Synthesis of new conjugated coumarin-benzimidazole hybrids and their anticancer activity

DOI: 10.1016/j.bmcl.2012.12.071

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Bioorganic and Medicinal Chemistry Letters p. 3667 - 3672 (2013)

Update date:2022-08-02

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Paul, Kamaldeep

Bindal, Shweta

Luxami, Vijay

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Article abstract of DOI:10.1016/j.bmcl.2012.12.071

A series of novel coumarin-benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2- yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor act

Full text of DOI:10.1016/j.bmcl.2012.12.071

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: w ww.elsevier.com/locate/bmcl

Synthesis of new conjugated coumarin–benzimidazole hybrids

and their anticancer activity

⇑

Kamaldeep Paul , Shweta Bindal, Vijay Luxami

School of Chemistry and Biochemistry, Thapar University, Patiala 147004, India

a r t i c l e i n f o

a b s t r a c t

Article history:

A series of novel coumarin–benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-

2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized

compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel

assay. A signiﬁcant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition)

compared with other compounds and active known drug 5-ﬂuorouracil (in some cell lines) as positive

control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and

breast cancer cell lines.

Received 9 October 2012

Revised 5 December 2012

Accepted 21 December 2012

Available online xxxx

Keywords:

Coumarin

Benzimidazole

Hybrids

Anticancer agents

Molecular docking

Coumarin and its derivatives are important compounds due to

their presence in naturally occurring products and their wide-range

applications in agrochemicals, drugs and pharmaceuticals^1–5such as

anticancer,^6,7anti-HIV,⁸antituberculosis,⁹anti-inﬂuenza,¹⁰anti-

alzheimer,^11,12anti-inﬂammatory,¹³antiviral¹⁴and antimicrobial

agents.¹⁵Coumarin derivatives have also been shown to be novel

lipid lowering agents that possess moderate triglyceride lowering

activity.¹⁶Many coumarin derivatives have unique ability to

scavenge reactive oxygen species such as hydroxyl free radicals,

superoxide radicals, or hypochlorous acid to prevent free radical

injury.¹⁷Certain coumarin derivatives have been shown to func-

tion as HIV integrase inhibitors and evaluated in the treatment of

HIV infection,¹⁸whereas others evaluated as anti-invasive com-

pounds due to their inhibitory activity against some serine prote-

ases and matrix metalloproteases (MMPs).¹⁹6-Nitro-7-hydroxy

coumarin acts as a selective anti-proliferative agent by activating

p38, stress activated protein kinase (SAPK), p21WAF1/CIP1 cyclin

dependent kinase inhibitor and human renal cell carcinoma cell

line, A-498.^20,21Coumarin showed the inhibition of polymerization

of tubulin and arrest cells in mitotic phase by inhibiting microtu-

bule formation.²²The benzimidazole moiety also exist in many

biologically active natural products, synthetic compounds²³and

are well known for clinical values toward tumor cells,^24–26and

antiviral agents.^27–312-Arylbenzimidazole-5-carboxylic acids were

shown to inhibit the HCV NS5B RNA polymerase.^32,33Coumarin–

benzimidazole hybrids showed diverse biological activity with sig-

niﬁcant clinical potential, such as anti-angiogenesis³⁴and

antihepatitis.³⁵

Despite numerous attempts in search for more effective antitu-

mor agents, coumarin still remains as one of the most versatile

class of compound against cancer cell lines and are an important

component among the molecules in drug discovery. Most of hybrid

molecules have been reported where both coumarin and

benzimidazole moieties were attached via spacer³⁵as shown in

Figure 1(A–C). Still, rare examples are known for coumarin–

benzimidazole hybrids as antitumor agents. Here, we reported

the synthesis, evaluation and molecular docking of combinations

of two biological active coumarin and benzimidazole moiety with-

out any linkage or spacer and the corresponding amines at position

7 of coumarin moiety that exhibit better anticancer activity.

The synthetic strategy to obtain the targets 5, 7–14 and 18 are

depicted in Schemes 1 and 2. In order to synthesize compounds of

amino substituted coumarin–benzimidazole hybrids, we began

with the commercially available starting material 5-bromosalicyl-

aldehyde (1) and diethylmalonate (2). 5-Bromosalicylaldehyde (1)

was reﬂuxed with diethylmalonate in the presence of piperidine,

acetic acid and ethanol for 3 h gave 7-bromo-2-oxo-2H-chro-

mene-3-carboxylic acid ethyl ester (3) with 86% yield followed

by hydrolysis with NaOH at room temperature to obtain 7-bro-

mo-2-oxo-2H-chromene-3-carboxylic acid (4) with 63% yield.

Compound 4 was reﬂuxed with o-phenylenediamine in polyphos-

phoric acid (PPA) for 12 h gave two types of products 5 and 6 and

separated through column chromatography in 62% and 20% yields,

respectively. Compound 5 was substituted with different primary

amines at 7-position of coumarin ring in ethanol using triethyl-

⇑

Corresponding author. Tel.: +91 9465670595; fax: +91 175 236 4498.

E-mail address: kpaul@thapar.edu (K. Paul).

http://dx.doi.org/10.1016/j.bmcl.2012.12.071

Please cite this article in press as: Paul, K.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2012.12.071

K. Paul et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx

Spacer

OMe

AcO

OAc

AcO

R³

R²

R¹

Spacer

¹R²RN

7-14, 18

R⁴

Reported molecules

Proposed molecules

Figure 1. Reported and proposed coumarin–benzimidazole hybrids.

COOH

COOEt

NaOH

Piperidine

+ EtO

OEt

Acetic acid

EtOH

H₂N

PPA

COOH

EtOH/Et₃N

HNR¹R²

NH₂

¹R²RN

7-10

HNR¹R²

ACN

K₂CO₃

7; NR¹R²= Ethylenediamine

8; NR¹R²= Ethanolamine

TBAHSO₄

9; NR¹R²= n-Butylamine

10; NR¹R²= Cyclohexylamine

11; NR¹R²= 4-Fluoroaniline

12; NR¹R²= Morpholine

13; NR¹R²= Methylpiperazine

14; NR¹R²= 2-Aminoethylmorpholine

¹R²RN

11-14

Scheme 1. Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-2H-chromen-2-one analogs (7–14).

NH₂

EtOH/Et₃N

H₂N

NH₂

IPA

H₃C

CH₃

H₃C

CH₃

H₃C

CH₃

Scheme 2. Synthesis of 5-dimethylamino-naphthalene-1-sulfonic acid {2-[3-(1H-benzimidazol-2-yl)-2-oxo-2H-chromen-7-ylamino]ethyl}-amide (18).

amine as base to obtain compounds 7–10. Compounds 11–14 were

not synthesized via this methodology and used alternate phase

transfer catalyzed approach to synthesize these compounds

(Scheme 1).

Compound 5 was reﬂuxed with primary and secondary amines

using K₂CO₃as base and TBAHSO₄as catalyst in acetonitrile for 6–

8 h, gave compounds 11–14 with moderate to good yields.

Treatment of 5-dimethylamino-naphthalene-1-sulfonyl chloride

(15) with excess of ethylenediamine (16) in ethanol using triethyl-

amine at reﬂuxing conditions for 7 h gave 5-dimethylamino-naph-

thalene-1-sulfonic acid-(2-amino-ethyl)-amide (17) and used

further without puriﬁcation. Compound 17 was reﬂuxed with

3-(1H-benzimidazol-2-yl)-7-bromo-chromen-2-one (5) in isopro-

pyl alcohol (IPA) for 8 h and after work up gave brown crystals of

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K. Paul et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx

5-dimethylamino-naphthalene-1-sulfonic acid {2-[3-(1H-ben-

zimidazol-2-yl)-2-oxo-2H-chromen-7-ylamino]ethyl}-amide

(Scheme 2). All synthesized compounds were well characterized by

¹H and ¹³C NMR (Supplementary data) as well as mass

spectroscopy.³⁶

tested derivatives its growth inhibition was much better than 5-

ﬂuorouracil (positive control). Regarding the activity towards most

active compounds 8, Leukemia cells HL-60 (TB), CCRF-CEM, K-562,

MOLT-4 and RPMI-8226 proved to be selective sensitive with GI

value of 80.51%, 72.52%, 57.34%, 38.03% and 46.65%, respectively,

breast cancer cells T-47D, MDA-MB-231/ATCC, MDA-MB-468, BT-

549 with GI values 70.68%, 58.91%, 48.37% and 33.10%, respec-

tively, colon cancer cells HCT-15 and HCT-116 with GI values

72.67% and 62.25%, melanoma cancer cell LOX IMVI and prostate

cancer cell PC-3 GI value of 54.29% and 56.69%, respectively. Only

K-562 selective to 13 with GI values of more than 50% inhibition.

Other compounds also show some sensitivity towards various cell

lines. Thus, Table 1 revealed that compound 8 is more active to-

wards numerous cancer cell lines belonging to different tumor

subpanels.

Compounds 5, 7, 8, 12–14 were selected by National Cancer

Institute, Bethesda, Maryland, USA on the basis of degree of the

structure variation and computer modeling techniques for evalua-

tion of their anticancer activity. The selected compounds were sub-

jected to in vitro anticancer assay against tumor cells in a full panel

of 60-cell lines^37–40at single dose concentration of 10

lM, and the

percentages of growth inhibition over sixty tested cell lines were

determined (Table 1).

Preliminary in vitro antitumor screening revealed that com-

pounds 5, 7, 12–14 showed moderate inhibition (20.11–56.30%)

for the most cancer cell lines, while compound 8 exhibited more

than 50% inhibition for most of the cell lines and for some of the

We calculated the compliance of compounds to the Lipinski’s

rule of ﬁve.⁴¹Brieﬂy, this simple rule is based upon the observation

Table 1

Percentages growth inhibition of compounds 5, 7, 8, 12–14 over the full panel of 60 tumor cell lines at 10 lM

Cell line type

Leukemia

Cell line name

5-Fluorouracil

CCRF-CEM

HL-60(TB)

K-562

MOLT-4

RPMI-8226

A549/ATCC

HOP-62

HOP-92

NCI-H226

NCI-H23

NCI-H322M

NCI-H522

HCC-2998

HCT-116

HCT-15

KM12

SW-620

SF-268

—

21.50

—

20.11

—

20.59

—

22.87

—

72.52

80.51

57.34

38.03

46.65

—

24.75

—

29.98

32.85

29.69

23.66

—

62.25

72.67

—

21.38

26.15

24.51

25.85

—

20.74

54.29

29.78

25.43

—

20.70

—

26.47

27.15

56.39

—

35.44

—

41.12

—

25.50

—

23.26

—

22.91

—

57.1

47.9

42.3

43.1

41.4

24.8

34.2

47.8

50.6

69.5

39.0

59.5

58.0

17.8

26.5

40.7

—

59.0

69.0

65.9

50.3

30.4

58.2

95.5

19.5

33.7

39.7

51.2

47.4

59.4

44.3

47.6

77.5

—

–

—

20.58

—

Non-small cell lung cancer

Colon Cancer

CNS cancer

Melanoma

SF-295

SF-539

SNB-75

U251

—

LOX IMVI

MALME-3M

M14

SK-MEL-2

SK-MEL-28

SK-MEL-5

UACC-257

UACC-62

IGROV1

OVCAR-3

OVCAR-4

OVCAR-5

OVCAR-8

NCI/ADR-RES

SK-OV-3

A498

—

35.75

27.96

27.16

24.51

32.83

44.75

—

31.45

23.70

—

25.30

Ovarian cancer

Renal cancer

20.11

—

29.75

—

ACHN

CAKI-1

SN 12C

UO-31

PC-3

DU-145

MCF7

MDA-MB-231/ATCC

HS 578T

BT-549

T-47D

MDA-MB-468

—

22.67

—

23.65

29.96

26.00

25.08

—

20.28

—

33.98

—

24.87

—

62.12

—

34.60

—

26.33

—

34.31

—

39.3

39.4

54.0

41.3

58.2

35.5

11.5

78.1

22.41

41.85

56.69

—

62.12

58.91

—

Prostate cancer

Breast cancer

33.10

70.68

48.37

—

37.8

56.7

28.42

—

23.12

31.72

—GI% less than 20%, nt: not tested, L: lethal.

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K. Paul et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx

that most biological active drugs have a molecular weight (MW) of

500 or less, a logP no higher than 5, ﬁve or fewer hydrogen bond

donor sites and ten or fewer hydrogen bond acceptor sites (N or

O atoms). These results display in Table 2, show that all the synthe-

sized compounds comply with this rule.

Introduction of primary and secondary substituted amines to

coumarin moiety resulted decrease in logP (lipophilic factor) but

increased TPSA (total polar surface area) and molar refractometry

(steric factors) values determined by SciGress program⁴²for each

compound. Within the series of these compounds, compound 8

(most active in this series) has higher TPSA and lower logP and mo-

lar refractometry which showed not lipophilicity but hydrophilic-

ity is the key role for antitumor activity and less steric

interaction (MR = 90.7) favors the higher activity. From Table 2 it

is clear that lipophilicity and molar refractometry of the molecules

are not a crucial factor for the activity and differences in their bio-

activity cannot be attributed to these parameters.

Although the cellular target were not deﬁned in the experimen-

tal anticancer investigations of these molecules, to look into the

possible interactions at the enzymatic level, we carried out the

docking studies⁴³of compound 8 in the active site of topoisomer-

ase II (Topo II, pdb ID 1BJT, enzymes responsible for DNA replica-

tion), ribonucleotide reductase (RNR, pdbID 4R1R) and

dihydrofolate reductase (DHFR) containing NADPH and folate

(pdb ID 3FRD). Docking of compound 8 in the active site of Topo

II showed H-bond interaction between N atom of benzimidazole

moiety with L557 (d = 2.75 Å) amino acid residue of active site, car-

bonyl group and oxygen atom of coumarin moiety with M522

(d = 1.88 Å) and I523 (d = 2.93 Å) amino acid residues respectively,

NH group of ethanolamine with V446 (d = 2.93 Å) and L447

(d = 1.73 Å) and OH group of ethanolamine with NH (d = 2.60 Å)

and CO (d = 2.05 Å) groups of A453 amino acid residues (Fig. 2A).

Similarly compound 8 was also docked with active site of ribo-

nucleotide reductase (another enzyme involved in the propagation

of cancer, synthesis of raw material for replication of DNA). It

showed H-bond interaction between NH group and N atom of

benzimidazole with L1725 (d = 2.66 Å and d = 2.69 Å) and T1944

(d = 2.99 Å) amino acid residues respectively, carbonyl oxygen

and O atom of coumarin with Q1933 (d = 2.71 Å) and N1755

(d = 2.27 Å) amino acid residues respectively and NH group of eth-

anolamine with I523 (d = 2.44 Å) amino acid residue (Fig. 2B).

Molecular docking study was also carried out for compounds 8

with active site of DHFR. Docking of compound 8 in the active

group of benzimidazole moiety (N-atom) with L5 (d = 2.63 Å) ami-

no acid residue, OH group of ethanolamine with H23 amino acid

residues of carbonyl group (d = 2.74 Å) and NH group (d = 2.93 Å)

(Fig. 2C).

Figure 2. Compound 8 docked in active site of (A) Topo II, (B) RNR and (C) DHFR; H-

bonds between compound 8 and different amino acids residues are visible. Carbon

atoms are given in different colour.

Therefore, docking of compound 8 in the active site of these en-

zymes indicated the probable mode of action for anticancer activ-

ities. Remarkable, such correlations between the experimental data

and docking studies are useful for reﬁning the structure of the mol-

ecules and improving their efﬁciencies.

Table 2

TPSA, molar refractometry and calculated Lipinski’s rule of ﬁve for compounds under

biological investigation

In conclusion, the present work led to the development of novel

antitumor molecules 5, 7, 8, 12, 13 and 14. From the preliminary

biological activity of coumarin–benzimidazole hybrids, compound

8 exhibits much better growth inhibition for most of the cell lines.

We found that the introduction ethanolamine at position-7 of cou-

marin–benzimidazole hybrid (8) shows higher selectivity against

leukemia cancer cells (CCRF-CEM, HL-60(TB), K-562, RPMI-8226),

colon cancer cells (HCT-116, HCT-15), melanoma cancer cells

(LOX IMVI, UACC-257) and breast cancer cells (MCF7, T-47D).

Molecular docking also showed H-bonding interaction in the active

site of Topo II, RNR and DHFR that also supports its activity. These

compounds will be useful as templates for the synthesis of more

potent antitumor agents.

Comp No LogP^aMR^b

TPSA^cMW^dnON^enOHNH^fNviolations^g

4.3

2.1

2.7

3.5

3.2

81.9

92.4

90.7

97.7

104.5 65.4

111.5 83.3

58.8

96.9

91.1

71.4

341

320

321

347

360

390

Calculated lipophilicity.

Molar refractometry (Å³).

Total polar surface area (hydrophilicity).

Molecular weight.

No of hydrogen bond acceptor.

No of hydrogen bond donors.

No of violations from Lipinski’s rule of ﬁve.

Please cite this article in press as: Paul, K.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2012.12.071

K. Paul et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx

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36. Experimental: All chemicals and solvents of commercial grade used without

further puriﬁcation and were supplied by loba, spectrochemicals and Aldrich

chemicals. Melting points were determined in capillaries and are uncorrected.

¹H and ¹³C NMR spectra were run on Bruker 400 and 100 MHz NMR

spectrometer respectively, using CDCl₃and DMSO-d₆as solvents. The

chemical shifts were expressed in parts per million with TMS as internal

reference. J Values are given in hertz. Chromatography was performed with

silica gel 60–120 mesh and reactions were monitored by thin layer

chromatography (TLC) with silica plate coated with silica gel HF-254.

Petroleum ether/ethyl acetate and chloroform/methanol were the adopted

solvent system.

We thank to Council of Scientiﬁc and Industrial Research

(02(0034)/11/EMR-II) and Department of Science and Technology,

New Delhi (SR/FT/CS-40/2010) for the research grant. We also

thank Punjab University, Chandigarh for recording NMR and mass

spectra. NCI, USA is gratefully acknowledged for investigating anti-

tumor activities.

Supplementary data

Supplementary data associated with this article can be found, in

the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.

12.071.

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3-(1H-Benzo[d]imidazol-2-yl)-7-bromo-2H-chromen-2-one

(5).

Yellow

powder; yield 62%; mp >250 °C; ¹H NMR (DMSO-d₆, 400 MHz): d 12.52 (br s,

1H, NH), 9.11 (s, 1H, CH), 8.20 (t, 1H, J = 2.32 Hz, ArH), 7.80 (dd, 1H, ²J = 6.44 Hz,

³J = 2.36 Hz, ArH), 7.69 (t, 2H, J = 9.12 Hz, ArH), 7.45 (d, 1H, J = 8.84 Hz, ArH),

7.21 (m, 2H, ArH); ¹³C NMR (DMSO-d₆, 100 MHz): d 158.69, 152.16, 145.18,

142.81, 140.75, 134.95, 134.79, 131.27, 122.78, 122.11, 120.79, 118.47, 118.17,

117.67, 116.73, 112.75; EIMS, m/z: 342 (M⁺+1). 7-(2-Aminophenylamino)-2-

oxo-2H-chromene-3-carboxylic acid (6). Yellow powder; yield 20%; mp

>250 °C; ¹H NMR (DMSO-d₆, 400 MHz): d 10.19 (s, 1H, NH), 9.16 (s, 1H, CH),

8.34 (d, 1H, J = 3.72 Hz, ArH), 7.86 (t, 2H, J = 9.96 Hz, ArH), 7.16 (t, 1H,

J = 3.12 Hz, ArH), 6.98 (t, 1H, J = 1.44 Hz, ArH), 6.85 (dd, 1H, ²J = 3.00 Hz,

³J = 4.12 Hz, ArH), 6.71 (dd, 1H, ²J = 1.60 ³J = 7.36 Hz, Hz, ArH), 4.73 (s, 2H,

NH₂); ¹³C NMR (DMSO-d₆, 100 MHz): d 158.67, 152.05, 146.57, 145.01, 140.50,

134.89, 131.91, 130.99, 122.80, 122.11, 118.41, 117.98, 117.60, 117.21, 116.92,

112.60; EIMS, m/z: 296 (M⁺+1)

General procedure for preparation of 7-(substituted amino)-3-(1H-

benzo[d]imidazol-2-yl)-2H-chromen-2-one (7–10).

benzo[d]imidazol-2-yl)-7-bromo-2H-chromen-2-one

mixture of 3-(1H-

(5) (100 mg,

0.029 mmol), amines (0.058 mmol) (excess in case of ethylenediamine),

triethylamine (2 drops) in ethanol (10 ml) were heated under reﬂux for 6–

8 h. The reaction mixture was cooled and extracted with chloroform and water.

The organic layer was separated, dried over anhydrous sodium sulphate,

ﬁltered and concentrated. The obtained residue was column chromatographed

on silica gel using chloroform/methanol (80:20) as eluents to afford

compounds 7–10. 3-(1H-Benzo[d]imidazol-2-yl)-7-(2-ethylenediamino)-2H-

chromen-2-one (7). Brown crystals; yield 77.41%; mp 138–140 °C; ¹H NMR

(CDCl₃, 400 MHz): d 10.22 (s, 1H, NH), 8.46 (s, 1H, CH), 7.93 (s, 1H, ArH), 7.49 (s,

2H, ArH), 7.39 (m, 2H, ArH), 7.14 (t, 1H, J = 2.24 Hz, ArH), 6.82 (d, 1H,

J = 9.08 Hz, ArH), 3.76 (s, 2H, NH₂), 3.69 (t, 2H, J = 3.28 Hz, CH₂), 3.57 (t, 2H,

J = 5.72 Hz, CH₂); ¹³C NMR (DMSO-d₆, 100 MHz): d 165.46, 159.75, 151.74,

151.64, 142.01, 133.83, 131.99, 131.34, 131.14, 124.42, 121.96, 119.96, 117.04,

116.68, 111.57, 110.23, 108.20, 60.81, 60.33; EIMS, m/z: 322 (M⁺+1). 3-(1H-

Benzo[d]imidazol-2-yl)-7-(2-hydroxyethyl amino)-2H-chromen-2-one (8).

Yellow liquid; yield 79%; ¹H NMR (CDCl₃, 400 MHz): d 11.21 (s, 1H, NH),

9.12 (s, 1H, CH), 8.20 (t, 1H, J = 2.96 Hz, ArH), 7.80 (dd, 1H, ²J = 2.76 Hz,

³J = 9.20 Hz, ArH), 7.67 (t, 2H, J = 9.12 Hz, ArH), 7.45 (d, 1H, J = 12.84 Hz, ArH),

7.23 (d, 2H, J = 3.08 Hz, ArH), 3.74 (t, 2H, J = 6.44 Hz, CH₂), 3.68 (t, 2H,

J = 3.96 Hz, CH₂), 2.76 (s, 1H, OH); ¹³C NMR (CDCl₃, 100 MHz): d 164.81, 160.27,

158.12, 157.38, 147.83, 140.67, 134.13, 133.03, 131.22, 122.91, 121.12, 119.80,

118.61, 108.69, 48.73, 46.48; EIMS, m/z: 321 (M⁺+1). 3-(1H-Benzo[d]imidazol-

2-yl)-7-(butylamino)-2H-chromen-2-one (9). Yellow liquid; yield 50%; ¹H

NMR (CDCl₃, 400 MHz): d 11.22 (s, 1H, NH), 9.11 (s, 1H, CH), 8.19 (t, 1H,

J = 2.32 Hz, ArH), 7.78 (dd, 1H, ²J = 2.36 Hz, ³J = 9.20 Hz, ArH), 7.67 (t, 2H,

J = 5.28 Hz, ArH), 7.43 (d, 1H, J = 12.84 Hz, ArH), 7.21 (m, 2H, ArH), 3.30 (q, 2H,

J = 5.96 Hz, CH₂), 1.58 (m, 2H, CH₂), 1.41 (m, 2H, CH₂), 0.92 (t, 3H, J = 7.28 Hz,

24. (a) Andrzejewska, M.; Y e ´p ez-Mulia, L.; Cedillo-Rivera, R.; Tapia, A.; Vilpo, L.;

Vilpo, J.; Kazimierczuk, Z. Eur. J. Med. Chem. 2002 , 37 , 973; (b) Gumus, F.; Algul,

O.; Eren, G.; Eroglu, H.; Diril, N.; Gur, S.; Ozkul, A. Eur. J. Med. Chem. 2003 , 38 ,

473; (c) Kamal, A.; Ramulu, P.; Srinivas, O.; Ramesh, G.; Kumar, P. P. Bioorg.

Med. Chem. Lett. 2004 , 14 , 4791; (d) Chauhan, P. M. S.; Martins, C. J. A.; Horwell,

D. C. Bioorg. Med. Chem. Lett. 2005 , 13 , 3513.

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Lett. 2000 , 10 , 2193; (b) Demirayak, S.; Mohsen, U. A.; Karaburun, A. C. Eur. J.

Med. Chem. 2002 , 37 , 255.

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Pudova, O. Eur. J. Med. Chem. 2001 , 36 , 507; (b) Handratta, V. D.; Vasaitis, T. S.;

Njar, V. C. O.; Gediya, L. K.; Kataria, R.; Chopra, P., Jr.; Farquhar, R.; Guo, Z.; Qiu,

Y.; Brodie, A. M. H. J. Med. Chem. 2005 , 48 , 2972.

27. (a) Komazin, G.; Ptak, R. G.; Emmer, B. T.; Townsend, L. B.; Drach, J. C.

Nucleosides Nucleotides Nucleic Acids 2003 , 22 , 1725; (b) Bretner, M.; Baier, A.;

Kopanska, K.; Najda, A.; Schoof, A.; Reinholz, M.; Lipniacki, A.; Piasek, A.;

Kulikowsi, T.; Borowski, P. Antiviral Chem. Chemother. 2005 , 16 , 315.

28. Devivar, R. V.; Kawashima, E.; Revankar, G. R.; Breitenbach, J. M.; Kreske, E. D.;

Drach, J. C.; Townsend, L. B. J. Med. Chem. 1994 , 37 , 2942.

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Goulet, S.; McKercher, G.; Poupart, M.-A.; Valois, S.; Kukolj, G. Bioorg. Med.

Chem. Lett. 2004 , 14 , 967.

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31. McKercher, G.; Beaulieu, P. L.; Lamarre, D.; LaPlante, S.; Lefebvre, S.; Pellerin, C.;

Thauvette, L.; Kukolj, G. Nucleic Acids Res. 2004 , 32 , 422.

Please cite this article in press as: Paul, K.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2012.12.071

K. Paul et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx

CH₂); ¹³C NMR (CDCl₃, 100 MHz): d 158.93, 157.79, 152.98, 152.34, 142.76,

sodium sulphate, ﬁltered and concentrated to get orange crystals of 5-

dimethylamino-naphthalene-1-sulfonic acid-(2-amino-ethyl)-amide (17).

Compound 17 (80 mg, 0.27 mmol) was reﬂuxed with 3-(1H-

benzo[d]imidazol-2-yl)-7-bromo-2H-chromen-2-one (5) (90 mg, 0.27 mmol)

in IPA for 8 h. The obtained residue was column chromatographed on silica gel

using chloroform/methanol as eluents to afford compound 18. Dark brown

crystals; yield 60%; mp 170–175 °C; ¹H NMR (CDCl₃, 400 MHz): d 8.89 (s, 1H,

CH), 8.53 (d, 2H, J = 8.40 Hz, ArH), 8.41 (d, 2H, J = 7.40 Hz, ArH), 8.17 (s, 1H,

ArH), 8.04 (d, 1H, J = 7.72 Hz, ArH), 7.98 (d, 1H, J = 8.08 Hz, ArH), 7.86 (d, 1H,

J = 10.36 Hz, ArH), 7.76 (d, 2H, J = 8.40 Hz, ArH), 7.63 (t, 1H, J = 7.72 Hz, ArH),

7.50 (t, 2H, J = 7.88 Hz, ArH), 4.06 (s, 2H, NH), 3.97 (t, 2H, J = 13.64 Hz, CH₂),

2.92 (t, 2H, J = 9.28 Hz, CH₂), 2.83 (s, 6H, N–CH₃); ¹³C NMR (CDCl₃, 100 MHz): d

163.08, 162.62, 162.18, 161.75, 157.35, 155.92, 152.17, 146.86, 142.55, 142.29,

141.42, 139.40, 134.32, 131.96, 131.77, 118.18, 117.27, 117.04, 116.83, 116.70,

114.33, 109.81, 106.53, 52.81, 45.68, 25.59; EIMS, m/z: 554 (M⁺+1).

133.70, 132.57, 131.98, 131.66, 126.03, 120.81, 120.74, 117.52, 117.33, 112.13,

110.38, 108.85, 46.10, 26.02, 26.07, 13.79; EIMS, m/z: 334 (M⁺+1). 3-(1H-

Benzo[d]imidazol-2-yl)-7-(cyclohexylamino)-2H-chromen-2-one (10). Brown

liquid; yield 52%; ¹H NMR (DMSO-d₆, 400 MHz): d 12.20 (br s, 1H, NH), 9.00 (s,

1H, CH), 8.14 (t, 2H, J = 9.96 Hz, CH), 7.46 (s, 2H, ArH), 7.10 m, 3H, ArH), 3.67

(m, 1H, CH), 1.78 (t, 2H, J = 5.08 Hz, CH₂), 1.67 (m, 2H, CH₂), 1.56 (m, 2H, CH₂),

1.31 (m, 4H, CH₂); ¹³C NMR (CDCl₃, 100 MHz): d 157.33, 156.97, 151.74,

151.64, 142.01, 133.83, 131.99, 131.34, 131.14, 124.42, 121.96, 119.96, 117.04,

116.68, 111.57, 110.23, 46.31, 45.33, 25.08, 13.28; EIMS, m/z: 360 (M⁺+1).

General procedure for preparation of 3-(1H-benzo[d]imidazol-2-yl)-7-

(substituted amino)-2H-chromen-2-one (11–14).

benzo[d]imidazol-2-yl)-7-bromo-2H-chromen-2-one

mixture of 3-(1H-

(5) (100 mg,

0.029 mmol), amines (0.058 mmol), potassium carbonate (0.035 mmol) and

catalytic amount of tetrabutylammonium hydrogen sulphate (TBAHSO₄) in

acetonitrile (10 ml) were heated under reﬂux for 6–8 h. After completion of the

reaction (monitored by TLC), the reaction mixture was cooled and extracted

with chloroform and water. The organic layer was separated, dried over

anhydrous sodium sulphate, ﬁltered and concentrated. The obtained residue

was column chromatographed on silica gel using chloroform:methanol as

eluents to afford pure compounds 11–14. (1H-benzo[d]imidazol-2-yl)-7-(4-

ﬂuorophenylamino)-2H-chromen-2-one (11). Brown liquid; yield 74%; ¹H

NMR (CDCl₃, 400 MHz): d 9.06 (s, 1H, CH), 8.53 (d, 1H, J = 7.8 Hz, ArH), 8.06 (s,

1H, ArH), 7.96 (d, 1H, J = 11.08 Hz, ArH), 7.93 (t, 1H, J = 3.00 Hz, ArH), 7.79 (d,

1H, J = 5.44 Hz, ArH), 7.56 (m, 3H, ArH), 7.36 (d, 1H, J = 4.64 Hz, ArH), 7.16 (m,

2H, ArH); ¹³C NMR (CDCl₃, 100 MHz): d 159.04, 155.82, 150.63, 150.44, 150.03,

140.61, 137.08, 134.28, 133.81, 129.73, 129.37, 127.74, 126.73, 126.50, 126.21,

123.66, 121.89, 121.21, 119.01, 118.20, 114.23, 113.72, 111.59; EIMS, m/z: 372

(M⁺+1). 3-(1H-Benzo[d]imidazol-2-yl)-7-morpholino-2H-chromen-2-one (12).

Brown liquid; yield 74%; ¹H NMR (CDCl₃, 400 MHz): d 11.78 (br s, 1H, NH), 9.01

(s, 1H, CH), 7.93 (dd, 1H, ²J = 1.88 Hz, ³J = 7.76 Hz, ArH), 7.67 (m, 3H, ArH), 7.46

(m, 1H, ArH), 7.40 (m, 1H, ArH), 7.21 (dd, 1H, ²J = 3.16 Hz, ³J = 6.08 Hz, ArH),

3.81 (t, 4H, J = 4.88 Hz, CH₂), 3.70 (t, 4H, J = 5.6 Hz, CH₂); ¹³C NMR (CDCl₃,

100 MHz): d 158.84, 148.49, 144.66, 136.78, 130.70, 130.10, 129.11, 128.87,

128.40, 127.80, 126.23, 123.47, 122.38, 120.88, 119.00, 116.38, 115.77, 68.78,

63.04; EIMS, m/z: 348 (M⁺+1).

37. Grever, M. R.; Sehepartz, S. A.; Chabners, B. A. Semin. Oncol. 1992 , 19 , 622.

38. Monks, A.; Schudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose,

C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.;

Mayo, J.; Boyd, M. J. Natl. Cancer Inst. 1991 , 83 , 757.

39. Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995 , 34 , 91.

40. Antitumor methodology: The human tumor cell lines of the cancer screening

panel were grown in RPMI 1640 medium containing 5% fetal bovine serum and

2.0 mM

-glutamine. For a typical screening experiment, cells were inoculated

l at plating densities ranging from 5000

into 96 well microtiter plates in 100

to 40,000 cells/well depending on the doubling time of individual cell lines.

After cell inoculation, the microtiter plates were incubated at 37 °C, 5% CO₂,

95% air and 100% relative humidity for 24 h prior to addition of experimental

drugs. After 24 h, two plates of each cell line were ﬁxed in situ with TCA, to

represent a measurement of the cell population for each cell line at the time of

drug addition (Tz). Experimental drugs were solubilized in dimethyl sulfoxide

at 400-fold the desired ﬁnal maximum test concentration and stored frozen

prior to use. At the time of drug addition, an aliquot of frozen concentrate was

thawed and diluted to twice the desired ﬁnal maximum test concentration

with complete medium containing 50

this drug dilution was added to the appropriate microtiter wells already

containing 100 of medium, resulting in the required ﬁnal drug

lg/ml gentamicin. Aliquot of 100 ll of

3-(1H-Benzo[d]imidazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one

(13). Brown liquid; yield 70%; ¹H NMR (DMSO-d₆, 400 MHz): d 12.49 (br s, 1H,

NH), 9.12 (s, 1H, CH), 7.94 (d, 1H, J = 6.28 Hz, ArH), 7.69 (m, 3H, ArH), 7.48 (m,

2H, ArH), 7.19 (m, 1H, ArH), 3.88 (s, 4H, CH₂), 2.60 (t, 4H, J = 4.28 Hz, CH₂), 2.39

(s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 100 MHz): d 163.76, 162,88, 152.17, 148.19,

131.97, 131.30, 130.22, 129.44, 128.47, 122.84, 122.13, 121.27, 115.80, 115.50,

110.48, 108.14, 52.81, 44.38, 25.59; EIMS, m/z: 361 (M⁺+1).

concentrations. Following drug addition, the plates were incubated for an

additional 48 h at 37 °C, 5% CO₂, 95% air, and 100% relative humidity. For

adherent cells, the assay was terminated by the addition of cold TCA. Cells

were ﬁxed in situ by the gentle addition of 50 ll of cold 50% (w/v) TCA (ﬁnal

concentration, 10% TCA) and incubated for 60 min at 4 °C. The supernatant was

discarded, and the plates were washed ﬁve times with tap water and air dried.

Sulforhodamine B (SRB) solution (100 ll) at 0.4% (w/v) in 1% acetic acid was

3-(1H-Benzo[d]imidazol-2-yl)-7-(2-morpholinoethyl amino)-2H-chromen-2-

one (14). Brown liquid; yield 65%; ¹H NMR (CDCl₃, 400 MHz): d 10.93 (s, 1H,

NH), 8.94 (s, 1H, CH), 8.14 (d, 1H, J = 1.62 Hz, ArH), 7.46 (d, 1H, J = 8.64 Hz,

ArH), 7.31 (m, 5H, ArH), 3.73 (m, 4H, CH₂), 3.61 (s, 4H, CH₂), 2.45 (t, 2H,

J = 4.52 Hz, CH₂), 2.27 (t, 2H, J = 4.36 Hz, CH₂); ¹³C NMR (DMSO-d₆, 100 MHz): d

158.12, 151.87, 141.99, 133.33, 132.30, 132.20, 131.68, 122.91, 120.87, 117.85,

116.51, 112.42, 110.78, 108.55, 54.05, 45.37, 45.02, 42.93; EIMS, m/z: 391

(M⁺+1).

added to each well, and plates were incubated for 10 min at room temperature.

After staining, unbound dye was removed by washing 5 times with 1% acetic

acid and the plates were air dried. Bound stain was subsequently solubilized

with 10 mM trizma base, and the absorbance is read on an automated plate

reader at a wavelength of 515 nm. For suspension cells, the methodology is the

same except that the assay is terminated by ﬁxing settled cells at the bottom of

the wells by gently adding 50 ll of 80% TCA (ﬁnal concentration, 16% TCA).

41. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.

2001 , 46 , 3.

5-Dimethylamino-naphthalene-1-sulfonic acid {2-[3-(1H-benzimidazol-2-yl)-

2-oxo-2H-chromen-7-ylamino]ethyl}-amide

(18).

5-Dimethylamino-

42. SciGress Ultra: Molecular Modeling System 7.7.0.47 (1981, FujitsuKyushu

Systems, Fukuoka-Shi, Japan), http://jp.fujitsu.com/group/kyushu/en.

43. Compounds were constructed and docked with builder toolkit of the software

package ArgusLab 4.0.1 (www.arguslab.com).

naphthalene-1-sulfonyl chloride (15) (100 mg, 0.37 mmol) in EtOH (10 ml)

was reﬂuxed with ethylenediamine (0.23 g, 3.7 mmol) using triethylamine (2

drops) as base for 7 h. After completion of reaction (monitored by TLC), the

reaction mixture was cooled, extracted with chloroform, dried over anhydrous

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