Letters in Drug Design & Discovery, 2009, 6, 201-209

201

Synthesis of Coumarin linked Naphthalimide Conjugates as Potential

Anticancer and Antimicrobial Agents
Ahmed Kamal*,a, S.F. Adila, Jaki R. Tambolia, B. Siddardhab and U.S.N. Murthyb
a

Chemical Biology Laboratory, Division of Organic Chemistry; bBiology Division, Indian Institute of Chemical
Technology, Hyderabad 500 067, India
Received October 10, 2008: Revised December 22, 2008: Accepted December 22, 2008

Abstract: A series of new coumarin linked naphthalimides (16a-g; 18a-g) was synthesised and evaluated for their in vitro
anticancer activity against six cancer cell lines. Most of the compounds investigated have shown good to moderate anticancer activity against colon, breast and lung cancer cell lines. Thermal denaturation studies indicated that some compounds exhibited DNA binding ability. They were also found to be active against gram-positive and gram-negative bacterial strains as well as a few fungal strains.

Keywords: Coumarin-thaizolyl, Naphthalimide, Anticancer, Antimicrobial, DNA binding affinity.

INTRODUCTION

precursor in a number of cases. As an example, the naphthalimide linked pyrolobenzodiazepine hybrids 7-9 [23, 24],
have exhibited better anticancer activity against certain cancer cell lines and improved DNA binding affinity than their
precursor DC-81, a naturally occurring pyrolobenzodiazepine molecule used as a standard to measure DNA binding affinity.

Coumarin derivatives have been reported to possess various biological activities including antiviral [1], antitumour
[2-5], DNA-repair deficiencies [6, 7], anti-inflammation [812], antiallergic and antihaemorrhagic activities [13]. Amino
thaizolyl derivatives of coumarin have been reported to possess mild antimicrobial activity, which on further derivatisation with different moieties, have been reported to possess
significant antimicrobial 1 and anticancer activities 2, 3 [1419].

In the last few years, we have been engaged in the structural modifications for different pharmacophores as well as
the development of new synthetic strategies for the preparation of biologically important heterocycles, particularly antiR1

R1
O

O
N

X
X= H, Br
1

R3

R2

NHR
S

R
N

CH3
N

R2

C
R3

N
S

R
N

NH2
N

C
NH2

2
Biologically active coumarin-thiazole derivatives

Naphthalimides and its derivatives have a profound history in the field of medicinal chemistry and especially in the
area of anticancer drugs due to their mode and specificity of
interaction with particular DNA sequences, which has drawn
considerable interest in chemistry, biology and medicine.
Naphthalimide analogues have been reported as a potential
class of antineoplastic agents with compounds like amonafide (Quinomed, 4), mitonafide (5) and azonafide (6),
known to inhibit DNA and RNA synthesis, and intercalate
DNA [20-22]. Many naphthalimide linked conjugates have
also shown to exhibit superior anticancer activity than their
*Address correspondence to this author at the Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 067, India; Tel: +91-40-27193157; Fax: +91-4027193189; E-mail: ahmedkamal@iict.res.in
1570-1808/09 $55.00+.00

cancer agents [25]. The above findings regarding the diverse

biological activity of coumarins as well as naphthalimide
derivatives prompted us to synthesise and evaluate the anticancer and antimicrobial activity of some new coumarin
linked naphthalimide conjugates.
CHEMISTRY
The preparation of substituted 3-(2-amino-4-thiazolyl)2H-l-benzopyran-2-ones (14a-g) was carried out by the condensation of substituted salicylaldehydes (10a-g) with ethyl
acetoacetate (11) in the presence of piperidine, to yield substituted 3-acetyl-2H-l-benzopyran-2-ones (12a-g). The intermediates (12a-g) were brominated to give substituted 3bromoacetyl-2H-l-benzopyran-2-ones (13a-g), which were
inturn condensed with thiourea to yield substituted 3-(2 2009 Bentham Science Publishers Ltd.

202 Letters in Drug Design & Discovery, 2009, Vol. 6, No. 3

Kamal et al.

N
O

HCl

HCl

X
Amonafide, (4) X = NH2

Azonafide, (6)

Mitonafide, (5) X = NO2

O
N

BnO

H
N

n
O

H3CO

( )

N
H

O
H3CO

n=1-3,6,8

n=2,3

8
O
N

H
O

H3CO

N
H

N
O

R1

R1
O

OH
+
R2

O
OC2H5

CHO

(i)
R2

COCH3
R3

R3
11

10a-g

12a-g
(ii)

R1

R1
O

(iii)
N

R2
R3

R2
NH2

14a-g
14a : R1 = R2 = R3 = H
14b : R1 = OCH3 R2 = R3 = H
14c : R2 = Cl R1 = R3 = H
14d : R1= H R2 = R3= CHCH2CH2CH
14e : R1 = R2 = Cl R3 = H
14f : R2 = Br R1 = R3= H
14g : R1 = R2 = Br R3 = H

Scheme 1. Reagents and conditions: (i) Piperidine; (ii) Br2, CHCl3; (iii) CS(NH2)2, C2H5OH, reflux.

COCH2Br
R3
13a-g

Synthesis of Coumarin linked Naphthalimide Conjugates

R1

Letters in Drug Design & Discovery, 2009, Vol. 6, No. 3

O
O

R1

O
O

R2
R2

203

R2

NH2

R2
15

14a-g

N
S
16a-g

O
16a: R1 = R2 = R3 = H;
16b: R1 = OCH3 R2 = R3 = H;
16c: R2 = Cl R1 = R3 = H
16d: R1= H R2 = R3= CHCH2CH2CH;
16e: R1 = R2 = Cl R3 = H;
16f: R2 = Br R1 = R3= H;
16g: R1 = R2 = Br R3 = H

Scheme 2. Reagents and conditions: CH3OH, 60 oC, 10% aq. NaOH.

RESULT AND DISCUSSION

amino-4-thiazolyl)-2H-l-benzopyran-2-ones (14a-g) as shown

in Scheme 1.

Antitumour Activity

The
precursors
of
3-(2-amino-4-thiazolyl)-2H-lbenzopyran-2-ones (14a-g) were reacted with naphthalic
anhydride 15 by heating both the reactants in methanol followed by the addition of aq. NaOH (10%) and the resulting
solutions were stirred overnight to yield the desired coumarin-naphthalimide conjugates 16a-g linked through the
thiazolyl ring, as illustrated in Scheme 2.

Compounds 16 and 18 have been evaluated for their in

vitro cytotoxicity against selected human tumour cell lines of
lung, breast, oral and prostrate cancers using the sulforhodamine (SRB) method [26, 27]. Table 1 reveals that all the
compounds have shown moderate activity against selective
cell lines, while compound 16e is active against all the cell
lines and is tested against IC50 values ranging from 0.19 to
31 M. It has shown good activity against Colo205 and
A549 cancer cell lines, and compounds 18a and 18b have
shown substantial activity against A2780. Most of the compounds have shown good activity against the MCF7 cell line.
Overall, most of the compounds have shown potential anti-

Moreover, condensation of 3-(2-amino-4-thiazolyl)-2H-lbenzopyran-2-ones (14a-g) with naphthalic dianhydride 17

in acetic acid under reflux conditions provided the additional
desired conjugates 19a-g that possessed two coumarin moieties linked through thaizolyl rings to the two nitrogens of the
naphthalic diimide ring system (Scheme 3).
R1
O

O
N

R2
R3

+
NH2

17

14a-g

R1

R1
O

O
N

R2
R3

S
O

O
18a-g

18a: R1 = R2 = R3 = H
18b: R1 = OCH3 R2 = R3 = H
18c: R2 = Cl R1 = R3 = H
18d: R1= H R2 = R3= CHCH2CH2CH
18e: R1 = R2 = Cl R3 = H
18f: R2 = Br R1 = R3= H
18g: R1 = R2 = Br R3 = H

Scheme 3. Reagents and conditions: CH3 COOH, reflux, 5-6h.

R2
R3

204 Letters in Drug Design & Discovery, 2009, Vol. 6, No. 3

Table 1.

Kamal et al.

Cytotoxicity Data of Compounds 16 and 18

GI50 (M)

Compd.
Colo205

PC3

-g

16a

SiHa

-g

-g

MCF7d

Zr-75-1d

A2780e

A549f

2.1

26

-g

29

29

27

16b

24.0

24

28.0

4.2

16c

-g

24

-g

0.17

-g

24

29

16e

2.28

26

31.0

2.1

2.1

29

0.19

16f

0.15

-g

16g

-g

-g

-g

2.0

24

25

-g

18a

23

28

27

0.16

21

0.1

26

18b

28

0.13

<0.1

-g

18c

24

26

-g

3.5

23

25

28

25

2.3

30

31

28

28.0

2.4

27

27

24

0.15

2.38

-g

<0.10

<0.10

0.002

13.0

18e

27.0

18f

18g

25.0

ADR
a

28.0

14.7
b

30.0

<0.10
c

1.9
d

Colon Cancer; Prostrate Cancer; Cervical Cancer; Breast Cancer; Ovarian Cancer; Non-Small-Cell Lung Cancer; IC50 value not attained at the concentrations used in the
assay; ADR, Adriamycin.

cancer activity against a broad spectrum of tumour subpanels.

Thermal Denaturation Studies
Compounds were subjected to thermal denaturation studies with duplex-form CT-DNA. The DNA binding ability for
Table 2.

these coumarin-naphthalimide derivatives (16a-g and 18a-g)

has been determined by thermal denaturation studies [28]
using calf thymus (CT)-DNA and has been summarised in
Table 2. These studies were carried out at a Compd./DNA
molar ratio of 1:5. All these compounds (16a-g and 18a-g)
elevated the helix melting temperature of CT-DNA. Interestingly one of the compounds 18c showed the
Tm of 24.3 oC

Thermal Denaturation Studies for Compounds 16 and 18

Compd.

[Compd.]:[DNA]

Tm (C)b After Incubation at 37 C

Molar Ratioa

0h

18 h

16a

1:5

1.0

1.2

16b

1:5

0.4

0.5

16c

1:5

1.0

1.0

16d

1:5

0.1

0.1

16e

1:5

3.8

3.8

16f

1:5

0.4

0.5

16g

1:5

0.3

0.7

18a

1:5

1.2

1.5

18b

1:5

0.9

1.1

18c

1:5

24.3

26.2

18d

1:5

4.5

4.5

18e

1:5

3.9

3.9

18f

1:5

0.1

0.3

18g

1:5

0.8

0.9

DC-81

1:5

0.3

0.7

For CT-DNA alone at pH 7.00 0.01, Tm = 69.2 C 0.01 (mean value from 10 separate determinations), all
Tm values are 0.1 - 0.2 C.
b
For a 1:5 molar ratio of [Compd.]/[DNA], where CT-DNA concentration = 100 M and ligand concentration = 20 M in aqueous sodium phosphate buffer [10 mM sodium phosphate + 1 mM EDTA, pH 7.00 0.01].
a

Synthesis of Coumarin linked Naphthalimide Conjugates

Table 3.

Letters in Drug Design & Discovery, 2009, Vol. 6, No. 3

205

Antibacterial Activity of Compounds 16 and 18

MIC (g/mL)

Compd.

Gram-Positive

Gram-Negative

S. aureus

S. epidermidis

E. coli

P. aeruginosa

16a

37.5

37.5

18.75

75

16b

18.75

37.5

18.75

37.5

16c

18.75

18.75

18.75

37.5

16d

37.5

37.5

18.75

75

16e

18.75

18.75

18.75

37.5

16f

37.5

37.5

18.75

75

16g

37.5

37.5

18.75

75

18a

37.5

37.5

18.75

75

18b

18.75

37.5

18.75

37.5

18c

18.75

37.5

18.75

37.5

18d

37.5

18.75

18.75

75

18e

37.5

18.75

18.75

75

18f

37.5

37.5

18.75

37.5

18g

37.5

37.5

18.75

75

CIPR

18.75

18.75

18.75

37.5

CIPR: Ciprofloxacin.

at 0 h and 26.2 oC after 18 h of incubation. However, the

naturally occurring DC-81 exhibited a
Tm of 0.7 o C under
similar conditions.
Antimicrobial Activity
The compounds 16 and 18 have been evaluated for their
efficacy as antibacterial agents by agar-well diffusion
method [29-31] against various microbial strains. The in
vitro antibacterial activity of the newly synthesised compounds 16ag and 18a-g has been studied against the bacterial strains; Gram-positive organisms, viz., Staphylococcus
aureus (MTCC 96) and Staphylococcus epidermidis (MTCC
435), and Gram-negative organisms, viz., Escherichia coli
(MTCC 443) and Pseudomonas aeruginosa (MTCC 741) by
agar well diffusion method. Ciprofloxacin was used as a
standard.
From the results shown in Table 3, it has been observed
that the compounds 16a-g and 18a-g were active against the
gram positive and gram negative bacteria. These compounds
exhibited equipotent inhibition of bacterial growth as compared to the standard. However, some of the compounds
16b, 16c, 16e, 18b, and 18c have shown significant inhibition against S. aureus while 16c, 16e, 18d, and 18e have
shown activity against S. epidermidis. All the compounds
have shown equipotent inhibition against E. coli, whereas
compounds 16b, 16c, 16e, 18b, 18c and 18f have shown
significant inhibition against P. aeruginosa.
The in vitro antifungal activity of the newly synthesised
compound has been studied against the fungal strains, viz.,
Aspergillus niger (MTCC 282), Rhizopus oryzae (MTCC

262), Candida albicans (MTCC 227), and Saccharomyces

cereviseae (MTCC 36) by agar-well diffusion method.
Clotrimazole was used as a standard.
From the results given in Table 4, it is observed that all
the compounds exhibited equipotent inhibition of fungal
growth compared to the standard. The compounds 16a, 16f,
and 18c showed significant inhibition against S. cerevisiae,
whereas compound 18c alone was shown to be active against
C. albicans, while only 6f was shown to be active against A.
niger with a zone of inhibition (mm) equal to that of the
standard used. Compounds 16c, 16e, 16e, 18b, 18c and 18f
showed equipotent inhibition to that of the standard against
R. oryzae.
CONCLUSION
In summary, some of the coumarin linked conjugates
have been synthesised that exhibit mild to moderate anticancer activity in the cell lines evaluated. The DNA binding
ability for these compounds is also moderate for most of the
compounds except for 3-4 compounds and there seems to be
no direct correlation with the in vitro anti-cancer activity.
Similarly, antimicrobial activity exhibited by these compounds is moderate for most of the compounds, however, a
few compounds have exhibited appreciable antimicrobial
activity.
EXPERIMENTAL SECTION
Substituted salisaldehydes and thiourea were purchased
from local available SRL Chemicals Ltd., while cyclodextrin

206 Letters in Drug Design & Discovery, 2009, Vol. 6, No. 3

Table 4.

Kamal et al.

Antifungal Activity of Compounds 16 and 18

Zone of inhibition (mm)
Compd.

Yeast

Filamantous Fungi

S. cerevisiae

C.albicans

A. niger

R. oryzae

16a

23

20

20

14

16b

18

18

21

22

16c

18

18

18

23

16d

15

16

18

15

16e

18

18

16

23

16f

23

16

19

14

16g

16

16

18

14

18a

16

16

18

12

18b

18

16

18

23

18c

23

23

20

23

18d

16

18

21

12

18e

16

17

21

12

18f

16

15

22

23

18g

16

18

20

13

CLTM

23

24

22

23

CLTM, clotrimazole (100 g/mL).

was purchased from Sigma Aldrich Chemicals. 1HNMR

spectra were recorded in a GEMINI (200 MHz, Varian Inc.,
Palo Alto, CA, USA) Brucker instrument and Mass Spectra
on Aglinet 1100 series instrument. Infrared spectra were
recorded on Perkin-Elmer (FT-IR-8300) in KBr pellets. The
elemental analyses of the compounds were performed using
Elementa Analyser, Model Vario EL, Elementar, Germany.
The purity of the compounds was checked by thin layer
chromatography. Melting points were determined in open
capillaries and are uncorrected.
General Procedure for Preparation of Substituted 3acetyl-2H-l-benzopyran-2-ones (12a-g)
To the mixture of ethyl acetoacetate (11) (10.5 gms,
1.035 moles) and catalytic amount of piperidine in an ice
bath, substituted salisaldehyde 10a-g (10.2 gms, 1 mole) was
added slowly and the reaction mixture was left for stirring
for about 30 mins. Then, the solid was allowed to settle, and
then after filtering through a sintered funnel, the solid was
washed with ether, and dried over calcium hydroxide to give
the desired product substituted 3-acetyl-2H-l-benzopyran-2ones 12a-g.
General Procedure for Bromination of Substituted 3acetyl-2H-l-benzopyran-2-ones (13a-g)
The solid compound 12a-g obtained from the previous
reaction, was dissolved in chloroform and an equimolar
amount of bromine was added dropwise. The reaction was
left for stirring for 15-18 h. The solid formed in the reaction
was then filtered and washed with ice cold water and dried in

a desiccator to give the desired product substituted 3-(2bromoacetyl)-2H-l-benzopyran-2-ones 13a-g.

General Procedure for Preparation of Substituted 3-(2amino-1,3-thiazol-5-yl)-2H-1-benzopyran-2-ones (14a-g)
The bromoacetyl compounds of the substituted benzopyranones synthesised were taken in ethanol and the
equimolar quantity of thiourea was added to it. The resulting
mixture was heated at reflux temperature for about 5-6 hours
and the reaction was monitored by TLC analysis. On consumption of the starting, material the reaction was stopped
and the solution was filtered. The solid obtained was the
desired compound substituted 3-(2-amino-1,3-thiazol-5-yl)2H-l-benzopyran-2-ones 14a-g.
General Procedure for Preparation of Substituted 2-[4(2-oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]-2,3-dihydro-1Hbenzo[d,e]isoquinoline-1,3-dione (16a-g)
Naphthalic anhydride (15) (0.505 mmol) and substituted
3-(2-amino-1,3-thiazol-5-yl)-2H-l-benzopyran-2-ones (14ag) (0.558 mmol) were added to methanol (10 mL). The reaction mixture was heated on water bath at 50-60 oC for about
5 hours. For the completion of reaction, a catalytic amount of
10% aq. NaOH solution was added for the cyclisation of the
formed N-naphthalamic acids. The mixture was left at room
temperature overnight and upon decanting of the filtrate, the
resultant products were formed as crude products, which
were further purified by recrystallisation to give the desired
product (16a-g).

Synthesis of Coumarin linked Naphthalimide Conjugates

General Procedure for Preparation of Substituted 2,7di[4-(2-oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]-1,2,3,6,7,8hexahydrobenzo-[lmn][3,8]phenanthroline-1,3,6,8-tetraone (18a-g)

Naphthalic dianhydride (17) (0.37 mmol) and substituted
3-(2-amino-1,3-thiazol-5-yl)-2H-l-benzopyran-2-ones (14ag) (0.74 mmol) were added to glacial acetic acid (10 mL).
The reaction mixture was heated at reflux temperature for 5
hours. The reaction mixture was then poured on crushed ice
and filtered. The resultant crude products formed were further purified by recrystallisation to give the desired products
(18a-g).
Spectral Data
2-[4-(2-Oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]-2,3-dihydro1H-benzo[d,e]isoquinoline-1,3-dione (16a)
Yield 205 mg, 96%; Pale green solid; mp 212-214 oC; IR
(KBr):
3087, 1793, 1731, 1627, 1478, 1343, 1084, 1001,
783, 711 cm-1 ; 1H NMR (200 MHz, DMSO-d6):
ppm 7.31
(d, J = 6.4 Hz, 4H), 7.72-7.63 (m, 4H), 7.91 (s, 2H), 8.06 (d,
J = 7.4 Hz, 2H,), 8.32-8.41 (m, 2H), 8.50 (d, J = 5.3 Hz, 2H),
8.76 (s, 2H); MS (FAB): m/z 424 (M+); Anal. Calcd for
C24H12N2O4S: C, 67.92; H, 2.85; N, 6.60; Found: C, 67.95;
H, 2.80; N, 6.56%.
2-[4-(6-Chloro-2-oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]2,3-dihydro-1H-benzo[d,e]isoquinoline-1,3-dione (16b)
Yield 219 mg, 95%; Yellow solid; mp 278-280 oC; IR
(KBr):
3088, 1768, 1708, 1462, 1301, 1108, 1046, 728,
630, 538 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm 7.31
(d, J = 7.29 Hz, 1H), 7.72-7.63 (m, 2H), 7.91 (s, 1H), 8.06
(d, J = 7.4 Hz, 2H,), 8.32-8.41 (m, 2H), 8.50 (d, J=5.3 Hz,
2H), 8.76 (s, 1H); 13C NMR (75 MHz, DMSO-d6):
ppm
167.0, 158.3, 151.7, 150.7, 136.7, 135.4, 132.5, 130.9, 128.5,
127.6, 127.2, 125.5, 121.3, 120.7, 115.8, 112.5, 110.6; MS
(FAB): m/z 459 (M+); Anal. Calcd for C24H11ClN2O4S: C,
62.82; H, 2.42; N, 6.10; Found: C, 62.79; H, 2.40; N, 6.08%.
2-[4-(6,8-Dichloro-2-oxo-2H-3-chromenyl)-1,3-thiazol-2yl]-2,3-dihydro-1H-benzo[d,e]isoquinoline-1,3-dione (16c)
Yield 231 mg, 93%; Light yellow solid; mp 252-254 oC;
IR (KBr):
3067, 1766, 1712, 1458, 1402, 1276, 1099,
1054, 732, 624, 542 cm-1 ; 1H NMR (200 MHz, DMSO-d6):

ppm 7.71-7.64 (m, 4H), 7.89 (s, 2H), 8.06 (d, J = 7.4 Hz,
2H,), 8.32-8.41 (m, 2H), 8.50 (d, J=5.3 Hz, 2H), 8.77 (s,
2H); MS (FAB): m/z 493 (M+); Anal. Calcd for
C24H10Cl2N2O4S: C, 58.43; H, 2.04; N, 5.68; Found: C,
58.40; H, 2.10; N, 5.63 %.
2-[4-(6-Bromo-2-oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]2,3-dihydro-1H-benzo[d,e]isoquinoline-1,3-dione (16d)
Yield 231 mg, 91%; Yellow solid; mp 238-240 oC; IR
(KBr):
3074, 1793, 1727, 1338, 1096, 784, 711, 592 cm-1 ;
1
H NMR (200 MHz, DMSO-d6):
ppm 7.34(d, J = 7.3 Hz,
1H), 7.70-7.65 (m, 2H), 7.93 (s, 1H), 8.08 (d, J = 7.4 Hz,
2H), 8.33-8.40 (m, 2H), 8.51 (d, J = 5.3 Hz, 2H), 8.77 (s,
1H); MS (FAB): m/z 503 (M+); Anal. Calcd for
C24H11BrN2O4S: C, 57.27; H, 2.20; N, 5.57; Found: C,
57.20; H, 2.18; N, 5.60%.

Letters in Drug Design & Discovery, 2009, Vol. 6, No. 3

207

2-[4-(6,8-Dibromo-2-oxo-2H-3-chromenyl)-1,3-thiazol-2yl]-2,3-dihydro-1H-benzo[d,e]isoquinoline-1,3-dione (16e)
Yield 273 mg, 93%; Yellow solid; mp >300 oC; IR (KBr):
3056, 1772, 1732, 1368, 1209, 1097, 1104, 962, 638,
458 cm-1 ; 1H NMR (200 MHz, DMSO-d6):
ppm 7.43 (s,
1H), 7.71-7.64 (m, 1H), 7.89 (s, 1H) 8.04 (d, J = 7.5 Hz,
2H), 8.32-8.41 (m, 2H), 8.51 (d, J = 7.2 Hz, 2H), 8.77 (s,
1H); MS (FAB): m/z 582 (M+); Anal. Calcd for
C24H10Br2N2O4S: C, 49.51; H, 1.73; N, 4.81; Found: C,
49.60; H, 1.71; N, 4.80%.
2-[4-(8-Methoxy-2-oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]2,3-dihydro-1H-benzo[d,e]isoquinoline-1,3-dione (16f)
Yield 210 mg, 92%; Yellow solid; mp 202-203 oC; IR
(KBr):
3027, 2985, 1767, 1721, 1656, 1493, 1377, 1207,
1089, 939, 642 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm
3.92 (s, 3H), 7.28 (d, J = 7.6 Hz, 2H), 7.69-7.61 (m, 2H),
7.93 (s, 1H), 8.06 (d, J = 7.4 Hz, 2H), 8.34-8.43 (m, 2H),
8.55 (d, J = 7.3 Hz, 2H), 8.79 (s, 1H); 13C NMR (75 MHz,
DMSO-d6):
ppm 167.0, 158.3, 151.7, 150.7, 143.0, 136.7,
135.4, 132.5, 130.9, 128.5, 127.6, 127.2, 125.5, 121.3, 120.7,
117.7, 109.6, 55.9; MS (FAB): m/z 454 (M+); Anal. Calcd
for C25H14N2O5S: C, 66.07; H, 3.11; N, 6.16; Found: C,
66.03; H, 3.12; N, 6.10%.
2-[4-(3-Oxo-3H-benzo[f]chromenyl)-1,3-thiazol-2-yl]-2,3dihydro-1H-benzo[d,e]isoquinoline-1,3-dione (16g)
Yield 227 mg, 95%; Green solid; mp 262-263 oC; IR (KBr):
3083, 1774, 1726, 1624, 1555, 1209, 1099, 995, 783,
741 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm 7.30-7.32
(m, 2H), 7.72-7.63 (m, 4H), 7.91 (s, 1H), 8.06 (d, J = 7.4 Hz,
2H), 8.32-8.41 (m, 2H), 8.51 (d, J = 6.5 Hz, 2H), 8.76 (s,
1H); MS (FAB): m/z 474 (M+); Anal. Calcd for
C28H14N2O4S: C, 70.88; H, 2.97; N, 5.90; Found: C, 70.60;
H, 2.95; N, 5.88%.
2,7-Di[4-(2-oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]-1,2,3,6,
7,8-hexahydrobenzo[lmn][3,8]phenanthroline-1,3,6,8-tetraone (18a)
Yield 279 mg, 51%; Light green solid; mp 262-263 oC;
IR (KBr):
3087, 1793, 1731, 1627, 1478, 1343, 1084,
1001, 783, 711 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm
7.31 (d, J = 6.3 Hz, 4H), 7.72-7.63 (m, 4H), 7.91 (s, 2H),
8.23 (s, 4H), 8.76 (s, 2H); 13C NMR (75 MHz, DMSO-d6):

ppm 169.0, 168.4, 168.2, 167.7, 141.3, 137.4, 136.6, 135.6,
131.6, 130.75, 130.41, 129.6, 125.4, 124.6, 121.9, 116.25,
115.5, 109.9; MS (FAB): m/z 721 (M+); Anal. Calcd for
C38H16N4O8S2: C, 63.33; H, 2.24; N, 7.77; Found: C, 63.28;
H, 2.20; N, 7.73%.
2,7-Di[5-(6-chloro-2-oxo-2H-3-chromenyl)-1,3-thiazol-2-yl]1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenanthroline-1,3,
6,8-tetraone (18b)
Yield 317 mg, 54%; Yellow solid; mp 220-222 oC; IR
(KBr):
3088, 1768, 1708, 1462, 1301, 1108, 1046, 728,
630, 538 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm 7.31
(d, J = 7.3 Hz, 2H), 7.72-7.63 (m, 4H), 7.91 (s, 2H), 8.21 (s,
4H), 8.76 (s, 2H); MS (FAB): m/z 790 (M+); Anal. Calcd for
C38H14Cl2N4O8S2: C, 57.80; H, 1.79 N, 7.10; Found: C,
57.78; H, 1.80; N, 7.08%.

208 Letters in Drug Design & Discovery, 2009, Vol. 6, No. 3

2,7-Di[5-(6,8-dichloro-2-oxo-2H-3-chromenyl)-1,3-thiazol2-yl]-1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenanthroline-1,3,6,8-tetraone (18c)
Yield 312 mg, 49%; Yellow solid; mp 202-203 oC; IR
(KBr):  3067, 1766, 1712, 1458, 1402, 1276, 1099, 1054,
732, 624, 542 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm
7.71-7.64 (m, 4H), 7.89 (s, 2H), 8.22 (s, 4H), 8.77 (s, 2H);
MS (FAB): m/z 858 (M+); Anal. Calcd for C38H12Cl4N4O8S2:
C, 53.17; H, 1.41; N, 6.53; Found: C, 53.10; H, 1.38; N,
6.55%.
2,7-Di[5-(6-bromo-2-oxo-2H-3-chromenyl)-1,3-thiazol-2yl]-1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenanthroline1,3,6,8-tetraone (18d)
Yield 345mg, 52%; Green solid; mp 252-254 oC; IR (KBr):  3074, 1793, 1727, 1338, 1096, 784, 711, 592 cm-1; 1H
NMR (200 MHz, DMSO-d6):
ppm 7.34 (d, J = 7.3 Hz,
2H), 7.70-7.65 (m, 4H), 7.93 (s, 2H), 8.24 (s, 4H), 8.75 (s,
2H); MS (FAB) m/z 878 (M+); Anal. Calcd for
C38H14Br2N4O8S2: C, 51.95; H, 1.61; N, 6.38; Found: C,
51.96; H, 1.59; N, 6.35%.
2,7-Di[5-(6,8-dibromo-2-oxo-2H-3-chromenyl)-1,3-thiazol2-yl]-1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenanthroline-1,3,6,8-tetraone (18e)
Yield 392mg, 51%; Pale yellow solid; mp 238-240 oC;
IR (KBr):  3056, 1772, 1732, 1368, 1209, 1097, 1104, 962,
638, 458 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm 7.43
(s, 2H), 7.71-7.64 (m, 2H), 7.89 (s, 2H), 8.22 (s, 4H), 8.77 (s,
2H); 13C NMR (75 MHz, DMSO-d6):
ppm 169.0, 168.4,
168.2, 167.7, 141.3, 137.4, 136.6, 135.6, 131.6, 130.75,
130.41, 129.6, 125.4, 124.6, 121.9, 116.25, 115.5, 109.9; MS
(FAB): m/z 1036 (M+); Anal. Calcd for C38H12Br4N4O8S2: C,
44.04; H, 1.17; N, 5.41; Found: C, 44.02; H, 1.18; N, 5.40%.
2,7-Di[5-(8-methoxy-2-oxo-2H-3-chromenyl)-1,3-thiazol-2yl]-1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenanthroline1,3,6,8-tetraone (18f)
Yield 296mg, 54%; Pale green solid; mp 223-225 oC; IR
(KBr):  3027, 2985, 1767, 1721, 1656, 1493, 1377, 1207,
1089, 939, 642 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm
3.92 (s, 6H), 7.28 (d, J = 7. 6 Hz, 4H), 7.69-7.61 (m, 4H),
7.93 (s, 2H), 8.22 (s, 4H), 8.79 (s, 1H); MS (FAB): m/z 781
(M+); Anal. Calcd for C40H20N4O10S2: C, 61.54; H, 2.58; N,
7.18; Found: C, 61.55; H, 2.56; N, 7.16%.
2,7-Di[5-(3-oxo-3H-benzo[f]chromen-2-yl)-1,3-thiazol-2yl]-1,2,3,6,7,8-hexahydrobenzo[lmn][3,8]phenanthroline1,3,6,8-tetraone (18g)
Yield 340mg, 56%; Yellow solid; mp 252-255 oC; IR
(KBr):  3083, 1774, 1726, 1624, 1555, 1209, 1099, 995,
783, 741 cm-1; 1H NMR (200 MHz, DMSO-d6):
ppm 7.307.32 (m, 8H), 7.72-7.63 (m, 8H), 7.91(s, 2H), 8.23 (s, 4H),
8.76 (s, 2H); MS (FAB): m/z 821 (M+); Anal. Calcd for
C46H20N4O8S2: C, 67.31; H, 2.46; N, 6.83; Found: C, 67.29;
H, 2.43; N, 6.84%.

Kamal et al.

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ACKNOWLEDGEMENTS
The authors SFA and JRT are grateful to DST, New
Delhi for the financial assistance.

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