Synthesis and primary cytotoxicity evaluation of new 5-benzylidene-2,4- thiazolidinedione derivatives

DOI: 10.1016/j.ejmech.2010.07.014

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European Journal of Medicinal Chemistry p. 4539 - 4544 (2010)

Update date:2022-07-29

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Authors:

Patil, Vijay

Tilekar, Kalpana

Mehendale-Munj, Sonali

Mohan, Rhea

Ramaa Ramaa

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Article abstract of DOI:10.1016/j.ejmech.2010.07.014

In the present work, ten novel derivatives (3a-3j) of 5-benzylidene-2,4- thiazolidinediones were synthesized and their structures were determined by analytical and spectral (FTIR, ¹H NMR, ¹³C NMR) methods. The newly synthesized compounds were evaluated for their antiproliferative activity at Tata Memorial's Advanced Center for Treatment, Research and Education in Cancer (ACTREC), India, in a panel of 7 cancer cell lines using four concentrations at 10-fold dilutions. Sulforhodamine B (SRB) protein assay was used to estimate cell stability or growth. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most marked effect was observed by compound 3e in MCF7 (breast cancer), K562 (leukemia) and GURAV (nasopharyngeal cancer) cell lines with log₁₀ GI₅₀ values of -6.7, -6.72 and -6.73 respectively.

Full text of DOI:10.1016/j.ejmech.2010.07.014

European Journal of Medicinal Chemistry 45 (2010) 4539e4544

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European Journal of Medicinal Chemistry

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Original article

Synthesis and primary cytotoxicity evaluation of new 5-benzylidene-2,

4-thiazolidinedione derivatives

Vijay Patil, Kalpana Tilekar, Sonali Mehendale-Munj, Rhea Mohan, C.S. Ramaa

Bharati Vidyapeeth’s College of Pharmacy, Department of Pharmaceutical Chemistry, Sector 8, C. B. D. Belapur, Navi Mumbai 400614, Maharashtra, India

a r t i c l e i n f o

a b s t r a c t

Article history:

In the present work, ten novel derivatives (3ae3j) of 5-benzylidene-2,4-thiazolidinediones were

synthesized and their structures were determined by analytical and spectral (FTIR, ¹H NMR, ¹³C NMR)

methods. The newly synthesized compounds were evaluated for their antiproliferative activity at Tata

Memorial’s Advanced Center for Treatment, Research and Education in Cancer (ACTREC), India, in a panel

of 7 cancer cell lines using four concentrations at 10-fold dilutions. Sulforhodamine B (SRB) protein assay

was used to estimate cell stability or growth. Though the compounds showed varying degrees of cyto-

toxicity in the tested cell lines, most marked effect was observed by compound 3e in MCF7 (breast

cancer), K562 (leukemia) and GURAV (nasopharyngeal cancer) cell lines with log₁₀GI₅₀values of ꢀ6.7,

ꢀ6.72 and ꢀ6.73 respectively.

Received 18 March 2010

Received in revised form

5 June 2010

Accepted 5 July 2010

Available online 11 July 2010

Keywords:

5-benzylidene-2,4-thiazolidinediones

Knoevenagel condensation

Cytotoxicity

Sulforhodamine B assay

1. Introduction

respectively in suppressing cell proliferation in cancer cells. This

prompted us to develop TZD analogs with a double bond adjacent

Thiazolidinediones (TZDs) are a class of insulin sensitizing drugs

which include ciglitazone, pioglitazone, troglitazone and rosiglita-

zone, although troglitazone was removed from the market in 2000

due to hepatotoxicity. Apart from their known antidiabetic activity,

the ability of TZDs to contribute to cancer therapy has been evi-

denced by numerous in vitro and in vivo studies [1e9]. While TZDs

to the TZD ring. A carbonyl carbon in the form of amide linkage has

been introduced in the linker chain between the lipophilic tail and

central aryl portion for a better metabolic proﬁle. We have reported

the synthesis and antidiabetic activity of the compound (3g) in an

earlier work but its anticancer activity has not been described [16].

are known to stimulate PPAR-

receptor, they also have multiple

acti-

2. Chemistry

PPAR- independent effects and the speciﬁc role of PPAR-

vation in the anticancer effects of TZDs is still under investigation.

It has been reported that there exists a 3 orders-of-magnitude

discrepancy between the concentration required to mediate anti-

The synthetic route of the compounds is outlined in Scheme 1.

A series of 5-benzylidene-2,4-thiazolidinediones (3ae3j) were

synthesized in three steps. 5-(4-hydroxybenzylidene)-2,4-thiazo-

lidinedione (1) was prepared by Knoevenagel condensation reac-

tion between 4-hydroxy benzaldehyde and 2,4-TZD. This

intermediate was common to all molecules being synthesized.

Further, this moiety was condensed with various chloroacetylated

heteroaromatic amines or heterocyclic nitrogen containing

compounds. The chloroacetylated moieties (2ae2j) were prepared

by acetylation of respective amines or imides with chloroacetyl

chloride under basic conditions. The structures of all synthesized

compounds were determined by CHN elemental analysis and

spectral data (FTIR, ¹H NMR and ¹³C NMR).

tumor effects and that for PPAR-g activation [10]. Thus, the dose

required for anticancer activity of thiazolidinediones would be

signiﬁcantly lower than that required to bring about hypoglycemic

activity. We report herein the synthesis and anticancer activity of

a novel series of benzylidene thiazolidinedione analogs of general

formula (Fig. 1). The TZD ring has been used as scaffold to develop

this novel class of anticancer agents, encouraged by the literature

report that toxicity of troglitazone is not due to the TZD ring

[11e13]. C. C. Yang et al. [14] and J.W. Huang et al. [15] have reported

D2TG and D2CG, the benzylidene analogs of troglitazone and

In the ¹H NMR spectra, the presence of characteristic singlet at

ciglitazone to be more potent than their parent compounds

7.67 ppm for benzylidene proton provided evidence for forma-

tion of (1). Formation of the chloroacetylated moieties (2ae2j)

was characterized by a peculiar singlet for eCH₂protons reso-

nating at 4.0e4.8 ppm. In the IR spectra of 3ae3j the COeNHeCO

* Corresponding author. Tel.: þ91 022 27572131/1122; fax: þ91 022 27574515.

E-mail address: sinha_ramaa@hotmail.com (C.S. Ramaa).

doi:10.1016/j.ejmech.2010.07.014

4540

V. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 4539e4544

vitro on the 7-cell line panel consisting of HOP62 (Lung cancer), PC3

(Prostate cancer), MCF7 (Breast cancer), HEPG2 (Hepatoma), K562

(Leukemia), GURAV (Oral cancer), and KB (Nasopharyngeal cancer).

Primary anticancer assay was performed in accordance with the US

NCI protocol [18e20].

Y=R NH for 3b, 3c, 3e, 3f, 3g, 3i and 3j

Y= R for 3a, 3d and 3h

The cytotoxic effects of synthesized compounds were tested in

vitro against the panel of cell lines at 10-fold dilutions of four

concentrations ranging from 10^ꢀ4to 10^ꢀ7M. The percentage

growth was evaluated spectrophotometrically versus negative

control not treated with test agents and positive control, treated

with doxorubicin, a proven anticancer agent. A 48 h continuous

drug exposure protocol was followed and an SRB protein assay was

used to estimate cell viability or growth. For the compounds, the

50% growth inhibition (GI₅₀) and total growth inhibition (TGI) were

obtained for each cell line. The log₁₀GI₅₀and log₁₀TGI were then

determined, deﬁned as the mean of the log₁₀’s of the individual GI₅₀

and TGI values. Negative values indicated the most sensitive cell

lines. Compounds having log₁₀GI₅₀value ꢀ4.0 and <ꢀ4.0 were

declared to be active (Table 1).

Amongst the compounds tested, compound 3e showed most

promising results in the preliminary antiproliferative activity

testing. It showed potent cytotoxicity against ﬁve of the seven

tested cell lines, viz., MCF 7 (log₁₀GI₅₀ꢀ 6.71), PC3 (log₁₀GI₅₀

ꢀ 5.60), KB (log₁₀GI₅₀ꢀ 5.65), GURAV (log₁₀GI₅₀ꢀ 6.74) and K562

(log₁₀GI₅₀ꢀ 6.73).

Fig. 1. General formula.

and C]O bands were observed in the region 3460e3446 cm^ꢀ1

and 1735e1670 cm^ꢀ1respectively. In the ¹H NMR spectra, pres-

ence of resonance assigned to the eCH₂protons provides

evidence for formation of eCH₂eOe linkage in ﬁnal thiazolidi-

nedione analogs (3ae3j). These protons resonated in 4.4e5.0 ppm

region as singlet. Momose et al have calculated the value of

methine proton in to ¹H NMR be at

d 7.90 in the Z-conﬁgurations

in good accordance with the observations. Thus the conﬁguration

was determined to be Z [17]. Additional spectral characteristics

are presented in Section 4.

3. Anticancer evaluation and discussion

After successful synthesis of the derivatives of 5-benzylidene-

2,4-thiazolidinediones, their anticancer activity was evaluated in

Step 1: Synthesis of 1 (Knoevenagel condensation)

Piperidinebenzoate

CHO

Toluene

4-Hydroxybenzaldehyde

Reflux

[1]

Thiazolidine-2,4-dione

5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione

Step 2: Synthesis of 2a-2j (chloroacetylation)

NH₂

Chloroacetyl chloride

2a-2j

Step 3: Synthesis of 3a-3j (Condensation of 2a-2j and 1)

2a-2j

[1]

DMF

K₂CO₃

3a-3j

Scheme 1. General synthetic route for synthesis of 3ae3j.

V. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 4539e4544

Table 1 (continued)

4541

Table 1

In vitro anticancer activity in 7 human tumor cell lines for 3ae3j.

Compound

Disease

Cancer cell

line

Log₁₀GI₅₀

ꢀ5.59

Log₁₀TGI

Compound

Disease

Cancer cell

line

Log₁₀GI₅₀

Log₁₀TGI

(mM)

(

Doxorubicin

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

K562

MCF7

HEPG2

HOP62

PC3

>ꢀ4.0

ꢀ5.68

ꢀ6.87

ꢀ4.45

ꢀ5.68

ꢀ6.80

ꢀ6.85

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

Nasopharyngeal cancer

Leukemia

Breast cancer

Hepatoma

NSC lung cancer

Prostate cancer

Oral cancer

K562

MCF7

HEPG2

HOP62

PC3

>ꢀ4.0

ꢀ4.53

>ꢀ4.0

ꢀ6.72

ꢀ4.53

>ꢀ4.0

ꢀ6.73

>ꢀ4.0

ꢀ5.65

>ꢀ4.0

ꢀ4.51

ꢀ5.65

ꢀ6.71

>ꢀ4.0

ꢀ4.55

>ꢀ4.0

ꢀ4.53

>ꢀ4.0

ꢀ6.72

ꢀ6.71

>ꢀ4.0

ꢀ5.60

ꢀ6.73

ꢀ5.65

>ꢀ4.0

ꢀ4.60

>ꢀ4.0

ꢀ6.77

ꢀ4.55

>ꢀ4.0

ꢀ5.57

ꢀ4.43

>ꢀ4.0

ꢀ4.50

>ꢀ4.0

ꢀ4.53

>ꢀ4.0

ꢀ5.64

ꢀ4.53

>ꢀ4.0

ꢀ5.56

ꢀ4.40

>ꢀ4.0

ꢀ4.41

>ꢀ4.0

ꢀ4.54

>ꢀ4.0

ꢀ4.43

ꢀ4.49

>ꢀ4.0

ꢀ4.52

>ꢀ4.0

ꢀ4.52

>ꢀ4.0

ꢀ4.54

>ꢀ4.0

ꢀ6.88

<ꢀ7.0

ꢀ6.97

ꢀ6.96

ꢀ6.97

<ꢀ7.0

GURAV

Nasopharyngeal cancer

K562

MCF7

HEPG2

HOP62

PC3

Compounds 3a, 3b and 3f were highly active in the in vitro screen

on NSC lung cancer cell line (HOP62). The log₁₀GI₅₀values of these

compounds were ꢀ6.72, ꢀ6.73 and ꢀ6.77 respectively. In addition 3d

(log₁₀GI₅₀value ꢀ4.55) and 3i (log₁₀GI₅₀value ꢀ5.64) have also

demonstrated marked effects on NSC lung cancer cell line (HOP62).

Compounds 3a (log₁₀GI₅₀value ꢀ4.53), 3d (log₁₀GI₅₀ꢀ5.65), 3e

(log₁₀GI₅₀ꢀ 5.60), 3f (log₁₀GI₅₀value ꢀ4.55) and 3i (log₁₀GI₅₀value

ꢀ 4.53) exhibited favorable activity on prostate cancer cell line PC3.

In breast cancer cell line MCF7 3a, 3d, 3e, 3f, 3h, 3i and 3j were

found to be active with log₁₀GI₅₀value ꢀ4.53, ꢀ4.55, ꢀ6.71, ꢀ4.60,

ꢀ4.43, ꢀ4.53 and ꢀ4.40 respectively.

GURAV

K562

MCF7

HEPG2

HOP62

PC3

GURAV

K562

MCF7

HEPG2

HOP62

PC3

Compounds 3c (log₁₀GI₅₀ꢀ5.65), 3e (log₁₀GI₅₀ꢀ6.73), 3h (log₁₀

GI₅₀ꢀ5.57) and 3j (log₁₀GI₅₀ꢀ5.56) yielded good antiproliferative

activity against K562 leukemia cell line. Compound 3e was found

be ten times more potent than positive control, doxorubicin

(log₁₀GI₅₀ꢀ5.59). Compounds 3c, 3h and 3j showed similar cyto-

toxicity to that of doxorubicin.

In GURAV oral cancer cell line, compounds 3c (log₁₀GI₅₀ꢀ6.71)

and 3e (log₁₀GI₅₀ꢀ6.73) showed activity comparable to that of

doxorubicin. In addition compounds 3h (log₁₀GI₅₀ꢀ4.50) and 3j

(log₁₀GI₅₀ꢀ4.41) exhibited favorable antiproliferative activity in

oral cancer.

None of the compounds showed cytotoxicity in HEPG2 liver

cancer cell line. This may be attributed to the easily metabolisable

amide linkage in the compounds which cleave in the presence of

amidases in liver, thus rendering them inactive. In conclusion, these

preliminary results are promising and some of these compounds

may be potential candidates for new anticancer agents.

GURAV

K562

MCF7

HEPG2

HOP62

PC3

GURAV

K562

MCF7

HEPG2

HOP62

PC3

GURAV

K562

MCF7

HEPG2

HOP62

PC3

4. Experimental

GURAV

4.1. Chemistry

K562

MCF7

HEPG2

HOP62

PC3

Melting points were determined with a Veego melting point

apparatus in open capillaries and are uncorrected. IR spectra were

recorded as KBr discs, using Shimadzu 8400S FTIR spectropho-

tometer. ¹H NMR (300 MHz) and ¹³C NMR (75 Mhz) spectra were

recorded on Varian Mercury Plus spectrometer, with DMSO-d₆as

a solvent and TMS as an internal standard. The elemental analysis

(C, H, and N) was performed using the Thermo ﬁnnigan FLASH EA

1112 analyzer and were within ꢁ0.4% of theoretical values. All

reactions as well as column chromatography were followed by TLC

using Merk pre-coated silica gel 60 F₂₅₄plates and spots were

visualized by observing in UV cabinet under short UV. All reagents

were used as received unless otherwise stated.

GURAV

K562

MCF7

HEPG2

HOP62

PC3

GURAV

K562

MCF7

HEPG2

HOP62

PC3

4.1.1. Procedure for synthesis of 5-(4-hydroxybenzylidene)-2,4-

thiazolidinedione (1)

GURAV

A mixture of p-hydroxy benzaldehyde (40 mmol) and 2,4-TZD

(40 mmol) with catalytic quantity of piperidinium benzoate was

reﬂuxed in toluene with continuous removal of water using Dean-

Stark apparatus for 4 h. The reaction mixture was cooled to 25 ^ꢂC

and solid separated was collected by ﬁltration.

Nasopharyngeal cancer

4542

V. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 4539e4544

Yield 93%, shiny dark yellow crystalline, mp 302e304 ^ꢂC (Lit.

mp-301e303 ^ꢂC) [21,22]. IR [KBr v cm^ꢀ1] 3404 (NeH), 1683 (C]O),

1718 (C]O). ¹H NMR [300 MHz,

, ppm, DMSO-d₆]: 7.67 (s 1H), 7.44

1770 (C]O), 1650 (C]N). This product was directly taken to next

step without recording ¹H NMR.

(d, J ¼ 8.4 Hz, 2H), 6.90 (d, J ¼ 8.4 Hz, 2H).

4.1.2.10. 2-Chloro-N-(5-methylisoxazol-3-yl) acetamide (2j). Solvent

used for recrystallization: Ethanol: Yield 67%, white needles, mp

190e191 ^ꢂC. IR [KBr v cm^ꢀ1]: 3222 (NeH), 1708 (C]O), 1573 (C]N),

4.1.2. General procedure for synthesis of 2ae2j

To heteroaromatic amine or heterocyclic nitrogen containing

compound (1.0 mol) was added 1.5 mol of chloroacetyl chloride

1190 (CeO). ¹H NMR [300 MHz,

d, ppm, DMSO-d₆]: 10.45 (s 1H),

6.61 (s 1H), 4.03 (s 2H), 2.36e2e37 (m 3H).

under cold conditions along with

a base in chloroform or

dichloromethane. Reaction was stirred overnight at room temper-

ature. Water was added to reaction mixture and organic layer was

separated. This was then passed through anhydrous Na₂SO₄.

Organic layer was distilled to get crude product (2ae2j). The

product was further puriﬁed by recrystallization by using a suitable

solvent.

4.1.3. General procedure for synthesis of 3ae3j

5-(4-hydroxybenzylidene)-2,4-thiazolidenedione (1) (1.0 mol)

along with 1.5 mol of potassium carbonate was taken in dimethyl

formamide (DMF) and added to this solution of chloroacetylated

product (2ae2h) (1.5 mol) in DMF. Reaction mixture was stirred at

room temperature till the completion of reaction and monitored by

TLC. After completion of reaction water was added to precipitate

product (3ae3j). If precipitate was not formed the product was

extracted in organic layer. All products were puriﬁed by column

chromatography (Table 2).

4.1.2.1. 2-Chloro-1-(10H-phenothiazin-10-yl) ethanone (2a). Yield

48.1%, white needles, mp 112e114 ^ꢂC. IR [KBr v cm^ꢀ1]: 1693(C]O),

1126,1168(CeN). ¹H NMR [300 MHz,

d, ppm, DMSO-d₆]: 7.68e7.70

(d, J ¼ 7.2 Hz, 2H), 7.57e7.60 (d, J ¼ 7.8 Hz, 2H), 7.34e7.45 (m 4H),

4.5 (s 2H).

4.1.3.1. 5-[4-Oxo-2-(10H-phenothiazin-10-yl) benzylidene] thiazoli-

dine-2,4-dione (3a). Eluent used for column chromatography: Chlo-

roform: Yield 59.8%, pale yellow powder, mp 219e220 ^ꢂC. IR [KBr v

cm^ꢀ1]: 3199 (NeH), 1735 (C]O), 1681 (C]O), 1147 (CeO). ¹H NMR

4.1.2.2. 2-Chloro-N-(1,5-dimethyl-3oxo-2-phenyl-2,3-dihydro-1H-pyr-

azol-4-yl) acetamide (2b). Yield 50.14%, white powder, mp

193e194 ^ꢂC. IR [KBr v cm^ꢀ1]: 3188 (NeH),1639,1687 (C]O). ¹H NMR

(300 MHz,

d, ppm, DMSO-d₆): 12.51 (bs 1H, eNH), 7.32e7.80

[300 MHz,

, ppm, DMSO-d₆]: 9.56 (s 1H), 7.48e7.55 (m 2H),

(m 11H, aromatic protons and benzylidene proton), 6.9

7.31e7.38 (m 3H), 4.60 (s 2H), 3.1(s 3H), 2.15 (s 3H).

(d, J ¼ 9.0 Hz, 2H, aromatic protons), 5.01 (s 2H, eCH₂e). ¹³C NMR

4.1.2.3. 2-Chloro-N-(5-methylthiazol-2-yl) acetamide (2c). Solvent

used for recrystallization: Chloroform: Yield 82%, white needle, mp

191e192 ^ꢂC. IR [KBr v cm^ꢀ1]: 3186 (NeH), 1704 (C]O), 1560 (C]N).

Table 2

R groups for 3ae3j.

¹H NMR [300 MHz,

(s 2H), 2.43 (s 3H).

d, ppm, DMSO-d₆]: 11.0 (bs 1H), 7.15 (s 1H), 4.24

Compound

4.1.2.4. 3-(2-Chloroacetyl)-2-propyl-1,3-diazaspiro[4,4] non-1-en-4-

one (2d). Solvent used for recrystallization: Benzene: Yield 42.24%,

white needles, mp 120e121 ^ꢂC. IR [KBr v cm^ꢀ1]: 1745, 1639 (C]O),

1539 (C]N). ¹H NMR [300 MHz,

, ppm, DMSO-d₆]: 4.60 (s 2H),

2.18e2.37 (m 4H), 1.73e1.93 (m 7H), 1.25e1.36 (m 3H), 0.9 (t 3H).

H₃C

CH₃

4.1.2.5. 2-Chloro-N-[3-(triﬂuoromethyl)

phenyl]

acetamide

(2e). Yield 67.0%, white crystalline, mp 129e130 ^ꢂC. IR [KBr v

O N

cm^ꢀ1]: 3305 (NeH), 1683 (C]O), 1070,1124 (CeF). ¹H NMR

[300 MHz, d, ppm, DMSO-d₆]: 10.05 (s 1H), 8.2 (s 1H), 7.95 (d 1H),

7.30e7.44 (m 2H), 4.38 (s 2H).

4.1.2.6. N-(Benzo[d]thiazol-2-yl)-2-chloroacetamide

(2f). Solvent

used for recrystallization: Chloroform: Yield 74%, white crystals, mp

143e144 ^ꢂC. IR [KBr v cm^ꢀ1]: 3181 (NeH), 1660 (C]O). ¹H NMR

H₃C

[300 MHz,

, ppm, DMSO-d₆]: 12.79 (s 1H), 8.01 (d, J ¼ 6.0 Hz, 1H),

7.77 (d, J ¼ 8.1 Hz, 1H), 7.46 (t 1H), 7.35 (t 1H), 4.22 (s 2H).

4.1.2.7. 2-Chloro-N-(5-nitrothiazol-2yl)acetamide (2g). Yield 82%,

yellow crystals, mp 146e147 ^ꢂC. IR [KBr v cm^ꢀ1]: 1687 (C]O), 1350

CH₃

(CeN). ¹H NMR [300 MHz,

d, ppm, DMSO-d₆]: 10.07 (bs 1H), 8.36 (s

1H), 4.14 (s 2H).

4.1.2.8. 2-Chloro-N-(1,1-dioxo-1,2-benzothiazole-3-one-2-yl)-acetamide

(2h). Solvent used for recrystallization: Acetonitrile: Ethanol (1:1).

Yield 42%, white needles, mp 145e146 ^ꢂC. IR [KBr v cm^ꢀ1]: 1747

(C]O), 1315, 1363 (O]S]O). ¹H NMR [300 MHz,

d₆]: 8.19 (m 1H), 7.8e8.07 (m 3H), 4.8(s 2H).

d, ppm, DMSO-

F₃C

H₃C

4.1.2.9. 2-Chloro-N-(pyridine-2-yl) acetamide (2i). Yield 69%,

brown sticky mass, mp 178e180 ^ꢂC. IR [KBr v cm^ꢀ1]: 3141(NeH),

V. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 4539e4544

4543

(75 MHz, DMSO-d₆,

): 167.4 (C]O), 166.9 (C]O), 165.1, 164.4

chromatography: Chloroform: Ethanol (10:0.3). Yield 51%, yellow

powder, mp 280e281 ^ꢂC. IR [KBr v cm^ꢀ1]: 3419(NeH), 1731 (C]O),

(C]O), 160.3, 159.3, 137.4, 137.2, 134.1, 132.7, 132.1, 131.8, 131.6,

128.2, 127.6, 127.1, 126.9, 126.0, 123.7, 120.7, 116.5, 116.1, 115.3, 65.7.

Calc. for C₂₄H₁₆N₂O₄S₂, %: C, 62.59; H, 3.50; N, 6.08. Found, %: C,

62.28; H, 3.56; N, 5.71.

1674 (C]O), 1172,1089 (CeO). ¹H NMR (300 MHz,

d, ppm, DMSO-

d₆): 12.8 (s 1H, eCOeNHeCOe), 10.4 (s 1H, eNHe), 7.94

(d, J ¼ 7.8 Hz, 1H, aromatic proton), 7.9 (s 1H, benzylidene proton),

7.77 (d, J ¼ 7.5 Hz, 1H, aromatic proton), 7.56 (d, J ¼ 8.4 Hz, 2H,

aromatic protons), 7.42e7.48 (m 1H, aromatic proton), 7.30e7.35

(m 1H, aromatic proton), 6.95 (d 2H, aromatic protons), 4.68 (s 2H,

4.1.3.2. N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-

yl)-2-[4-[(2,4-dioxo thiazolidin-5-ylidene) methyl] phenoxy] acet-

amide (3b). Eluent used for column chromatography: Hexane: Ethyl

acetate (3:2). Yield 44.5%, pale yellow powder, mp 224e225 ^ꢂC. IR

[KBr v cm^ꢀ1]: 3261 (NeH), 1735 (C]O), 1679 (C]O), 1149, 1095

eCH₂e). ¹³C NMR (75 MHz, DMSO-d₆,

d): 172.1, 167.3 (C]O), 165.7

(C]O), 165.4 (C]O), 160.4, 157.5, 148.5, 132.8, 131.5, 126.3, 126.1,

123.8, 123.6, 121.8, 121.7, 120.6, 116.5, 116.2, 61.2. Calc. for

C₁₉H₁₃N₃O₄S₂, %: C, 55.46; H, 3.18; N, 10.21. Found, %: C, 55.81; H,

3.42; N, 9.90.

(CeO). ¹H NMR (300 MHz,

d, ppm, DMSO-d₆): 10.4 (s 1H,

eCOeNHeCOe), 9.6 (s 1H, NH), 7.9 (s 1H, benzylidene proton), 7.5

(m 4H, aromatic protons), 7.35 (m 3H, aromatic protons), 6.95

(d, J ¼ 8.7 Hz, 2H, aromatic protons), 4.45 (s 2H, eCH₂e), 3.04 (s 3H,

4.1.3.7. 2-[4-[(2,4-Dioxothiazolidin-5-ylidene) methyl] phenoxy]-N-

(5-nitrothiazol-2-yl) acetamide (3g). Solvent used for recrystalliza-

tion: Ethanol: Yield 50%, yellow shiny powder, mp 254e256 ^ꢂC. IR

[KBr v cm^ꢀ1]: 1716 (C]O), 1664 (C]O), 1348 (CeN), 1286, 1176

CH₃eN <), 2.1 (s 3H, eCH₃). ¹³C NMR (75 MHz, DMSO-d₆,

d): 167.3

(C]O), 165.5 (C]O), 164.8 (C]O), 161.5 (C]O), 160.3, 152.1, 134.9,

133.9, 132.7, 129.1, 126.4, 123.8, 123.7, 116.5, 106.6, 66.8, 35.9, 11.2.

Calc. for C₂₃H₂₀N₄O₅S, %: C, 59.47; H, 4.34; N, 12.06. Found, %: C,

59.37; H, 4.52; N, 12.64.

(CeO). ¹H NMR (300 MHz,

d, ppm, DMSO-d₆): 13.59 (bs 1H,

eCOeNHeCOe), 10.44 (s 1H, eNHe), 8.78 (s 1H, tiazolyl proton),

7.9 (s 1H, benzylidene proton), 7.53 (d, J ¼ 8.4 Hz, 2H, aromatic

protons), 6.95 (d, J ¼ 8.7 Hz, 2H, aromatic protons), 4.7 (s 2H,

4.1.3.3. 2-[4-[(2,4-Dioxothiazolidin-5-ylidene) methyl] phenoxy]-N-

(5-methylthiazol-2-yl) acetamide (3c). Eluent used for column chro-

matography: Benzene: Methanol (10:0.25). Yield 48.0%, pale yellow

powder, mp 233e235 ^ꢂC. IR [KBr v cm^ꢀ1]: 3321 (NeH), 1790 (C]O),

eCH₂e). ¹³C NMR (75 MHz, DMSO-d₆,

d): 172.8 (C]O),167.4 (C]O),

165.7 (C]O), 160.2, 145.8, 136.7, 133.7, 132.7, 127.4, 123.9, 116.8,

116.5, 64.2.Calc. for C₁₅H₁₀N₄O₆S₂, %: C, 44.33; H, 2.48; N, 13.79.

Found, %: C, 43.95; H, 2.42; N, 13.48.

1635 (C]O), 1589 (C]N), 1153,1045 (CeO). ¹H NMR (300 MHz,

ppm, DMSO-d₆): 12.4 (bs 1H, eNH), 10.40 (s 1H, eCOeNHeCOe),

7.9 (s 1H, benzylidene proton), 7.52 (d, J ¼ 9.0 Hz, 2H, aromatic

protons), 7.16 (s 1H, thiazolyl proton), 6.94 (d, J ¼ 8.4 Hz, 2H,

aromatic protons), 4.88 (s 2H, eCH₂e), 2.4 (s 3H, eCH₃). ¹³C NMR

4.1.3.8. 2-[2-[4-[(2,4-Dioxothiazolidin-5-ylidene) methyl] phenoxy]

acetyl]-1,2-benzothiazol-3(2H)-one-1,1-dioxide (3h). Eluent used for

column chromatography: Hexane: Ethyl acetate (2:1).Yield 40%, pale

yellow powder, mp 246e248 ^ꢂC. IR [KBr v cm^ꢀ1]: 1695, 1743 (C]O),

(75 MHz, DMSO-d₆, d): 169.2 (C]O), 167.4 (C]O), 166.8 (C]O),

165.7, 160.3, 157.7, 140.1, 134.2, 132.8, 123.8, 120.0, 116.5, 65.7, 11.1.

Calc. for C₁₆H₁₃N₃O₄S₂, %: C, 51.19; H, 3.49; N, 11.19. Found, %: C,

50.85; H, 3.75; N, 11.15.

1319 (O]S]O), 1226, 1172 (CeO). ¹H NMR (300 MHz,

d, ppm,

DMSO-d₆): 10.45 (s 1H, eCOeNHeCOe), 7.93 (s 1H, benzylidene

proton), 7.68 (d, J ¼ 9.0 Hz, 2H, aromatic protons), 7.53 (d, J ¼ 8.4 Hz,

2H, aromatic protons), 7.34 (d, J ¼ 8.7 Hz, 2H, aromatic protons),

4.1.3.4. 5-[4-[2-(2-Butyl-4-oxo-1,3-diazaspiro[4,4]non-1-en-3-yl)-2-

oxoethoxy] benzylidene] thiazolidine-2,4-dione (3d). Eluent used for

column chromatography: Hexane: Ethyl acetate (2:1). Yield 97.0%,

pale yellow powder, mp 236e237 ^ꢂC. IR [KBr v cm^ꢀ1]: 3406 (NeH),

6.94 (d, J ¼ 8.4 Hz, 2H, aromatic protons), 4.70 (s 2H, eCH₂e). ¹³

NMR (75 MHz, DMSO-d₆, d): 168.1 (C]O), 167.3 (C]O), 167.0 (C]

O), 165.1, 160.5, 151.0, 134.9, 132.9, 132.4, 131.5, 131.3, 130.7, 124.0,

123.6, 122.5, 116.5, 115.6, 62.8. Calc. for C₁₉H₁₂N₂O₇S₂, %: C, 51.35; H,

2.72; N, 6.30. Found, %: C, 51.10; H, 2.57; N, 6.64.

1724 (C]O), 1677 (C]O), 1155 (CeO). ¹H NMR (300 MHz,

d, ppm,

DMSO-d₆): 10.83 (s 1H, eCOeNHeCOe), 7.88 (s 1H, benzylidene

proton), 7.5 (d, J ¼ 8.4 Hz, 2H, aromatic protons), 6.95 (d, J ¼ 8.4 Hz,

2H, aromatic protons), 4.73 (s 2H, eCH₂e), 1.2e1.82 (m 17H,

4.1.3.9. 2-[4-[(2,4-Dioxothiazolidin-5-ylidene) methyl] phenoxy] -N-

(pyridine-2-yl) acetamide (3i). Eluent used for column chromatog-

raphy: Hexane: Ethyl acetate (2:1).Yield 32.1%, yellow powder, mp

177e178 ^ꢂC. IR [KBr v cm^ꢀ1]: 3465 (NeH), 1735 (C]O), 1677 (C]O),

aliphatic and alicyclic protons). ¹³C NMR (75 MHz, DMSO-d₆,

d):

174.5 (C]O), 172.7 (C]O), 168.0 (C]O), 167.1 (C]O), 165.3, 160.3,

134.1, 132.8, 123.8, 116.5, 116.2, 66.5, 45.7, 35.8, 34.6, 27.1, 23.8, 21.8,

13.8. Calc. for C₂₃H₂₅N₃O₅S, %: C, 60.64; H, 5.53; N, 9.22. Found, %: C,

60.47; H, 5.56; N, 9.60.

1141,1085 (CeO). ¹H NMR (300 MHz,

d, ppm, DMSO-d₆): 10.97 (s 1H,

eCOeNHeCOe), 10.41(s 1H, eNHe), 8.34 (d, J ¼ 4.2 Hz, 1H,

aromatic protons), 7.69e7.98 (m 1H, aromatic protons), 7.88 (s

1H, benzylidene proton), 7.76e7.87 (m 1H, aromatic proton), 7.52

(d, J ¼ 8.7 Hz, 2H, aromatic protons), 7.11e7.15 (m 1H, aromatic

proton), 6.94 (d, J ¼ 8.4 Hz, 2H, aromatic protons), 4.57 (s 2H,

4.1.3.5. 2-[4-[(2,4-Dioxothiazolidin-5-ylidene) methyl] phenoxy]-N-

[3-(triﬂuromethyl) phenyl] acetamide (3e). Eluent used for column

chromatography: Hexane: Ethyl acetate (3:2). Yield 97%, pale yellow

power, mp 235e236 ^ꢂC. IR [KBr v cm^ꢀ1]: 3317 (NeH), 1731 (C]O),

eCH₂e). ¹³C NMR (75 MHz, DMSO-d₆,

d): 167.3 (C]O),165.5 (C]O),

164.8 (C]O), 160.3, 151.4, 148.1, 138.4, 134.1, 132.7, 123.8, 119.8,

116.5,116.3,113.5, 66.9. Calc. for C₁₇H₁₃N₃O₄S, %: C, 57.46; H, 3.69; N,

11.82. Found, %: C, 57.84; H, 4.00; N, 11.60.

1674 (C]O), 1146, 1176 (CeO). ¹H NMR (300 MHz,

d, ppm, DMSO-

d₆): 10.75 (s 1H, eCOeNHeCOe), 10.4 (s 1H, eNHe), 8.05 (s 1H,

aromatic proton), 7.9 (s 1H, benzylidene proton), 7.42e7.75 (m 5H,

aromatic protons), 6.9 (d, J ¼ 9.0 Hz, 2H, aromatic protons), 4.5

4.1.3.10. 2-[4-[(2,4-Dioxothiazolidin-5-ylidene) methyl] phenoxy]-N-

(5-methylisoxazol-3-yl) acetamide (3j). Eluent used for column

chromatography: Hexane: Ethyl acetate (3:2).Yield 76%, pale yellow

powder, mp 245e246 ^ꢂC. IR [KBr v cm^ꢀ1]: 3483 (NeH), 1739 (C]O),

(s 2H, eCH₂e). ¹³C NMR (75 MHz, DMSO-d₆,

d): 167.3 (C]O), 165.5

(C]O), 164.7 (C]O), 160.3, 139.1, 134.1, 132.8, 130.2, 129.8, 129.4,

125.8, 123.8, 122.8, 122.2, 120.0, 116.5, 116.3, 115.2, 66.2. Calc. for

C₁₉H₁₃F₃N₂O₄S, %: C, 54.03; H, 3.10; N, 6.63. Found, %: C, 53.83; H,

2.96; N, 6.32.

1689 (C]O), 1587 (C]N), 1143,1087 (CeO). ¹H NMR (300 MHz,

ppm, DMSO-d₆): 11.4 (s 1H, eCOeNHeCOe), 10.4 (s 1H, eNHe),

7.88 (s 1H, benzylidene proton), 7.52 (d, J ¼ 8.7 Hz, 2H, aromatic

protons), 6.93 (d, J ¼ 8.4 Hz, 2H, aromatic protons), 6.56 (s 1H,

isoxazolyl proton), 4.51 (s 2H, eCH₂e), 2.37 (s 3H, eCH₃). ¹³C NMR

4.1.3.6. N-(Benzo[d]thiazol-2-yl)-2-[4-[(2,4-dioxothiazolidin-5-yli-

dene) methyl] phenoxy] acetamide (3f). Eluent used for column

4544

V. Patil et al. / European Journal of Medicinal Chemistry 45 (2010) 4539e4544

(75 MHz, DMSO-d₆,

): 169.9, 167.3 (C]O), 165.4 (C]O), 164.5 (C]

[(Ti ꢀ Tz)/Tz] ꢃ 100 for concentrations for which Ti < Tz.

(Ti ꢀ Tz) negative.

O), 160.3, 157.6, 134.1, 132.8, 123.8, 116.5, 116.3, 96.1, 63.6, 12.1. Calc.

for C₁₆H₁₃N₃O₅S, %: C, 53.48; H, 3.65; N, 11.69. Found, %: C, 53.65; H,

3.97; N, 11.93.

The dose response parameters were calculated for each test

article. Growth inhibition of 50% (GI50) was calculated from

[(Ti ꢀ Tz)/(C ꢀ Tz)] ꢃ 100 ¼ 50, which is the drug concentration

resulting in a 50% reduction in the net protein increase (as

measured by SRB staining) in control cells during the drug incu-

bation. The drug concentration resulting in total growth inhibition

(TGI) was calculated from Ti ¼ Tz.

4.2. In vitro anticancer screening

The cell lines were grown in RPMI 1640 medium containing 10%

fetal bovine serum and 2 mM

experiment, cells were inoculated into 96 well microtiter plates in

L-glutamine. For present screening

Values were calculated for each of these parameters if the level

of activity was reached; however, if the effect was not reached or

was exceeded, the values for that parameter were expressed as

greater or less than the maximum or minimum concentration

tested.

mL at plating densities ranging of 5000 cells/well. After cell

inoculation, the microtiter plates were incubated at 37 ^ꢂC, 5% CO₂,

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

experimental drugs.

After 24 h, one plate of each cell line was ﬁxed in situ with

Trichloroacetic acid (TCA), to represent a measurement of the cell

population for each cell line at the time of drug addition (Tz). Test

compounds were solubilized in DMSO solvent at 400-fold the

desired ﬁnal maximum test concentration and stored frozen prior

to use. At the time of compound addition, an aliquot of frozen

concentrate was thawed and diluted to 10 times the desired ﬁnal

maximum test concentration with complete medium containing 1%

gentamicin. Additional three, 10-fold serial dilutions were made to

Appendix. Supplementary material

Supplementary material associated with this article can be

found in the online version, at doi:10.1016/j.ejmech.2010.07.014.

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of these different dilutions were added to the appropriate micro-

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ml of medium, resulting in the

required ﬁnal concentrations.

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(w/v) TCA (ﬁnal concentration, 10% TCA) and incubated for 60 min

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and plates were incubated for 20 min at room temperature. After

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Using the six absorbance measurements [time zero (Tz), control

growth (C), and test growth in the presence of drug at the four

concentration levels (Ti)], the percentage growth was calculated at

each of the drug concentration levels. Percentage growth inhibition

was calculated as:

[(Ti ꢀ Tz)/(C ꢀ Tz)] ꢃ 100 for concentrations for which Ti > / ¼

Tz (Ti ꢀ Tz) positive or zero.

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