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Synthesis of New Thiazole Derivatives as Antitumor Agents Eman M. H. Abbasa, Sobhi M. Gomha,b Thoraya A. Farghaly b,c* and Mohamed M. Abdallad a

Department of Chemistry, Natural and Microbial Products, National Research Center, Dokki, Cairo, Egypt; Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt; c) Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah, Saudi Arabia; d) Research Unit, Saco Pharm. Co., 6th October City, Egypt

b

Abstract: New series of substituted thiazole were prepared starting from thiosemicarbazone derivatives 1a,b by reacting with different reagents namely, hydrazonoyl chlorides, dimethyl acetylene dicarboxylate, phenacyl bromide, chloroacetone, and chloroacetic acid. The structures of the newly synthesized compounds were elucidated on the basis of elemental analyses and spectral data. Some representative examples of the newly synthesized compounds Thoraya A. Farghaly were screened as antitumor agents against all the 60 cell lines of the NCI-60 cell panels. The tested compounds were active only against MCF7, SF268, SF295, HT29, HT29, COLO205, COLO205, K562, HL60, A549-ATCC, H460, LOXIMVI, OVCAR3, OVCAR4, OVCAR5, OVCAR8, SKOV3, PC39, DU145 and A498 while inactive against other cell lines in the panel.

Keywords: Thiazole, Hydrazonoyl chlorides, Thiosemicarbazone, Antitumor activity. INTRODUCTION Thiazole derivatives, thiazolidine-4-one and organic compounds containing thiazole and thiazolidinone ring systems are used as antiviral agents [1,2] and recently found application in drug development for the treatment of allergies [3], hypertension [4], inflammation [5], schizophrenia [6], bacterial [7], HIV infections [8] hypnotics [9] and more recently for the treatment of pain [10], as fibrinogen receptor antagonists with antithrombotic activity [11] and as new inhibitors of bacterial DNA graze-B [12]. Based on the above observations and in continuation to our work in the synthesis of bioactive heterocyclic ring systems [13-26], we reported here the synthesis and antitumor activity of some substituted thiazole derivatives starting from thiosemicarbazone derivatives (1a or 1b). RESULTS AND DISCUSSION Reaction of thiosemicarbazones 1a,b (which were prepared according to the reported method [27,28]) with -keto-hydrazonoyl chlorides 2 in refluxing dioxane in the presence of triethylamine as a basic catalyst yielded one isolable product in each case. Such a product can have one form of the three tautomeric forms 3A-C, but, both spectroscopic data and elemental analyses couldn't distinguish between three tautomeric structures 3A-C (Scheme 1). Their electronic absorption spectra were first studied to elucidate the actual tautomeric form(s) of these compounds. The electronic absorption spectra of the compounds in dioxane showed in each case, two absorption bands in the regions 442–434 and 290–283 nm which analogous to that reported for the azo chromophore [29] (Table 1). This finding excludes the hydrazone tautomeric form 3C (Scheme 1). We concluded that the actual tautomeric structure of the product is 3B, this is from the NOE difference experiments for derivative 3a. This is because irradiation at the NH group resonance has not enhanced the CH3 signal in the thiazole ring, which is consistent with structure. The formation of compound 3 proceeds via the intermediate I followed by elimination of water molecule.

*Address correspondence to this author at the Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt; Tel: 202 35676608; Fax: 202 35676501; E-mail: [email protected]

1570-1794/16 $58.00+.00

On the other hand, reaction of hydrazonoyl chlorides 4 with thiosemicarbazone derivatives (1a or 1b) afforded one isolable product whose structure is one of the five tautomeric structures 5AE (Scheme 2). The spectral data, elemental analyses and electronic absorption spectra of the isolated products indicated that the product found in the tautomeric form 5B (Scheme 2). For example, the IR spectra of the products showed, in each case, one carbonyl band at 1736 cm1 and two NH bands in the regions 3421–3233 and 3144–3109 cm1. Their mass spectra of the latter products revealed in each case, the molecular ion peaks at the expected m/z values and their elemental analysis data were consistent with their assigned structures. The electronic absorption spectral data of the studied compounds 5 are summarized in Table 1. Each of the compounds 5 in dioxane exhibits two characteristic absorption bands in the regions 372–360 and 293–289 nm. Such an absorption pattern is similar to that of the typical hydrazone chromophore [30]. This finding excludes the azo tautomeric forms 5D and 5E and the IR spectra of the products exclude the enol-hydrazone form 5C (Scheme 2). 13C NMR spectrum of 5a revealed the signal at  179.52 ppm characteristic for the carbonyl carbon of the thiazole ring residue. Such a chemical shift value indicated the presence of a carbonyl group adjacent to the N=C group [31]. On the basis of all the above data, the isolated products were assigned the tautomeric form 5B. The reaction of thiosemicarbazone 1a,b with dimethyl acetylenedicarboxylate affords only one product as evidenced by TLC (Scheme 3), according to the literature survey [32-34] and the spectral data (IR, Mass and 1H NMR) the correct structure could be assigned to the thiazolidine 8 rather than the thiazinone structure 9 (see Experimental part). As shown in Scheme 3, compound 8 can be found in one of the three tautomeric structures 8A-C. 13C NMR spectrum of 8a revealed two signals of the carbonyl carbon at  160.01 and 167.23 ppm. Such a chemical shift value indicated the presence of a carbonyl group adjacent to NH group [35] which is coincident with the tautomeric form 8A. The thiosemicarbazide 1b was considered to be a useful intermediate for further synthesis of different heterocyclic compounds, thus, cyclization of 1b with various haloketones such as phenacyl bromide, chloroacetone and chloroacetic acid furnished the new thiazole derivatives 10-12 (Scheme 4). 1H NMR spectrum for 10 showed a singlet signal of the methine proton of thiazole ring at  6.23 ppm and the NH proton appeared as another singlet at  11.30 © 2016 Bentham Science Publishers

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Current Organic Synthesis, 2016, Vol. 13, No. ?

Abbas et al.

S NH2

NH

N

Cl H N ROC

+ 1

N

2

Dioxane / Et3N/ reflux Ar

-HCl, -H2O Ar

X

Ar

X : a, CH2; b, S

N

NH

N

N

S

COR R

N

S

N H

N

NH2

-H2O

N

N

Ar X

I

NH

N

Ar

X

3A R N

N

N

N

S

R

S

N N

N

N

3C

X

H 3B

X Ar

R

X

Compd. No.

Compd. No.

Ph

3a

CH2

Me

Ph

3e

S

Me

3b

CH2

Me

4-MeC6H4

3f

S

Me

3c

CH2

4-BrC6H4

3g

S

Ph

3d

Me

Ar

R

X

3-NO2C6H4 Ph

Ph

CH2 S

Scheme 1. Synthesis of compounds 3a-g. S NH

N

NH2 Cl +

EtOOC

H N

N

-HCl, -EtOH

4

X

Dioxane / Et3N/ reflux Ar

1 X : a, CH2; b, S

N NH

S

H N

N

N N

N

N

O

S

5A X

N NH

N N

OH

5C X H N N

S N 5E

X

S

Ar N

N

N

N N

O

H Ar

X

N

S

5B

Scheme 2. Synthesis of compounds 5a-d.

Ar NH

Ar

N

OH

H Ar

N

N

5D X

X / Ar: a, CH2 /Ph; b, CH2/4-MeC6H4; c, CH2/4-ClC6H4; d, S/Ph OH

Synthesis of New Thiazole Derivatives as Antitumor Agents

Current Organic Synthesis, 2016, Vol. 13, No. ?

3

Table 1. UV Spectra of compounds 3 and 5 in dioxane.  max (log )

Compd. no. 3a

434 (4.12), 283(4.22)

3b

438 (4.54), 290 (4.80)

3c

442 (4.45), 288 (4.01)

3d

441 (4.11), 286 (4.67)

5c

360 (4.20), 291 (3.89)

5d

367 (3.46), 293 (3.54)

5e

364 (4.46), 289 (4.90)

5f

372 (4.72), 290 (4.68)

S NH

N

NH2

+

MeOOC

C

C

COOMe 6

X 1

Methanol reflux

COOMe

S

COOMe

N

NH

N H

7 X

COOMe COOMe

S N

S

N N H 8A

X N

N

X

N N

COOMe

H

S

H N

8B

N

N

O

X

O

9

O COOMe

X : a, CH2; b, S

S N N 8C

OH

X Scheme 3. Synthesis of compounds 8a,b.

ppm. Mass spectrum of compound 11 revealed the presence of the molecular ion peak at m/z 275. The IR spectrum of compound 12 showed an absorption peak at 1676 cm-1 due to C=O stretching vibrations. It was of interest to condense compound 12 with benzaldehyde in glacial acetic acid containing anhydrous sodium acetate (Scheme 4) to afford benzothiazole 13. Its 1H NMR spectrum confirmed the proposed structure by revealing an increase in the integration of the aromatic protons relative to thiazole 12.

Anti-tumor Activities Many 2,4-disubstituted-thiazole analogs were reported as antitumor agents [36-38]. The demonstrated clinically effective antitumor activity of the thiazole nucleoside tiazofurn [39, 40], the reported facts about the groove binding property of distamycin [41], netropsin (I), thia-netropsin (II) [42] (Fig. 1), and the thiazole containing antitumor agent bleomycin [43] this information prompted us to test our newly synthesized derivatives as anti-tumor agents.

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Current Organic Synthesis, 2016, Vol. 13, No. ?

Abbas et al.

S NH2

NH

N PhCOCH2Br

ClCH2COOH S 1b

S

S

N N

N N H

ClCH2COCH3

Ph

N

N H

O

S N N

S

N H

S

CH3

12

10

PhCHO Ph

S 11

S N N

N H

O

S 13

Scheme 4. Synthesis of compounds 10-13.

CH3

O

CH3

N

N

O HN

H N

N H

H N

N H

NH

NH2

O netropsin I

NH2

O

O O H2N

N

N

NH

N H

N H

S

NH2

S

Thia-netropsin II Fig. (1). Structures of netropsin (I) and thia-netropsin (II).

Some representative examples of the newly synthesized compounds were screened as antitumor agents against all the 60 cell lines of the NCI-60 cell panelles. The tested compounds were active only against MCF7, SF268, SF295, HT29, HT29, COLO205, COLO205, K562, HL60, A549-ATCC, H460, LOXIMVI, OVCAR3, OVCAR4, OVCAR5, OVCAR8, SKOV3, PC39, DU145 and A498, while inactive against other cell lines in the panel (Tables 2-4). Searching the exact mechanism of the antitumor activities of these newly synthesized compounds it was found that they bear a minor groove binding activities.

Minor Groove Binder's Activity Hoechst 33342 is a fluorochrome that binds to the DNA minor groove and generates specific fluorescence. To confirm tested agent binding to DNA, we observed the effect of 4e on the fluorescence generated by DNA-bound Hoechst 33342 (Table 5). In a cell free system, the fluorescence of DNA-bound Hoechst 33342 was quenched after tested agent was added in a dose-dependent manner. Similar results were obtained when fluorescence was measured in the cellular system where 4e was exogenously added to L1210 cells that had been preincubated with Hoechst 33342. These results

Synthesis of New Thiazole Derivatives as Antitumor Agents

Current Organic Synthesis, 2016, Vol. 13, No. ?

Table 2. In vitro anti-Tumor activities. Compound No

IC50 {M} MCF7

SF268

SF295

HT29

HCT15

COLO205

COLO205

3a

12.10

16.7

8.8

32.0

33.8

22.2

56.8

3b

8.2

25.0

5.9

34.4

44.5

33.1

47.0

4a

34.3

34.0

4.9

54.8

35.6

44.9

57.1

4b

54.0

53.6

62.5

4.6

24.8

53.6

65.3

4c

57.4

44.4

87.8

6.5

13.9

45.5

78.1

4d

65.4

36.6

98.7

7.6

24.5

34.8

85.6

4e

2.6

12.7

7.5

6.5

8.8

12.3

19.1

4f

3.8

50.5

96.0

7.6

27.7

17.7

5.9

5a

2.6

69.9

85.9

5.8

36.5

38.7

95.9

5b

3.9

88.0

74.9

37.7

25.3

27.3

86.8

5c

4.6

97.0

62.8

65.8

44.5

46.3

75.7

5d

56.7

86.2

33.3

75.2

33.7

55.2

64.4

5e

54.4

5.5

21.8

32.5

24.9

64.9

55.4

5f

36.7

93.8

41.5

34.9

15.0

73.0

36.0

6a

45.8

84.6

61.0

32.0

27.4

64.8

47.2

6b

67.0

76.5

51.3

13.9

39.6

55.3

58.4

6c

43.5

57.4

71.5

4.6

20.6

46.2

67.2

7a

21.2

48.5

81.8

5.8

19.7

35.5

55.3

7b

23.5

39.7

91.4

6.9

28.5

54.2

33.4

8

6.0

68.9

2.0

7.4

37.8

43.6

44.8

10a

7.0

57.6

73.8

8.8

46.9

35.6

55.4

10b

89.1

66.6

54.9

90.9

55.8

36.4

66.9

10c

9.8

74.4

25.0

98.4

42.7

27.6

57.8

10d

9.8

85.2

16.4

76.9

33.0

38.7

46.5

10e

87.4

73.2

34.9

45.0

44.9

37.2

35.1

10f

65.5

62.3

43.8

34.9

33.5

46.1

45.0

Netropsin

5.98

9.89

15.16

3.44

0.98

8.9

18.09

Table 3. In vitro anti-Tumor activities. Compound

.

No

K562

HL60

A549-ATCC

H460

LOXIMVI

OVCAR3

OVCAR4

3a

12.8

15.0

9.4

44.0

44.9

87.3

12.2

3b

6.9

15.0

17.9

36.6

35.0

76.2

13.7

4a

5.9

16.9

17.9

45.0

15.0

75.3

12.6

4b

11.9

15.6

8.7

44.8

13.6

74.2

11.9

4c

9.5

16.9

9.5

53.6

36.8

64.4

13.9

4d

7.8

15.9

9.7

6.8

47.9

56.5

12.4

4e

5.9

16.6

11

5.8

9.4

67.6

14.7

4f

6.5

25.4

95.4

4.3

26.8

78.0

13.6

5a

7.7

26.3

12.9

5.9

15.9

80.0

35.3

5

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Current Organic Synthesis, 2016, Vol. 13, No. ?

Abbas et al.

Table 3. contd… Compound

.

No

K562

HL60

A549-ATCC

H460

LOXIMVI

OVCAR3

OVCAR4

5b

8.9

25.3

95.8

6.6

14.5

90.0

24.2

5c

76.8

17.0

84.9

47.9

53.9

89.3

13.4

5d

34.7

26.9

75.8

28.6

9.7

78.4

32.0

5e

32.2

15.0

54.6

18.5

9.5

67.1

24.0

5f

45.3

26.9

43.8

19.8

18.9

85.1

33.1

6a

45.4

29.7

32.4

36.7

64.0

74.0

42.3

6b

34.8

10.9

44.0

17.2

75.3

65.5

54.5

6c

43.6

19.4

73.3

28.0

56.9

76.6

45.7

7a

43.8

12.0

84.8

17.4

25.6

94.7

24.3

7b

32.5

17.9

65.3

16.3

10.7

73.3

43.9

8

45.7

15.7

54.2

4.9

9.6

84.6

32.1

10a

65.9

22.4

33.5

53.7

11.9

65.6

13.1

10b

78.0

33.0

44.6

25.3

33.4

73.6

24.2

10c

73.9

43.8

23.5

3.9

5.8

54.7

35.4

10d

45.5

24.1

33.5

43.4

43.5

65.3

46.5

10e

28.9

32.0

43.0

20.0

32.0

54.6

35.8

10f

46.2

43.4

34.1

10.9

23.8

45.2

24.4

Netropsin

5.43

5.43

6.78

12.54

8.9

0.89

0.05

Compound

IC 50 {M}

No

OVCAR5

OVCAR8

SKOV3

PC39

DU145

A498

3a

13.5

35.0

23.5

28.2

68.8

39.9

3b

24.6

24.4

33.8

36.8

98.9

12.8

4a

35.7

36.8

44.9

46.5

88.6

13.6

4b

44.8

48.0

55.0

57.4

77.9

12.9

4c

35.6

57.3

66.4

39.0

67.0

24.5

4d

57.8

43.1

48.3

40.8

58.5

43.6

4e

6.3

3..0

4.9

30.6

77.7

10.7

4f

75.2

45.5

48.6

47.7

56.8

15.5

5a

64.1

37.6

37.2

58.0

46.9

16.3

5b

84.1

48.9

26.7

59.8

96.8

55.7

5c

95.3

37.0

45.2

70.7

89.7

44.9

5d

84.5

46.4

34.7

77.4

78.5

53.4

5e

93.4

55.9

46.8

88.0

67.4

44.0

5f

74.0

63.0

35.6

69.6

86.8

54.8

6a

87.4

74.3

43.4

95.8

75.5

45.7

6b

76.3

55.9

32.6

76.6

76.7

46.3

6c

65.2

47.0

43.4

67.3

66.6

35.7

7a

54.6

36.4

34.6

98.1

67.4

44.8

7b

65.0

55.4

23.0

99.0

56.6

55.5

Synthesis of New Thiazole Derivatives as Antitumor Agents

Current Organic Synthesis, 2016, Vol. 13, No. ?

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Table 3. contd…

Compound

IC 50 {M}

No

OVCAR5

OVCAR8

SKOV3

PC39

DU145

A498

8

54.1

76.6

56.3

4.9

96.8.

34.6

10a

65.5

73.8

64.2

95.0

8.9

43.5

10b

77.8

43.3

76.4

86.9

78.6

34.4

10c

56.0

54.0

55.6

97.0

68.0

45.5

10d

65.2

64.3

34.8

98.3

97.8

56.2

10e

74.9

55.9

43.7

8.0

86.3

45.7

10f

65.3

44.1

9.4

89.0

76.3

54.9

Netropsin

5.32

1.23

4.32

5.47

5.67

4.87

Table 5. Minor groove binding activity of compound. 4e g/ml

RFU case-A

0.01

81

0.1

73

144

0.5

69

122

1

64

109

RFU Case-B

5

58

98

10

55

78

20

48

69

40

30

55

80

20

46

100

indicated that the tested agent may have displaced the DNA-bound Hoechst 33342 on the DNA [44]. Quenching of the fluorescence of DNA-bound Hoechst 33342 by 4e. The fluorescence of DNA-bound Hoechst 33342 was measured under the following conditions: A, calf thymus DNA was preincubated with Hoechst 33342 and then incubated with 4e; B, L1210 cells were preincubated with Hoechst 33342 and then incubated with 4e. The fluorescence derived from DNA-bound Hoechst 33342 decayed when tested agent was added to the two systems. EXPERIMENTAL General Methods Melting points were measured on an Electrothermal IA 9000 series digital melting point apparatus. IR spectra were recorded in potassium bromide discs on Pye Unicam SP 3300 and Shimadzu FTIR 8101 PC infrared spectrophotometers. NMR spectra were recorded on a Varian Mercury VX-300 NMR spectrometer operating at 300 MHz (1H NMR) or 75 MHz (13C NMR) and run in deuterated dimethylsulfoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCeMS-QP1000 EX mass spectrometer at 70 eV. Elemental analyses were measured by using a German made Elementar vario LIII CHNS analyzer. Antimicrobial activity was evaluated by the Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt. 2-(3,4-Dihydronaphthalen-1(2H)-ylidene)hydrazinecarbothioamide (1a), 2-(thiochroman-4-ylidene)hydrazinecar-

32

bothioamide (1b) and hydrazonoyl halides 2,4 were prepared as previously reported in the respective literature [27, 28,45]. Synthesis of 2,4,5-trisubstituted thiazoles (3a-g) A mixture of thiosemicarbazide derivatives (1a or 1b) (1 mmol of each) with appropriate hydrazonoyl halides 2 (1 mmol) in dioxane (20 mL) containing triethylamine (0.1 g, 1 mmol) was refluxed for 6-8 h. (monitored by TLC). The formed precipitate was isolated by filtration, washed with methanol, dried and recrystallized from an appropriate solvent to give products 3a–g. 2-(2-(3,4-Dihydronaphthalen-1(2H)-ylidene)hydrazinyl)-4methyl-5-(phenyldiazenyl)-thiazole (3a) Red solid (78%); mp = 214-216°C; IR (KBr): v 3437 (NH), 1597 (C=N) cm-1; 1H-NMR (DMSO-d6):  1.88 (m, J = 6 Hz, 2H, CH2), 2.59 (s, 3H, CH3), 2.83 (t, J = 6 Hz, 2H, CH2), 2.98 (t, J = 6 Hz, 2H, CH2), 6.96-8.26 (m, 9H, Ar-H), 10.55 (s, 1H, NH); 13CNMR (DMSO-d6):  15.1, 21.6, 25.1, 30.7, 121.5, 127.2, 128.2, 128.4, 129.6, 129.9, 131.2, 136.8, 137.9, 138.1, 139.0, 144.5, 145.9, 153.1. MS m/z (%): 362 (M++1, 21), 361 (M+, 67), 269 (24), 144 (30), 116 (74), 77 (100). Anal. Calcd. for C20H19N5S (361.46): C, 66.46; H, 5.30; N, 19.37. Found C, 66.41; H, 5.18; N, 19.26%. 2-(2-(3,4-Dihydronaphthalen-1(2H)-ylidene)hydrazinyl)-4methyl-5-(p-tolyldiazenyl)-thiazole (3b) Red solid (83%); mp = 209-211°C; IR (KBr): v 3418 (NH), 1597 (C=N) cm-1; 1H-NMR (DMSO-d6):  1.88 (m, J = 6 Hz, 2H,

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Current Organic Synthesis, 2016, Vol. 13, No. ?

CH2), 2.26 (s, 3H, CH3), 2.58 (s, 3H, CH3), 2.84 (t, J = 6 Hz, 2H, CH2), 2.96 (t, J = 6 Hz, 2H, CH2), 7.13-8.26 (m, 8H, Ar-H), 10.50 (s, 1H, NH); 13C-NMR (DMSO-d6):  15.7, 17.3, 20.1, 24.5, 29.9, 120.1, 126.3, 128.2, 128.9, 129.1, 129.4, 130.0, 134.8, 136.4, 137.0, 139.8, 142.1, 144.3, 154.8. MS m/z (%): 376 (M++1, 17), 375 (M+, 61), 269 (17), 144 (28), 91 (100), 77 (34). Anal. Calcd. for C21H21N5S (375.49): C, 67.17; H, 5.64; N, 18.65. Found C, 67.17; H, 5.64; N, 18.65%. 5-((4-Bromophenyl)diazenyl)-2-(2-(3,4-dihydronaphthalen1(2H)-ylidene)-hydrazinyl)-4-methylthiazole (3c) Red solid (78%); mp = 234-236°C; IR (KBr): v 3441 (NH), 1593 (C=N) cm-1; 1H-NMR (DMSO-d6):  1.88 (m, J = 6 Hz, 2H, CH2), 2.58 (s, 3H, CH3), 2.84 (t, J = 6 Hz, 2H, CH2), 2.97 (t, J = 6 Hz, 2H, CH2), 7.26-8.24 (m, 8H, Ar-H), 10.62 (s, 1H, NH); MS m/z (%): 442 (M++2, 10), 441 (M++1, 27), 440 (M+, 25), 269 (22), 144 (39), 116 (100), 77 (34). Anal. Calcd. for C20H18BrN5S (440.36): C, 54.55; H, 4.12; N, 15.90. Found C, 54.43; H, 4.19; N, 15.63%. 2-(2-(3,4-Dihydronaphthalen-1(2H)-ylidene)hydrazinyl)-5(phenyldiazenyl)-4-(thiophen-2-yl)thiazole (3d) Red solid (77%); mp = 262-264°C; IR (KBr): v 3445 (NH), 1597 (C=N) cm-1; 1H-NMR (DMSO-d6):  1.90 (m, J = 6 Hz, 2H, CH2), 2.50 (s, 3H, CH3), 2.84 (t, J = 6 Hz, 2H, CH2), 3.03 (t, J = 6 Hz, 2H, CH2), 7.03-8.39 (m, 12H, Ar-H), 10.72 (s, 1H, NH); MS m/z (%): 430 (M++1, 27), 429 (M+, 25), 285 (68), 143 (100), 117 (77), 77 (96). Anal. Calcd. for C23H19N5S2 (429.56): C, 64.31; H, 4.46; N, 16.30. Found C, 64.37; H, 4.41; N, 16.13%. 4-Methyl-5-(phenyldiazenyl)-2-(2-(thiochroman-4ylidene)hydrazinyl)thiazole (3e) Red solid (75%); mp = 193-195°C; IR (KBr): v 3418 (NH), 1599 (C=N) cm-1; 1H-NMR (DMSO-d6):  2.50 (s, 3H, CH3), 3.02, 3.28 (2t, J = 7.8Hz, 4H, 2CH2), 7.03-8.14 (m, 9H, Ar-H), 10.24 (s, 1H, NH); MS m/z (%): 379 (M+, 12), 218 (100), 162 (72), 118 (44), 77 (80). Anal. Calcd. for C19H17N5S2 (379.50): C, 60.13; H, 4.52; N, 18.45. Found C, 60.04; H, 4.34; N, 18.25%. 4-Methyl-5-((3-nitrophenyl)diazenyl)-2-(2-(thiochroman-4ylidene)hydrazinyl)-thiazole (3f) Dark red solid (75%); mp = 206-208°C; IR (KBr): v 3424 (NH), 1597 (C=N) cm-1; 1H-NMR (DMSO-d6):  2.51 (s, 3H, CH3), 3.03, 3.32 (2t, J = 7.8Hz, 4H, 2CH2), 7.20-8.29 (m, 8H, Ar-H), 10.91 (s, 1H, NH); MS m/z (%): 425 (M++1, 14), 424 (M+, 42), 262 (75), 162 (100), 135 (44), 76 (29). Anal. Calcd. for C19H16N6O2S2 (424.50): C, 53.76; H, 3.80; N, 19.80. Found C, 53.58; H, 3.67; N, 19.68%. 4-Phenyl-5-(phenyldiazenyl)-2-(2-(thiochroman-4ylidene)hydrazinyl)thiazole (3g) Red solid (74%); mp = 185-187°C; IR (KBr): v 3414 (NH), 1601 (C=N) cm-1; 1H-NMR (DMSO-d6):  2.49 (s, 3H, CH3), 3.03, 3.29 (2t, J = 7.8Hz, 4H, 2CH2), 7.08-8.47 (m, 14H, Ar-H), 10.21 (s, 1H, NH); MS m/z (%): 442 (M++1, 11), 441 (M+, 18), 398 (14), 236 (46), 135 (21), 77 (100). Anal. Calcd. for C24H19N5S2 (441.57): C, 65.28; H, 4.34; N, 15.86. Found C, 65.20; H, 4.25; N, 15.58%. Synthesis of 2,5-disubstituted thiazolidin-4-ones (5a-d) A mixture of thiosemicarbazide derivatives (3a or 3b) (1 mmol of each) with appropriate hydrazonoyl halides 4 (1 mmol) in dioxane (20 mL) containing triethylamine (0.1 g, 1 mmol) was refluxed for 6-8 h. (monitored by TLC). The formed precipitate was isolated by filtration, washed with methanol, dried and recrystallized from an appropriate solvent to give products 5a–d.

Abbas et al.

2-((3,4-Dihydronaphthalen-1(2H)-ylidene)hydrazono)-5-(2phenylhydrazono)-thiazolidin-4-one (5a) Yellow solid (72%); mp = 182-184°C; IR (KBr): v 3233, 3113 (2NH), 1736 (C=O) 1632 (C=N) cm-1; 1H-NMR (DMSO-d6):  1.85 (m, J = 6 Hz, 2H, CH2), 2.79 (t, J = 6 Hz, 2H, CH2), 2.92 (t, J = 6 Hz, 2H, CH2), 6.94-8.16 (m, 9H, Ar-H), 10.40 (s, 1H, NH), 12.51 (s, 1H, NH); 13C-NMR (DMSO-d6):  21.7, 27.0, 29.1(CH2), 113.9, 120.9, 124.7, 126.2, 128.7, 130.2, 131.6, 140.9, 143.0, 158.7 (ArC), 162.3, 165.5, 165.8 (C=N), 179.52 (C=O); MS m/z (%): 363 (M+, 25), 231 (12), 130 (100), 92 (64), 77 (38). Anal. Calcd. for C19H17N5OS (363.44): C, 62.79; H, 4.71; N, 19.27. Found C, 62.67; H, 4.77; N, 19.04%. 2-((3,4-Dihydronaphthalen-1(2H)-ylidene)hydrazono)-5-(2-(ptolyl)hydrazono)-thiazolidin-4-one (5b) Yellow solid (73%); mp = 173-175°C; IR (KBr): v 3421, 3144 (2NH), 1736 (C=O) 1597 (C=N) cm-1; 1H-NMR (DMSO-d6):  1.83 (m, J = 6 Hz, 2H, CH2), 2.37 (s, 3H, CH3), 2.76 (t, J = 6 Hz, 2H, CH2), 2.87 (t, J = 6 Hz, 2H, CH2), 7.21-8.14 (m, 8H, Ar-H), 10.40 (s, 1H, NH), 12.52 (s, 1H, NH); MS m/z (%): 378 (M++1, 14), 377 (M+, 47), 271 (31), 202 (26), 144 (12), 116 (100), 91 (89), 77 (85). Anal. Calcd. for C20H19N5OS (377.46): C, 63.64; H, 5.07; N, 18.55. Found C, 63.48; H, 5.01; N, 18.36%. 5-(2-(4-Chlorophenyl)hydrazono)-2-((3,4-dihydronaphthalen1(2H)-ylidene)-hydrazono)thiazolidin-4-one (5c) Yellow solid (72%); 194-196°C; IR (KBr): v 3233, 3109 (2NH), 1736 (C=O) 1632 (C=N) cm-1; 1H-NMR (DMSO-d6):  1.87 (m, J = 6 Hz, 2H, CH2), 2.82 (t, J = 6 Hz, 2H, CH2), 2.92 (t, J = 6 Hz, 2H, CH2), 7.24-8.17 (m, 8H, Ar-H), 10.51 (s, 1H, NH), 12.56 (s, 1H, NH); MS m/z (%): 399 (M++2, 24), 398 (M++1, 23), 397 (M+, 61), 271 (54), 186 (32), 144 (100), 116 (73), 63 (47). Anal. Calcd. for C19H16ClN5OS (397.88): C, 57.35; H, 4.05; N, 17.60. Found C, 57.19; H, 4.02; N, 17.45%. 5-(2-Phenylhydrazono)-2-(thiochroman-4-ylidenehydrazono) thiazolidin-4-one (5d) Yellow solid (74%); mp = 168-170°C; IR (KBr): v 3263, 3124 (2NH), 1734 (C=O) 1606 (C=N) cm-1; 1H-NMR (DMSO-d6):  3.08, 3.29 (2t, J = 6.8 Hz, 4H, 2CH2), 6.94-8.23 (m, 8H, Ar-H), 10.46 (s, 1H, NH), 12.58 (s, 1H, NH); MS m/z (%): 382 (M++1, 10), 381 (M+, 63), 220 (25), 162 (78), 144 (100), 92 (94), 65 (100). Anal. Calcd. for C18H15N5OS2 (381.47): C, 56.67; H, 3.96; N, 18.36. Found C, 56.49; H, 3.88; N, 18.16%. Reaction of Thiosemicarbazide Derivatives (3a or 3b) with DMAD (6) To a solution of thiosemicarbazide derivatives (3a or 3b) (1 mmol of each) in dry methanol (20 mL) dimethyl acetylene dicarboxylate 6 (0.142 g, 1 mmol) was added. The solution was refluxed for 2 h. The precipitate was filtered, washed with methanol, and recrystallized from ethanol to give the respective products 8a,b. (Methyl 2-(2-((3,4-dihydronaphthalen-1(2H)-ylidene)hydrazono)-4-oxothiazolidin-5-ylidene) acetate (8a) Canary yellow solid (78%); mp = 336-338°C; IR (KBr): v 3159 (NH), 1728, 1697 (2C=O), 1620 (C=N) cm-1; 1H-NMR (DMSOd6):  1.85 (m, J = 6 Hz, 2H, CH2), 2.79 (t, J = 6 Hz, 2H, CH2), 2.91 (t, J = 6 Hz, 2H, CH2), 3.79 (s, 3H, COOCH3), 6.67 (s, 1H, C=CH), 7.24-8.13 (m, 4H, Ar-H), 12.86 (s, 1H, NH); 13C-NMR (DMSO-d6):  21.2, 27.4, 29.0(CH2), 52.2(CH3), 114.4, 128.4, 128.8, 118.9, 131.7, 133.7, 134.1, 140.9 (Ar-C), 147.3, 160.8 (C=N), 160.01, 167.23 (C=O); MS m/z (%): 330 (M++1, 9), 329 (M+, 36), 213 (100), 143 (82), 117 (58), 77 (19). Anal. Calcd. for C16H15N3O3S

Synthesis of New Thiazole Derivatives as Antitumor Agents

(329.37): C, 58.34; H, 4.59; N, 12.76. Found C, 58.24; H, 4.55; N, 12.57%. (Methyl 2-(4-oxo-2-(thiochroman-4-ylidenehydrazono)thiazolidin-5-ylidene)acetate (8b). Canary yellow solid (81%); mp = 312-314°C; IR (KBr): v 3059 (NH), 1713, 1682 (2C=O), 1624 (C=N) cm-1; 1H-NMR (DMSOd6):  3.08, 3.30 (2t, J = 7.8Hz, 4H, 2CH2), 3.79 (s, 3H, COOCH3), 6.69 (s, 1H, C=CH), 7.22-8.18 (m, 4H, Ar-H), 12.93 (s, 1H, NH); MS m/z (%): 348 (M++1, 8), 347 (M+, 20), 295 (11), 161 (100), 77 (19). Anal. Calcd. for C15H13N3O3S2 (347.41): C, 51.86; H, 3.77; N, 12.10. Found C, 51.73; H, 3.65; N, 12.02%. Reaction of 2-(thiochroman-4-ylidene)hydrazinecarbothioamide (1b) with -haloketones A mixture of 1b (0.237 g, 1 mmol) and phenacyl bromide or chloroacetone (1 mmol for each) in ethanol (20 mL) was refluxed for 3-5 h. (monitored by TLC). The product started to separate out during the course of reaction. The solid product was filtered, washed with water, dried and recrystallized from DMF to give the corresponding compounds 10 and 11, respectively. 4-Phenyl-2-(thiochroman-4-ylidenehydrazono)-2,5-dihydrothiazole (10) Yellow solid (80%); mp = 182-184°C; IR (KBr): v 3191 (NH), 1616 (C=N) cm-1; 1H-NMR (DMSO-d6):  3.06, 3.29 (2t, J = 6.8Hz, 4H, 2CH2), 6.23 (s, 1H, thiazole-H), 7.18-8.07 (m, 9H, ArH), 11.30 (s, 1H, NH); MS m/z (%): 338 (M++1, 11), 337 (M+, 40), 176 (100), 134 (90), 77 (19). Anal. Calcd. for C18H15N3S2 (337.46): C, 64.06; H, 4.48; N, 12.45. Found C, 64.13; H, 4.41; N, 12.34%. 4-Methyl-2-(thiochroman-4-ylidenehydrazono)-2,5-dihydrothiazole (11) Yellow solid (78%); mp = 193-195°C; IR (KBr): v 3159 (NH), 1621 (C=N) cm-1; 1H-NMR (DMSO-d6):  2.15 (s, 3H, CH3), 3.04, 3.26 (2t, J = 6.8Hz, 4H, 2CH2), 6.29 (s, 1H, thiazole-H), 7.14-8.04 (m, 4H, Ar-H), 11.21 (s, 1H, NH); MS m/z (%): 275 (M+, 34), 218 (100), 162 (72), 77 (70). Anal. Calcd. for C13H13N3S2 (275.39): C, 56.70; H, 4.76; N, 15.26. Found C, 56.53; H, 4.54; N, 15.02%. Synthesis of 5-benzylidene-2-(thiochroman-4-ylidenehydrazono)thiazolidin-4-one (13) Method A: A mixture of 1b (0.237 g, 1 mmol), chloroacetic acid (0.1 g, 1 mmol) and benzaldehyde (0.106 g, 1 mmol) in glacial acetic acid (20 mL) containing anhydrous sodium acetate (0.33 g, 4 mmol) was refluxed for 8 h. The reaction mixture was left to cool and the formed solid was filtered off, washed with water, dried and recrystallized from ethanol to give 13. White solid (71%); mp = 213-215°C; IR (KBr): v 3147 (NH), 1676 (C=O), 1616 (C=N) cm-1; 1 H-NMR (DMSO-d6):  3.08, 3.26 (2t, J = 6.8Hz, 4H, 2CH2), 7.038.09 (m, 9H, Ar-H), 9.98 (s, 1H, CH= ), 11.67 (s, 1H, NH); 13CNMR (DMSO-d6):  20.9, 29.5, 114.3, 124.3, 125.6, 126.5, 127.8, 128.9, 129.1, 130.7, 131.8, 135.4, 142.6, 144.3, 149.1, 154.2, 170.2. MS m/z (%): 366 (M++1, 42), 365 (M+, 64), 268 (65), 176 (100), 77 (68). Anal. Calcd. for C19H15N3OS2 (365.47): C, 62.44; H, 4.14; N, 11.50. Found C, 62.31; H, 4.12; N, 11.34%.

Current Organic Synthesis, 2016, Vol. 13, No. ?

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(71%); mp = 192°C; IR (KBr): v 3147 (NH), 1676 (C=O), 1616 (C=N) cm-1; 1H-NMR (DMSO-d6):  3.13, 3.29 (2t, J = 7 Hz, 4H, 2CH2), 3.88 (s, 2H, CH2), 7.06-8.04 (m, 4H, Ar-H), 11.68 (s, 1H, NH); MS m/z (%): 278 (M++1, 18), 277 (M+, 63), 251 (52), 167 (100), 109 (91), 77 (64). Anal. Calcd. for C12H11N3OS2 (277.37): C, 51.96; H, 4.00; N, 15.15. Found C, 51.74; H, 4.12; N, 15.02%. II. Reaction of 12 with Bezaldehyde To a solution of 5-thiazolidinone 12 (0.277 g, 1 mmol) and benzaldehyde (0.106 g, 1 mmol) in glacial acetic acid (20 mL), anhydrous sodium acetate (0.33 g, 4 mmol) was refluxed for 6h. The product, so separated, was filtered, washed with water, dried and recrystallized from ethanol to give compounds which proved to be identical in all respects (mp, mixed mp and IR spectra) with the hydrazonothiazolidinone 13, obtained from method A. Anti-Tumor Activity The cytotoxicity of the newly synthesized compounds against cancer cell lines in vitro was performed with the MTT assay according to the Mosmann’s method. The MTT assay is based on the reduction of the soluble 3-(4,5-methyl-2-thiazolyl)-2,5-diphenyl2H-tetrazolium bromide (MTT) into a blue-purple formazan product, mainly by mitochondrial reductase activity inside living cells. The cells used in cytotoxicity assay were cultured in RPMI 1640 medium supplemented with 10% fetal calf serum. Cells suspended in the medium (2  104/mL) were plated in 96-well culture plates and incubated at 37°C in a 5% CO2 incubator. After 12 h, the test sample (2 μL) was added to the cells (2 104) in 96-well plates and cultured at 37°C for 3 days. The cultured cells were mixed with 20 μL of MTT solution and incubated for 4 h at 37°C. The supernatant was carefully removed from each well and 100 μL of DMSO was added to each well to dissolve the formazan crystals which were formed by the cellular reduction of MTT. After mixing with a mechanical plate mixer, the absorbance of each well was measured by a microplate reader, using a test wavelength of 570 nm. The results were expressed as the IC50 value, which inducing a 50% inhibition of cell growth of treated cells when compared to the growth of control cells. Each experiment was performed at least 3 times. There was a good reproducibility between replicate wells with standard errors below 10%. Measurement of Fluorescence of DNA-bound Hoechst 33342

Method B:

In the cell free system, 1 μg of calf thymus DNA and 0.8 μg of Hoechst 33342 were mixed in 0.2 ml of PBS() and preincubated for 10 min at room temperature in a 96-well plate. Then, TESTED COMPOUNDSwas added at final concentrations of 0.01–30 μg/ml. After 10-min incubation, the fluorescence derived from the Hoechst 33342 bound to DNA was measured with a fluorometer (excitation wavelength, 355 nm; and emission wavelength, 460 nm). In the cellular system, L1210 cells (4  105 cells in 1 ml of culture medium) were preincubated with Hoechst 33342 (4 μg/ml) at 37°C for 20 min. Then, tested agent was added at final concentrations of 0.01–100 μg/ml. After another 20-min incubation, the cells were washed once with ice-cold PBS(), resuspended in ice-cold PBS(), and transferred into a 96-well plate. Fluorescence was measured as described above.

I. Synthesis of 2-(thiochroman-4-ylidenehydrazono)thiazolidin-4one (12)

CONFLICT OF INTEREST

A mixture of 1b (0.237 g, 1 mmol), chloroacetic acid (0.1 g, 1 mmol) in glacial acetic acid (20 mL) containing anhydrous sodium acetate (0.33 g, 4 mmol) was refluxed for 4 h. The reaction mixture was left to cool and the formed solid was filtered off, washed with water, dried and recrystallized from ethanol to give 12. White solid

The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none.

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Abbas et al.

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Received: June 02, 2015

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Revised: August 17, 2015

Accepted: August 28, 2015