Antimicrobial study of newly synthesized 6-substituted indolo[1,2-c]quinazolines

Article abstract of DOI:10.1016/j.ejmech.2009.11.038

A new series of indolo[1,2-c]quinazoline derivatives were prepared in good yield through reaction of 2-(o-aminophenyl)indole with a variety of arylaldehydes. The structures of the newly synthesized compounds were confirmed by IR, ¹H NMR, ¹

Full text of DOI:10.1016/j.ejmech.2009.11.038

European Journal of Medicinal Chemistry 45 (2010) 1200–1205
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Antimicrobial study of newly synthesized 6-substituted indolo[1,2-c]quinazolines
,
,
,
a,
**
Rondla Rohini a c, P. Muralidhar Reddy a b, Kanne Shanker a, Anren Hu c , Vadde Ravinder
*
a Department of Chemistry, Kakatiya University, Warangal-506 009, India
b Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan
c Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of indolo[1,2-c]quinazoline derivatives were prepared in good yield through reaction of 2-
(o-aminophenyl)indole with a variety of arylaldehydes. The structures of the newly synthesized
compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral studies and elemental analysis.
All the title compounds were investigated for their activity against certain strains of Gram-positive
bacteria (Staphylococcus aureus, Bacillus subtilis and Streptococcus pyogenes), Gram-negative bacteria
(Salmonella typhimurium, Escherichia coli and Klebsiella pneumonia) and pathogenic Fungi (Aspergillus
niger, Candida albicans and Trichoderma viridae). Ampicillin and ketoconazole were used as reference
compounds. The results revealed that some of synthesized compounds displayed marked activity against
all the tested microorganisms.
Received 10 May 2009
Received in revised form
13 November 2009
Accepted 20 November 2009
Available online 26 November 2009
Keywords:
Indolo[1,2-c]quinazolines
Synthesis
Ó 2009 Elsevier Masson SAS. All rights reserved.
Antibacterial activity
Antifungal activity
1. Introduction
Indoles and their cyclic derivatives constitute an important class
of compounds for new drug development in order to discover
Nitrogen heterocycles are the basis of many essential pharma-
ceuticals, and of many physiologically-active natural products.
Amongst the indole is a crucial heterocyclic skeleton often associ-
ated with pharmacological properties [1–3]. The indole nucleus is
a fundamental constituent of a number of natural and synthetic
products with biological activity [4,5]. Due to the structural simi-
larity of indole nuclei with some naturally occurring compounds
such as Serotonin, tryptamine, Hinckdentine A, they can easily
interact with biomolecules of the living systems [6,7]. Heterocycles
bearing an indole moiety are reported to show a broad spectrum of
pharmacological and medicinal properties such as anti-inflamma-
tory [8,9], anticonvulsant [10], antimicrobial [11,12] antimalarial
[13,14] anticancer [15,16] and many other activities. The introduc-
tion of an additional substituent on the indole nuclei has been
increasing attention in the expectation that such changes could
potentially affect the interaction of the molecules with biological
targets. Moreover, fused cyclic indole derivatives, as indolocarba-
zoles [17,18], indolo[2,3-b]quinolines [19,20], indolo[l,2-c] quina-
zolines [21,22], bis-indoles [23,24] and many others, have also
interesting pharmacological properties.
an effective compound against multi-drug-resistant microbial
infections. Recently, Gurkok et al. [25] synthesized a series of
indole-3-aldehyde and 5-bromoindole-3-aldehyde hydrazide and
hydrazones and evaluated for their in vitro antimicrobial activities
using the 2-fold serial dilution technique against Staphylococcus
aureus, methicillin-resistant S. aureus (MRSA), Escherichia coli,
Bacillus subtilis and Candida albicans. In a similar study Sinha et al.
[12] synthesized novel heterocyclic Schiff bases derived from the
condensation reactions of indole 3-carboxaldehyde with different
L-amino acids (histidine, glutamic acid, aspartic acid, leucine,
valine) as well as with some aminophenols and screened for their
antimicrobial activity against B. subtilis, Pseudomonas fluorescens,
S. aureus, Aspergillus niger, C. albicans and Trichoderma rubrum. Very
recently, a series of 2-o-arylidineaminophenylindoles and their
cyclic derivatives were synthesized. The cyclic indole derivatives
with isoquinolyl and pyridyl substituents displayed potent anti-
bacterial as well as antifungal activities compared to those of the
respective standard drugs Ampicillin and Ketoconazole [26]. These
observations have encouraged us to synthesize some new products
containing the indole moiety hoping to obtain new compounds
with potential biological activity. In the present communication, we
describe the synthesis and biological evaluation of some new mono
and bis-6-arylindolo[1,2-c]quinazolines which are structurally
related to terrestrial or marine alkaloids (e.g. hinckdentine A for the
indolo[1,2-c]quinazoline ring, Fig. 1). In addition, some of new
* Corresponding author. Tel.: þ886 38565301 2334.
** Corresponding author. Tel.: þ91 9390100594.
E-mail addresses: anren@mail.tcu.edu.tw (A. Hu), ravichemku@rediffmail.com
(V. Ravinder).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.11.038

R. Rohini et al. / European Journal of Medicinal Chemistry 45 (2010) 1200–1205
1201
3. Pharmacology
Br
Br
O
H
3.1. Antimicrobial activity
NH
The newly obtained derivatives were evaluated for their in vitro
antimicrobial activity against S. aureus, B. subtilis, S. pyogenes
(Gram-positive), S. typhimurium, E. coli, K. pneumonia (Gram-
negative) bacterial strains and A. niger, C. albicans, Trichoderma
viridae fungal strains by cup plate method [28,29]. Ampicillin (for
bacteria) and Ketoconazole (for fungi) were used as standard drugs.
Preliminary screening of target compounds and standard drugs
Br
N
N
were performed at fixed concentrations of 1000 mg/ml. Inhibition
Fig. 1. Hinckdentine A.
was recorded by measuring the diameter of the inhibition zone at
the end of 24 h for bacteria and 72 h for fungi. Each experiment was
repeated thrice and the average of the three independent deter-
minations was recorded. Screening results are summarized in Table
1. As it indicated in Table 1 some of the compounds (IIa, IIf, IIh and
IIi) showed good activity against Gram-positive bacteria, low
activity on Gram-negative bacterial strains and fungus. In partic-
ular, compounds (IIb–e) which have heterocyclic moiety at C6
position exhibited excellent activity against all tested strains.
quinazolines were found to be superior in inhibiting all the bacte-
rial and fungal strains.
2. Chemistry
In this study we developed a simple, convenient three-step
synthesis for mono and bis-indolo[1,2-c]quinazolines (IIa–j) from
commercially available starting materials. Our synthetic plan for
IIa–j is shown in Scheme 1. The 2-(o-aminophenyl)indole (A) is the
key compound for the building of the indolo[1,2-c]quinazoline
framework. The key indole precursor A was obtained by the Fischer
indole cyclization of the phenylhydrazone of 2-amino acetophe-
none using a mixture of methane sulfonic acid and phosphorus
pentoxide [6]. The condensation of the various mono and di aryl
aldehydes (a-j); with the precursor A afforded the corresponding
mono and bis-2-(o-arylidineaminophenyl)indole intermediates
(1a-j), which on general oxidative cyclization [27] with powdered
KMnO4 in acetone furnished desired mono and bis-indolo[1,2-
c]quinazoline products (IIa–j) in excellent yields.
3.2. Determination of minimum inhibitory concentration (MIC)
The minimum inhibitory concentration of these potent quina-
zolines (IIa–e, IIf, IIh and IIi) was also verified by the liquid dilution
method [28,29] in which the effectiveness was observed at lower
concentrations. Comparison of the MICs (in
mg/ml) of potent
compounds and standard drugs against tested strains are presented
in Fig. 2. It was found that IIa, IIf, IIh and IIi compounds have
highest activity against all Gram-positive bacteria with MIC value
(5–20
mg/ml). Furthermore, compounds having heterocyclic
KMnO4 reflux
N
N
N
H
N
Ar
Ar
6-Arylindolo[1,2-c]quinazolines
2-(o-arylidineaminophenyl)indoles
( IIa-e )
( Ia-e )
Ar-CHO (a-e)
ethanol
1:1
Ar-CHO :
( a-e)
OHC-Ar-CHO :
(f-j)
N
NH2
Ar =
1.EtOH / AcOH
2. CH3SO3H / P2O5
N
H
NHNH2
N
H
H2N
O
O
H3CO
H3C
2-(o-aminophenyl)indole (A)
N
H
OHC-Ar-CHO(f-j)
2:1
ethanol
N
H
S
N
N
NH
N
KMnO4 ,reflux,
Ar
N
Ar
N
N
H
N
Bis-6-Arylindolo[1,2-c]quinazolines
Bis-2-(o-arylidineaminophenyl)indoles
( IIf-j )
( If-j )
Scheme 1. Synthetic route of mono, bis-indolo[1,2-c]quinazolines.

1202
R. Rohini et al. / European Journal of Medicinal Chemistry 45 (2010) 1200–1205
Table 1
Zone of inhibition of newly synthesized mono, bis-indolo(1,2-c)quinazolines against different bacteria and fungi.
Compound
Zone of inhibition (mm)
Gram-negative bacteria
(1000
m
g/ml)
Gram-positive bacteria
Fungi
S. aureus
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
50
51
50
52
55
50
18
52
51
25
48a
48
46
49
42
51
45
14
40
46
14
39a
42
49
39
45
48
39
13
46
48
18
35a
25
48
42
46
50
14
11
18
35
11
45a
35
52
50
42
48
12
14
16
20
16
40a
42
49
46
48
50
35
21
14
18
13
45a
22
46
49
50
52
17
10
20
12
12
45b
18
49
48
51
45
16
9
13
15
21
40b
21
50
49
46
49
12
18
18
21
9
IIj
Std
41b
a
Ampicillin.
Ketoconazole.
b
substituents at C6 position (IIa–e) exhibited potent inhibitory
activity (MIC range 2.5–20 g/ml) against all the bacterial and
fungal strains even than standard drugs Ampicillin and
Ketoconazole.
structure [6]. The condensation between A and aldehydes (a-j) was
confirmed by the disappearance of signals at 6.4 corresponding to
NH2 protons of compound A and appearance of signals at 8.16–
m
d
d
8.29 which is due to CH]N protons. However, the disappearance of
CH]N proton signals in all the final products suggests the forma-
tion of fused quinazolines [32].
4. Results and discussion
Furthermore, in the 13C NMR spectra of all the compounds the
signals corresponding to C]N carbon atoms [33] were appeared at
All newly synthesized intermediates as well as title compounds
were analyzed by elemental analysis and spectral (IR, 1H NMR, 13
NMR and mass) data.
C
141.1–167.9 ppm. The signals in the range of
were attributed to the various aromatic ring carbon atoms.
d
¼ 1112.1–157.9 ppm
4.3. FAB mass analysis
4.1. Infrared spectral analysis
The ESI–MS spectra of all the compounds showed a single peak
suggesting the molecular formulae. In addition, the FAB mass
spectrum of compound (IIa) shows a parent peak at m/z (Mþ) 371
(100%), which confirms the proposed formula C26H17N3. The major
fragments were observed at m/z values of 293 (39.2%), 256 (68.3%),
217 (21.5%), 192 (55.6%), 191 (87.5%), 77 (12.3%) and 76 (19.4%)
which indicate the fragmentation pattern of compound IIa.
The IR spectra of precursor, 2-(o-aminophenyl)indole (A) and
intermediate products (Ia-j) exhibits two absorption bands in the
region 3330–3400 cmꢀ1 and 1540–1560 cmꢀ1 were assigned to
–NH stretching and bending vibrations of indolyl ring, respectively
[30]. The formation of mono and bis-2-(o-arylideneaminopheny-
l)indole intermediates (Ia-j) was identified by disappearance of
peaks at 1680–1695 cmꢀ1 for–CHO and 3380–3440 cmꢀ1 for –NH2
of starting materials and at the same time appearance of band at
1610–1635 cmꢀ1 which is characteristic for –CH]N group [31]. The
formation of title quinazolines (IIa–j) were confirmed by the
appearance of characteristic absorption band at 1360–1380 cmꢀ1
for indolo[1,2-c]quinazoline ring with a tertiary nitrogen atom (C–
N) [32].
5. Conclusion
In conclusion, we have developed a simple and convenient
protocol for generation of mono and bis-indolo[1,2-c]quinazolines
in excellent yields from readily synthesized amino precursor and
various aryl aldehydes. Moreover, the antimicrobial screening of
some of the compounds has proved them potent antibacterial and
antifungal agents.
4.2. 1H and 13C NMR spectral analysis
In the 1H NMR spectra of A two singlets were observed at
d
6.4
6. Experimental protocols
for –NH2 and
d 8.48 for –NH, which confirmed the precursor
Chemicals and solvents were obtained from commercial sources
and used as received throughout the investigations. For purity tests,
TLC was performed on fluorescent silica gel plates (60 F254 from
Merck). Micro analytical (C, N, H) data was obtained by using
a Perkin–Elmer 2400 CHN elemental analyzer (Perkin–Elmer, USA).
The IR spectra were recorded in KBr pellets on Perkin–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 spectrometer (Agilent Series LC/MSD
Trap SL) equipped with an electrospray ionization (ESI) source was
used for MS analyses (Agilent, Palo Alto, CA, USA). Microorganisms
like S. aureus, B. subtilis, S. pyogenes (Gram-positive), S. typhimurium,
IIa
llb
llc
lld
lle
llf
llh
lli
40
35
30
25
20
15
10
5
0
Ampicillin
Ketoconazole
Bacteria and Fungi
Fig. 2. Comparison of MIC values (in
different bacteria and fungi.
m
g/ml) of quinazolines and standard drugs against

R. Rohini et al. / European Journal of Medicinal Chemistry 45 (2010) 1200–1205
1203
E. coli, K. pneumonia (Gram-negative) bacteria and A. niger, C. albi-
cans, T. viridae fungi were used in the present investigations.
(1C, –OCH3), 114.3, 118.5, 120.4, 122.7, 123.9, 125.1, 130.6, 131.8,
132.7, 140.6, 142,8, 146.1, 152.2, 154.2, 167.1 (24C, Ar–C); Anal.
Found: C, 78.90; H, 5.22; N,11.62%. Calcd for C24H19N3O: C, 78.88; H,
5.24; N, 11.50%. MS: [M]þ at m/z 365.
6.1. General method for the synthesis of precursor, 2-(o-
aminophenyl)indole (A)
6.3.4. N-[2-(1H-2-indolyl)phenyl]-N-[(E)-1-(5-methyl-1H-3-
The key indole derivative, 2-(o-aminophenyl)indole (A) was
obtained by the Fischer indole cyclization of the phenylhydrazone
of o-aminoacetophenone using a mixture of methane sulfonic acid
and phosphorus pentoxide at 85 ꢁC. Reactions were carried out
according to the method described by Billimoria and Cava [6].
indolyl)methylidene]amine (Id)
Yield 76%; mp 218–220 ꢁC; IR 3405,1641,1590,1558,1128, cmꢀ1
;
1H NMR (400 MHz, CDCl3)
Ar), 6.90–7.11 (m, 4H, Ar), 7.25–7.68 (m, 8H, Ar), 8.25 (s, 1H, CH]N),
8.56 (s, 2H, –NH); 13CNMR (67.93 MHz, CDCl3)
15.5 (1C, –CH3),
d in ppm 2.32 (S, 3H, Ar-CH3), 6.72 (s, 1H,
d
113.3, 115.0, 116.9, 120.8, 123.4, 126.1, 130.3, 131.8, 132.7, 135.9, 141.6,
144,4, 146.1, 149.5, 154.2, 163.9 (24C, Ar–C); Anal. Found: C, 82.68;
H, 5.49; N, 12.45%. Calcd for C24H19N3: C, 82.49; H, 5.48; N, 12.03%.
MS: [M]þ at m/z 349.
6.2. General method for the synthesis of mono, bis-2-o-
(arylideneamino)phenylindoles (Ia–e and Ii–j)
To a solution of 2 – (o-aminophenyl)indole (A, 0.418 g, 2 mmol
in case of Ia–e and 0.837 g, 4 mmol in case of Ii–j) in 20–40 ml of
ethanol, 2 mmol of Ar-CHO/OHC-Ar-CHO and few drops of acetic
acid was added with vigorous stirring. The resulting solution was
heated under reflux for 3 h. After cooling, the deposited solid
product was collected by filtration and recrystalized from an
ethanol or dichloromethane-methanol (2:8) mixture.
6.3.5. N-[(E)-1-benzo[b]thiophen-3-ylmethylidene]-N-[2-(1H-2-
indolyl)phenyl]amine (Ie)
Yield 72%; mp 228–230 ꢁC; IR 3400, 1646, 1580, 1552, 1120,
702 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d in ppm 6.73 (s,1H, Ar), 6.92–
7.12 (m, 2H, Ar), 7.25–7.37 (m, 4H, Ar), 7.45–7.68 (m, 5H, Ar), 7.76–
7.85 (m, 2H, Ar), 8.25 (s, 1H, CH]N), 8.58 (s, 1H, –NH); 13CNMR
(67.93 MHz, CDCl3)
d 113.8, 114.5, 120.5, 123.2, 125.8, 126.4, 129.2,
6.3. General method for the synthesis of mono, bis-6-substituted
indolo[1,2-c]quinazolines (IIa–e and IIi–j)
130.8, 131.5, 133.1, 140.5, 142,4, 144.7, 145.8, 146.0, 151.3, 164.2 (23C,
Ar–C); Anal. Found: C, 78.41; H, 4.72; N, 8.01%. Calcd for C23H16N2S:
C, 78.38; H, 4.58; N, 7.95%. MS: [M]þ at m/z 352.
The title products mono, bis-indolo[1,2-c]quinazolines (IIa–j)
were prepared from 2-(o-arylideneaminophenyl)indoles (Ia–j)
through oxidative cyclization method. To a stirred solution of the
intermediate compounds (Ia–j) in 60–80 ml of acetone was added
the appropriate amount of powdered KMnO4. The reaction mixture
was refluxed under heat for 30 min. It was then filtered hot, and an
equal volume of hot water added to the filtrate. The final products,
6-substituted indolo[1,2-c]quinazolines (IIa–j) rapidly separated,
and was collected by filtration and recrystalized from dime-
thylformamide or ethanol.
6.3.6. N1-(Z)-1-[3-([2-(1H-2-indolyl)phenyl]iminomethyl)-2-
naphthyl]methylidene-2-(1H-2-indolyl)aniline (If)
Yield 85%; mp 221–223 ꢁC; IR 3401, 1638, 1609, 1586, 1128 cmꢀ1
;
1H NMR (400 MHz,CDCl3)
4H, Ar), 7.28–7.69 (m, 14H, Ar), 7.89–8.03 (m, 4H, Ar), 8.16 (s, 2H,
CH]N), 8.28 (s, 2H, –NH); 13CNMR (67.93 MHz, CDCl3)
113.9,
d in ppm 6.72 (s, 2H, Ar), 6.93–7.12 (m,
d
118.0, 123.4, 125.1, 126.7, 128.2, 130.4, 131.3, 133.6, 138.8, 140.8,
142,2, 144.5, 146.2, 157.9, 165.4 (40C, Ar–C); Anal. Found: C, 85.23;
H, 5.09; N, 9.93%. Calcd for C40H28N4: C, 85.08; H, 5.00; N, 9.92%.
MS: [M]þ at m/z 564.
6.3.1. N-[2-(1H-2-indolyl)phenyl]-N-(E)-1-[4-(4-
pyridyl)phenyl]methylideneamine (Ia)
6.3.7. N1-((E)-1-4-[4-([2-(1H-2-indolyl)phenyl] iminomethyl)
phenoxy] phenyl methyl idene)-2-(1H-2-indolyl)aniline (Ig)
Yield 80%; mp 226–228 ꢁC; IR 3390, 1628, 1610, 1580, 1250,
Yield 78%; mp 196–198 ꢁC; IR 3395, 1632,1609, 1585, 1125 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
2H, Ar), 7.25–7.62 (m, 12H, Ar), 8.25 (s, 1H, CH¼N), 8.15 (s, 1H, –NH),
8.38–840 (m, 2H, Ar); 13CNMR (67.93 MHz, CDCl3)
114.7, 118.2,
d in ppm 6.71 (s, 1H, Ar), 7.10–7.12 (m,
1125 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
in ppm 6.74 (s, 2H, Ar),
6.92–7.15 (m, 12H, Ar), 7.26–7.62 (m, 12H, Ar), 8.16 (s, 2H, CH]N),
8.25 (s, 2H, –NH); 13CNMR (67.93 MHz, CDCl3)
113.8, 123.3, 124.6,
d
123.3, 124.5, 126.2, 130.5, 130.9, 131.2, 132.2, 136.5, 140.2, 142,8,
143.5, 146.3, 148.4, 155.9, 167.1 (26C, Ar–C); Anal. Found: C, 83.65;
H, 5.12; N, 11.31%. Calcd for C26H19N3: C, 83.62; H, 5.13; N, 11.25%.
MS: [M]þ at m/z 373.
d
125.9, 127.0, 128.2, 130.7, 131.9, 132.5, 134.8, 133.6, 135.0, 142.5,
144.6, 145.9, 146.2, 167.8 (42C, Ar–C); Anal. Found: C, 83.18; H, 4.99;
N, 9.29%. Calcd for C42H30N4O: C, 83.15; H, 4.98; N, 9.23%. MS: [M]þ
at m/z 606.
6.3.2. N-[(E)-1-(1H-3-indolyl)methylidene]-N-[2-(1H-2-
indolyl)phenyl]amine (Ib)
6.3.8. N1-(Z)-1-[2-([2-(1H-2-indolyl)phenyl]iminomethyl)-
phenyl]methylidene-2-(1H-2-indolyl)aniline (Ih)
Yield 72%; mp 219–221 ꢁC; IR 3400,1645,1588,1560,1128 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
3H, Ar), 7.29–7.59 (m, 8H, Ar), 7.65–7.72 (m, 2H, Ar), 8.16 (s, 1H,
CH]N), 8.25 (s, 2H, –NH); 13CNMR (67.93 MHz, CDCl3)
113.5,
119.2, 122.5, 124.6, 126.8, 130.3, 131.5, 132.2, 136.4, 141.0, 142,6,
143.5, 146.1, 165.9 (23C, Ar–C); Anal. Found: C, 82.41; H, 5.25; N,
12.51%. Calcd for C23H17N3: C, 82.36; H, 5.11; N, 12.53%. MS: [M]þ at
m/z 335.
d
in ppm 6.72 (s, 1H, Ar), 6.95–7.18 (m,
Yield 79%; mp 201–203 ꢁC; IR 3400, 1645, 1609, 1580,
1130 cmꢀ1
;
1H NMR (400 MHz,CDCl3)
d
in ppm 6.73 (s, 2H, Ar),
6.90–7.15 (m, 4H, Ar), 7.28–7.69 (m, 16H, Ar), 8.15 (s, 2H, CH]N),
8.29 (s, 2H, –NH); 13C NMR (67.93 MHz, CDCl3)
113.8, 117.8, 122.5,
d
d
123.4, 126.1, 127.5, 128.2, 130.1, 131.5, 132.7, 133.4,138.8, 140.7, 142,4,
144.6, 145.8, 159.1 (36C, Ar-C); Anal. Found: C, 84.13; H, 5.11; N,
10.90%. Calcd for C36H26N4: C, 84.02; H, 5.09; N, 10.89%. MS: [M]þ at
m/z 514.
6.3.3. N-[2-(1H-2-indolyl) phenyl]-N-[(E)-1-(5-methoxy-1H-3-
indolyl) methylidene] amine (Ic)
6.3.9. N1-(E)-1-[3-([2-(1H-2-indolyl)phenyl]iminomethyl)-
Yield 81%; mp 205–207 ꢁC; IR 3398, 1645, 1590, 1560, 1100,
phenyl]methylidene-2-(1H-2- indolyl)aniline (Ii)
1040 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
in ppm 3.62 (s, 3H, –OCH3),
6.73 (s, 1H, Ar), 6.92–7.12 (m, 3H, Ar), 7.21–7.76 (m, 9H, Ar), 8.18 (s,
1H, CH]N), 8.29 (s, 2H, –NH); 13CNMR (67.93 MHz, CDCl3)
56.4
Yield 80%; mp 233–235 ꢁC; IR 3406,1630,1610,1578,1128 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
4H, Ar), 7.27–7.65 (m, 16H, Ar), 8.14 (s, 2H, CH]N), 8.28 (s, 2H,
d in ppm 6.72 (s, 2H, Ar), 6.92–7.12 (m,
d

1204
R. Rohini et al. / European Journal of Medicinal Chemistry 45 (2010) 1200–1205
–NH); 13C NMR (67.93 MHz, CDCl3)
d
114.2, 115.1, 122.8, 123.3, 124.6,
6.3.16. 6-(3-indolo[1,2-c]quinazolin-6-yl-2-naphthyl)indolo[1,2-
126.5, 127.1, 128.7, 130.2, 131.5, 132.6, 134.8, 133.2, 136.4, 140.2,
142.5, 144.6, 145.8, 146.2, 167.9 (36C, Ar–C); Anal. Found: C, 84.05;
H, 5.08; N, 10.88%. Calcd for C36H26N4: C, 84.02; H, 5.09; N, 10.89%.
MS: [M]þ at m/z 514.
c]quinazoline (IIf)
Yield 82%; mp 232–234 ꢁC; IR 1638, 1609, 1458, 1379, 1128, 774,
748, 740 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
d
7.02–7.42 (m, 10H,
Ar), 7.50–8.10 (m, 12H, Ar), 8.75 (s, 2H, Ar); 13CNMR (67.93 MHz,
DMSO-d6) 113.2, 114.5, 119.9, 123.2, 125.2, 126.5, 128.4, 130.8,
d
6.3.10. N1-(E)-1-[4-([2-(1H-2-indolyl)phenyl]iminomethyl)-
phenyl]methylidene-2-(1H-2-indolyl)aniline (Ij)
132.4, 135.6, 143.1, 146.6, 152.3, 154.5, 165.7 (40C, Ar–C); Anal.
Found: C, 85.72; H, 4.37; N, 9.98%. Calcd for C40H24N4: C, 85.69; H,
4.31; N, 9.99%. MS: [M]þ at m/z 560.
Yield 72%; mp 245–247 ꢁC; IR 3400, 1620, 1605, 1585,
1130 cmꢀ1
;
1H NMR (400 MHz,CDCl3)
d
in ppm 6.73 (s, 2H, Ar),
6.91–7.13 (m, 4H, Ar), 7.28–7.63 (m, 16H, Ar), 8.15 (s, 2H, CH]N),
8.29 (s, 2H,–NH); 13C NMR (67.93 MHz, CDCl3)
113.9, 114.0, 122.6,
6.3.17. 6-[4-(4-indolo[1,2-c]quinazolin-6-ylphenoxy)phenyl]-
indolo[1,2-c]quinazoline (IIg)
d
123.2, 124.5, 126.8, 127.5, 129.4, 130.3, 131.7, 132.1, 136.5, 140.2,
142,4, 144.5, 147.3, 167.6 (36C, Ar–C); Anal. Found: C, 84.10; H, 5.10;
N, 10.91%. Calcd for C36H26N4: C, 84.02; H, 5.09; N, 10.89%. MS:
[M]þ at m/z 514.
Yield 85%; mp 208–210 ꢁC; IR 1620, 1605, 1460, 1386, 1130, 774,
759, 740 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
in ppm 7.01–7.15
(m, 6H, Ar), 7.25–7.48 (m, 12H, Ar), 7.64–7.81 (m, 8H, Ar); 13CNMR
(67.93 MHz, DMSO-d6) 113.3, 120.2, 121.6, 123.2, 124.4, 125.8,
d
129.1, 130.8, 132.2, 141.3, 145.7, 152.2, 156.6, 165.9 (42C, Ar–C); Anal.
Found: C, 83.71; H, 4.39; N, 9.41%. Calcd for C42H26N4O: C, 83.70; H,
4.35; N, 9.30%. MS: [M]þ at m/z 602.
6.3.11. 6-[4-(4-pyridyl)phenyl]indolo[1,2-c]quinazoline (IIa)
Yield 80%; mp 210–212 ꢁC; IR 1625, 1580, 1531, 1455, 1380, 1042,
775, 741, 730 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
d
in ppm 6.92 (m,
1H, Ar), 7.17–7.83 (m, 12H, Ar), 8.05–8.11 (m, 2H, Ar) 8.38–8.40 (m,
2H, Ar); 13CNMR (67.93 MHz, DMSO-d6)
113.6, 120.6, 123.2, 125.5,
6.3.18. 6-(2-indolo[1,2-c]quinazolin-6-ylphenyl)indolo[1,2-
c]quinazoline (IIh)
d
126.7, 129.6, 130.1, 132.4, 133.9, 144.8, 146.2, 150.5, 166.2 (26C, Ar–
C); Anal. Found: C, 84.09; H, 4.70; N, 11.36%. Calcd for C26H17N3: C,
84.07; H, 4.61; N, 11.31%. MS: [M]þ at m/z 371.
Yield 76%; mp 224–226 ꢁC; IR 1638, 1606, 1459, 1382, 1130, 778,
741, 738 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
in ppm 7.02–7.04
(m, 2H, Ar), 7.22–7.68 (m, 16H, Ar), 7.87–7.91 (m, 2H, Ar), 8.23–8.26
(m, 2H, Ar); 13C NMR (67.93 MHz, DMSO-d6)
113.2, 115.1, 120.3,
d
6.3.12. 6-(1H-3-indolyl)indolo[1,2-c]quinazoline (IIb)
121.2, 123.5, 125.6, 126.2, 128.5, 130.5, 132.6, 135.2, 142.9, 143.2,
144.5,145.5, 153.4, 155.1, (36C, Ar–C); Anal. Found: C, 84.70; H, 4.37;
N, 10.98%. Calcd for C36H22N4: C, 84.68; H, 4.34; N, 10.97%. MS: [M]þ
at m/z 510.
Yield 67%; mp 208–210 ꢁC; IR 3404, 1642, 1620, 1565, 1472,
1368, 771, 745, 735 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
in ppm
6.89–7.04 (m, 2H, Ar), 7.21–7.87 (m, 12H, Ar), 8.51 (s, 1H, –NH);
13CNMR (67.93 MHz, DMSO-d6)
113.2, 114.8, 119.0, 120.3, 123.6,
d
124.5, 125.1, 127.8, 129.2, 132.9, 141.0, 143.3, 145.9, 148.5, 153.6,
164.4 (23 C, Ar–C); Anal. Found: C, 82.90; H, 4.61; N, 12.64%.
Calcd for C23H15N3: C, 82.86; H, 4.53; N, 12.60%. MS: [M]þ at m/z
333.
6.3.19. 6-(3-indolo[1,2-c]quinazolin-6-ylphenyl)indolo[1,2-
c]quinazoline (IIi)
Yield 78%; mp 218–220 ꢁC; IR 1621, 1608, 1459, 1388, 1128, 777,
759, 740 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
in ppm 7.01–7.05
(m, 2H, Ar), 7.26–7.41 (m, 8H, Ar), 7.58–7.78 (m, 11H, Ar), 8.78 (m,
1H, Ar); 13C NMR (67.93 MHz, DMSO-d6)
113.2, 114.6, 119.2,
6.3.13. 6-(5-Methoxy-1H-3-indolyl)indolo[1,2-c]quinazoline (IIc)
Yield 75%; mp 214–216 ꢁC; IR 3395, 1645, 1621, 1585,1559, 1530,
1458, 1365,1040, 773, 740, 737 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
d
120.7, 122.6, 124.3, 126.7, 128.2, 130.4, 133.3, 142.6, 143.4, 145.4,
146.2, 152.3, 156.9, (36C, Ar–C); Anal. Found: C, 84.69; H, 4.35; N,
10.99%. Calcd for C36H22N4: C, 84.68; H, 4.34; N, 10.97%. MS: [M]þ
at m/z 510.
d
in ppm 3.76 (s, 3H, -OCH3), 7.02–7.64 (m,12H, Ar), 7.89 (m,1H, Ar),
8.45 (s, 1H, –NH); 13CNMR (67.93 MHz, DMSO-d6)
d
56.2 (1C,
–OCH3), 112.8, 113.9, 119.2, 120.7, 123.1, 124.7, 125.1, 126.8, 128.4,
134.2, 142.0, 144.5, 146.7, 150.8, 153.2, 166.1 (24C, Ar–C); Anal.
Found: C, 79.37; H, 4.80; N, 11.58%. Calcd for C24H17N3O: C, 79.32; H,
4.71; N, 11.56%. MS: [M]þ at m/z 363.
6.3.20. 6-(4-indolo[1,2-c]quinazolin-6-ylphenyl)indolo[1,2-
c]quinazoline (IIj)
Yield 72%; mp 252–254 ꢁC; IR 1620, 1602, 1458, 1386, 1130, 778,
775, 731 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
in ppm 7.02–7.06
(m, 2H, Ar), 7.22–7.39 (m, 8H, Ar), 7.61–7.80 (m, 8H, Ar), 8.31 (s, 4H,
Ar); 13C NMR (67.93 MHz, DMSO-d6)
113.1, 119.4, 120.5, 121.7,
6.3.14. 6-(5-Methyl-1H-3-indolyl)indolo[1,2-c]quinazoline (IId)
Yield 72%; mp 221–223 ꢁC; IR 3400, 1642, 1625, 1586,1561,
d
1480, 1382, 776, 749, 732 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
d
in
123.5, 126.8, 129.2, 130.1, 133.2, 135.5, 138.6, 140.6, 143.2, 145.7,
149.8, 152.1, 157.1 (36C, Ar–C); Anal. Found: C, 84.73; H, 4.32; N,
10.95%. Calcd for C36H22N4: C, 84.68; H, 4.34; N, 10.97%. MS: [M]þ at
m/z 510.
ppm 2.34 (S, 3H, Ar-CH3), 6.89–7.05 (m, 4H, Ar), 7.25–7.52 (m, 4H,
Ar), 7.62–7.71 (m, 4H, Ar), 7.87 (m, 1H, Ar), 8.52 (s, 1H,–NH);
13CNMR (67.93 MHz, DMSO-d6)
d 15.5 (1C, -CH3), 112.9, 114.4, 116.5,
121.2, 123.4, 124.6, 125.2, 127.8, 129.1, 131.7, 141.8, 143.5, 146.2,
151.0, 152.4, 166.1 (24C, Ar–C); Anal. Found: C, 82.99; H, 5.01; N,
12.08%. Calcd for C24H17N3: C, 82.97; H, 4.93; N, 12.09%. MS: [M]þ
at m/z 347.
Acknowledgment
The authors thank the University Grant Commission (UGC, F. No.
34-363/2008(SR)), New Delhi, India and National Science Council
(NSC), Taiwan for financially supporting this research.
6.3.15. 6-benzo[b]thiophen-3-ylindolo[1,2-c]quinazoline (IIe)
Yield 79%; mp 225–227 ꢁC; IR 1642, 1608, 1582, 1461, 1388, 776,
741, 746, 692 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6)
d
in ppm 6.71–
7.02 (m, 2H, Ar), 7.24–7.71 (m, 9H, Ar), 7.81–7.97 (m, 3H, Ar);
13CNMR (67.93 MHz, DMSO-d6)
112.1, 118.5, 121.2,, 122.9, 124.3,
d
Appendix. Supplementary data
125.6, 128.9, 130.2, 133.4, 138.2, 143.5, 146.4, 148.5, 152.1, 164.1 (23C,
Ar–C); Anal. Found: C, 78.85; H, 4.09 N, 8.02%. Calcd for C23H14N2S:
C, 78.83; H, 4.03 N, 7.99%. MS: [M]þ at m/z 350.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.ejmech.2009.11.038.

R. Rohini et al. / European Journal of Medicinal Chemistry 45 (2010) 1200–1205
1205
[18] P. Moreau, M. Sancelme, C. Bailly, S. Leonce, A. Pierre, J. Hickman, B. Pfeiffer,
M. Prudhomme, Eur. J. Med. Chem. 36 (2001) 887–897.
[19] X.Y. Zhu, L.G. Mardenborough, S. Li, A. Khan, W. Zhang, P. Fan, M. Jacob,
S. Khan, L. Walkerb, S.Y. Ablordeppeya, Bioorg. Med. Chem. 15 (2007)
686–695.
[20] Y.L. Chen, H.M. Hung, C.M. Lu, K.C. Li, C.C. Tzeng, Bioorg. Med. Chem. 12 (2004)
6539–6546.
[21] J. Scovill, E. Blank, M. Konnick, E. Nenortas, T. Shapiro, Antimicrob. Agents
Chemother. 46 (2002) 882–883.
[22] V.M. Sharma, P. Prasanna, K.V.A. Seshu, B. Renuka, C.V. Laxman Rao,
G.S. Kumar, C.P. Narasimhulu, P.A. Babu, R.C. Puranik, D. Subramanyam,
A. Venkateswarlu, S. Rajagopal, K.B.S. Kumar, C.S. Rao, N.V.S.R. Mamidi,
D.S. Deevi, R. Ajaykumar, R. Rajagopalan, Bioorg. Med. Chem. Lett. 12 (2002)
2303–2307.
[23] C. Hong, G.L. Firestone, L.F. Bjeldanes, Biochem. Pharmacol. 63 (2002)
1085–1097.
[24] T.R. Garbe, M. Kobayashi, N. Shimizu, N. Takesue, M. Ozawa, H. Yukawa, J. Nat.
Prod. 63 (2000) 596–598.
References
[1] E. Conchon, B. Aboab, R.M. Golsteyn, F. Cruzalegui, T. Edmonds, S. Leonce,
B. Pfeiffer, M. Prudhomme, Eur. J. Med. Chem. 41 (2006) 1470–1477.
[2] L.D. Via, O. Gia, S.M. Magno, A.D. Settimo, G. Primofiore, F.D. Settimo,
F. Simorini, A.M. Marini, Eur. J. Med. Chem. 37 (2002) 475–486.
[3] U. Heinelt, S. Herok, H. Matter, P. Wildgoose, Bioorg. Med. Chem. Lett. 11
(2001) 227–230.
[4] M. Lounasmaa, A. Tolvanen, Nat. Prod. Rep. 17 (2000) 175–191.
[5] M. Toyota, M. Ihara, Nat. Prod. Rep. (1998) 327–340.
[6] A.D. Billimmoria, M.P. Cava, J. Org. Chem. 59 (1994) 6777–6782.
[7] A. Blackman, T.W. Hambley, R. Picker, W.C. Taylor, N. Thirasana, Tetrahedron
Lett. 28 (1987) 5561–5564.
[8] S.K. Bhati, A. Kumar, Eur. J. Med. Chem. 43 (2008) 2323–2330.
[9] V.N. Sonar, S.K. Yazadan, N. Sreenivasulu, Ind. J. Heterocycl. Chem. 19 (2001)
299–302.
[10] P. Archna Rani,, K. Bajaj, V.K. Srivastava, R. Chandra, A. Kumar, Arzneim-
Forsch./Drug Res. 55 (2003) 31–306.
[11] E. Wincent, H. Shirani, J. Bergman, U. Rannug, T. Janosik, Bioorg. Med. Chem. 17
(2009) 1648–1653.
[12] D. Sinha, A.K. Tiwari, S. Singh, G. Shukl, P. Mishra, H. Chandra, A.K. Mishra, Eur.
J. Med. Chem. 43 (2008) 160–165.
[25] G. Gurkok, N. Altanlar, S. Suzen, Chemotherapy 55 (2009) 15–19.
[26] R. Rohini, K. Shanker, P.M. Reddy, V.C. Sekhar, V. Ravinder, Arch. Pharm. Chem.
Life Sci. 342 (2009) 533–554.
[27] M. Davis, F.G. Mann, J. Chem. Soc. (1962) 945–954.
[28] P.M. Reddy, Y.P. Ho, K. Shanker, R. Rohini, V. Ravinder, Eur. J. Med. Chem. 44
(2009) 2621–2625.
[13] S.V. Miert, S. Hostyn, B.U.M. Maes, K. Cimanga, R. Brun, M. Kaiser, P. Matyus,
R. Dommisse, G. Lemiere, A. Vlietinck, L. Pieters, J. Nat. Prod. 68 (2005) 674–677.
[14] A.K. Bhattacharjee, M.G. Hartell, D.A. Nichols, R.P. Hicks, B. Stanton, J.E. van
Hamont, W.K. Milhous, Eur. J. Med. Chem. 39 (2004) 59–67.
[15] M. Prudhomme, Eur. J. Med. Chem. 38 (2003) 123–140.
[16] L. He, H. Chang, T.C. Chou, N. Savaraj, C.C. Cheng, Eur. J. Med. Chem. 38 (2003)
101–107.
[29] R. Rohini, K. Shanker, P.M. Reddy, Y.P. Ho, V. Ravinder, Eur. J. Med. Chem. 44
(2009) 3330–3339.
[30] H. Talbi, B. Humbert, D. Billaud, Synth. Met 84 (1997) 875–876.
[31] P. Amudha, P. Akilan, M. Kandaswamy, Polyhedron 18 (1999) 1355–1362.
´
[32] L.N. Vostrova, T.A. Voronina, T.L. Karaseva, S.A. Gernega, E.I. Ivanov,
A.M. Kirichenko, M.Yu. Totrova, Pharma. Chem. J. 20 (1986) 404–406.
[33] H.J. Jung, N. Singh, D.O. Jang, Tetrahedron Lett. 49 (2008) 2960–2964.
[17] E. Caballero, M. Adeva, S. Calderon, H. Sahagun, F. Tome, M. Medarde,
J. Fernandez, M.L. Lazaroc, M.J. Ayuso, Bioorg. Med. Chem. 11 (2003) 3413–3421.