
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