Share This Article:

The Uses of 2-Amino-4-Phenylthiazole in the Synthesis of Coumarin, Pyran, Pyridine and Thiazole Derivatives with Antitumor Activities

DOI: 10.4236/oalib.1103526    941 Downloads   1,598 Views   Citations

ABSTRACT

The thiazole derivative 3 was used for a series of heterocyclization reaction to produce pyran, pyridine and thiazole derivatives. The cytotoxicity of the newly synthesized compounds was studied against the six cancer cell lines namely NUGC, HR, DLD1, HA22T, HEPG2, MCF, HONE1 and normal fibroblast cells (WI38). The results showed that most of the synthesized compounds were of high potency. Among the tested compounds, 2-Amino-4-(4-chlorophenyl)-6-(4-phenylthiazol-2-yl)-4H-pyran-3,5-dicarbonitrile 17b showed the highest potency among the tested compounds.

1. Introduction

Thiazole is a core structural motif present in a variety of natural products, such as vitamin B1 (thiamine) and penicillin. Thiazole derivatives also exhibit a broad spectrum of medicinal and biological properties, such as antibacterial, antifungal [1] , anti-inflammatory [2] , antiviral [3] , antimalarial [4] and anti-HIV activities [5] . Thiazole analogs have also been reported as ligands at estrogen receptors [6] , neuropeptide Y5 [7] , adenosine receptors [8] , and act as inhibitors of human platelet aggregation factor [9] , urokinase [10] and poly (ADP-Ribose) polymerase-1 [11] . Selenazoles have been reported to possess antibacterial [12] , and superoxide anion scavenging activity [13] , and exhibit cytotoxicity and DNA fragmentation effects in human HT-1080 fibrosarcoma cells [14] . The structures of sulfathiazole, meloxicam, and selenazofurin and their pharmacological activities are given in Figure 1.

2. Results and Discussion

The reaction of ɷ-bromoacetophenone (1) with thiourea (2) in ethanol gave the thiazole derivative (3) [15] .

The latter compound underwent acetylation when reacted with acetic anhydride to give the N-acetyl derivative 5. The structure of compound 5 was confirmed on the basis of analytical and spectral data. The reaction of compound 3 with phenylisothiocyanate gave the N-phenylthiourea derivative 7. On the other hand, the reaction of compound 3 with ethyl cyanoacetate in dimethylformamide gave N-cyanoacetamide derivative 9. The reaction of compound 9 with any of the aromatic aldehydes namely benzaldehyde (10a), 4-chlorobenzaldehyde (10b) or 4-methoxybenzaldehyde (10c) gave benzylidene derivatives 11a-c, respectively. In addition, the reaction of compound 9 with salicylaldehyde (12) gave the coumarin derivative 13 (Figure 2).

The structure of compound 13 was established on the basis of analytical and spectral data. Thus, the 1H NMR spectrum showed δ = 6.13 (s, 1H, thiazole H-5), 6.29 (s, 1H, coumarin H-4), 7.21 - 7.43 (m, 9H, C6H5, C6H4), 8.30 (s, 1H, D2O exchangeable, NH). The reaction of compound 9 with any of the benzenediazonium chloride derivatives 14a-c gave aryl hydrazone derivatives 15a-c, respectively. Moreover, the multi-component reaction of compound 9 with any of the aromatic aldehydes 10a, 10b or 10c and malononitrile (16) gave the pyran derivatives 17a-c, respectively (Figure 3).

The analytical and spectral data of 17a-c were the basis of their structural identification. Thus, the 1H NMR spectrum of compound 17a (as an example) showed δ = 4.82 (s, 2H, D2O exchangeable, NH2), 6.14 (s, 1H, thiazole H-5), 6.28 (s, 1H, D2O exchangeable, NH), 6.49 (s, 1H, pyran H-4), 7.28 - 7.42 (m, 10H, 2C6H5). Similarly, the multi-component reaction of compound 9 with any of the aromatic aldehydes 10a, 10b or 10c and ethyl cyanoacetate (8) gave the pyran derivatives 18a-c, respectively (Figure 4).

The analytical and spectral data of 18a-c were the basis of their structural identification. In addition, the multi-component reaction of compound 9 with any of the aromatic aldehydes 10a, 10b or 10c and thiourea (2) gave the pyrimidine derivatives 19a-c, respectively. The analytical and spectral data of 19a-c

Figure 1. Biologically active thiazole and selenazole derivatives.

Figure 2. Compounds 3, 5, 7, 9,11a-c, 13.

were the basis of their structural identification. Thus, the 1H NMR spectra of compound 19a (as an example) showed δ = 6.18 (s, 1H, thiazole H-5), 6.28 (s, 1H, D2O exchangeable, NH), 7.29 - 7.36 (m, 10H, 2C6H5), 8.24 (s, 1H, D2O exchangeable, NH). Compound 9 was capable for thiazole synthesis, thus the reaction of compound 9 with elemental sulfur and phenylisothiocyanate (6) gave the thiazole derivative 20.

3. Experiment

General

All melting points were determined on an electrothermal digital melting point apparatus and are uncorrected. IR spectra (KBr discs) were recorded on a FTIR plus 460 or PyeUnicam SP-1000 spectrophotometer. 1H NMR spectra were recorded with Varian Gemini-200 (200 MHz) and Jeol AS 500 MHz instruments spectra were performed in DMSO-d6 as solvent using TMS as internal standard-

Figure 3. Compounds 15a-c, 17a-c.

and chemical shifts are expressed as δ ppm. MS (EI) spectra were recorded with Hewlett Packard 5988 A GC/MS system and GCMS-QP 1000 Ex Shimadzu instruments. Analytical data were obtained from the Micro-analytical Data Unit at Cairo University and were performed on Vario EL III Elemental analyzer. Compound 3 was synthesized according to method reported in literature [15] . All synthesized compounds are filtered using Whatman filter paper 42 Ashless.

1) N-(4-phenylthiazol-2-yl)acetamide (5)

To a solution of compound 3 (1.76 g, 0.01 mol) in acetic acid (40 mL) acetic anhydride (10 mL) was added. The reaction mixture was heated under reflux (118˚C) for 2 h then poured onto ice/water and left to room temperature for 4 h. The formed solid product was collected by filtration.

Yellow crystals from ethanol, yield 70% (1.52 g), m.p. 206˚C - 208˚C. Anal. Calculated for C11H10N2OS (218.27): C, 60.53; H, 4.62; N, 12.83; S, 14.69. Found: C, 60.74; H, 4.59; N, 12.93; S, 14.80. MS: m/e 218 (M+, 28%). IR, υ: 3492 - 3330 (NH), 3056 (CH, aromatic), 2970 (CH3), 1688 (CO), 1638 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 2.80 (s, 3H, CH3), 6.12 (s, 1H, thiazole H-5), 7.26 -

Figure 4. Compounds 18a-c, 19a-c, 20.

7.39 (m, 5H, C6H5), 8.30 (s, 1H, D2O exchangeable, NH).

2) 1-phenyl-3-(4-phenylthiazol-2-yl)thiourea (7)

To a solution of compound 3 (1.76 g, 0.01 mol) in 1,4-dioxane (20 mL) phenylisothiocyanate (1.35 g, 0.01 mol) was added. The reaction mixture was heated under reflux (101˚C) for 3 h then poured onto ice/water and the formed solid product was collected by filtration.

Orange crystals from ethanol, yield 78% (2.42 g), m.p. 130˚C - 132˚C. Anal. Calculated for C16H13N2S2 (311.42): C, 61.71; H, 4.21; N, 13.49; S, 20.59. Found: C, 61.95; H, 4.31; N, 14.22; S, 20.72. MS: m/e 311 (M+, 22%). IR, υ: 3468 - 3324 (2NH), 3054 (CH, aromatic), 1638 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.14 (s, 1H, thiazole H-5), 7.23 - 7.42 (m, 10H, 2C6H5), 8.26, 8.32 (2s, 2H, D2O exchangeable, 2NH).

3) 2-Cyano-N-(4-phenylthiazol-2-yl)acetamide (9)

To a solution of compound 3 (1.76 g, 0.01 mol) in dimethylformamide (20 mL) ethyl cyanoacetate (1.13 g, 0.01 mol) was added. The reaction mixture was heated under reflux (153˚C) for 2 h then poured onto ice/water and the formed solid product was collected by filtration.

Orange crystals from ethanol, yield 67% (1.63 g), m.p. 154˚C - 157˚C. Anal. Calculated for C12H9N3OS (243.28): C, 59.24; H, 3.73; N, 17.27; S, 13.18. Found: C, 59.36; H, 4.01; N, 16.96; S, 13.47. MS: m/e 243 (M+, 36%). IR, υ: 3452-3328 (NH), 3057 (CH, aromatic), 2220 (CN), 1678 (CO), 1632 (C=C),. 1H NMR (DMSO-d6, 200 MHz): δ = 3.84 (s, 2H, CH2), 6.13 (s, 1H, thiazole H-5), 7.28 - 7.39 (m, 5H, C6H5), 8.30 (s, 1H, D2O exchangeable, NH).

4) General procedure for the synthesis of the benzylidine derivatives 11a-c

To a solution of compound 9 (2.43 g, 0.01 mol) in 1,4-dioxane (40 mL) containing piperidine (0.50 mL), any of benzaldehyde (1.08 g, 0.01 mol), 4-chloro- benzaldehyde (1.40 g, 0.01 mol) or 4-methoxybenzaldehyde (1.36 g, 0.01 mol) was added. The reaction mixture was heated under reflux (101˚C) for 3 h then poured onto ice/water containing few drops of hydrochloric acid. The formed solid product, formed in each case was collected by filtration.

5) 2-Cyano-3-phenyl-N-(4-phenylthiazol-2-yl)acrylamide (11a)

Pale brown crystals from ethanol, yield 70% (2.32 g), m.p. 139˚C - 141˚C. Anal. Calculated for C19H13N3OS (331.39): C, 68.86; H, 3.95; N, 12.68; S, 9.68. Found: C, 68.47; H, 4.16; N, 12.51; S, 9.38. MS: m/e 331 (M+, 28%). IR, υ: 3462 - 3341 (NH), 3053 (CH, aromatic), 2220 (CN), 1682 (CO), 1635 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.09 (s, 1H, CH), 6.14 (s, 1H, thiazole H-5), 7.25-7.37 (m, 10H, 2C6H5), 8.32 (s, 1H, D2O exchangeable, NH).

6) 3-(4-chlorophenyl)-2-cyano-N-(4-phenylthiazol-2-yl)acrylamide (11b)

Pale brown crystals from ethanol, yield 66% (2.41 g), m.p. 188˚C - 191˚C. Anal. Calculated for C19H12ClN3OS (365.84): C, 62.38; H, 3.31; N, 11.49; S, 8.76. Found: C, 62.19; H, 3.53; N, 11.60; S, 8.57. MS: m/e 365 (M+, 40%). IR, υ: 3472 - 3329 (NH), 3056 (CH, aromatic), 2222 (CN), 1680 (CO), 1632 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.06 (s, 1H, CH), 6.12 (s, 1H, thiazole H-5), 7.23-7.42 (m, 9H, C6H5, C6H4), 8.34 (s, 1H, D2O exchangeable, NH).

7) 2-cyano-3-(4-methoxyphenyl)-N-(4-phenylthiazol-2-yl)acrylamide (11c)

Yellow crystals from ethanol, yield 78% (2.83 g), m.p. 166-169˚C. Anal. Calculated for C20H15N3O2S (361.42): C, 66.46; H, 4.18; N, 11.63; S, 8.87. Found: C, 66.37; H, 3.86; N, 11.41; S, 8.72. MS: m/e 361 (M+, 22%). IR, υ: 3463 - 3342 (NH), 3053 (CH, aromatic), 2220 (CN), 1682 (CO), 1631 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 3.68 (s, 3H, OCH3), 6.08 (s, 1H, CH), 6.14 (s, 1H, thiazole H-5), 7.24-7.38 (m, 9H, C6H5, C6H4), 8.32 (s, 1H, D2O exchangeable, NH).

8) 2-Oxo-N-(4-phenylthiazol-2-yl)-2H-chromene-3-carboxamide (13)

To a solution of compound 9 (2.43 g, 0.01 mol) in 1,4-dioxane (40 mL) containing piperidine (0.50 mL) salicylaldehyde (1.22 g, 0.01 mol) was added. The reaction mixture was heated under reflux (101˚C) for 2 h then poured onto ice/water containing few drops of hydrochloric acid. The formed solid product was collected by filtration.

Yellow crystals from ethanol, yield 62% (2.16 g), m.p. 122˚C - 124˚C. Anal. Calculated for C19H12N2O3S (348.38): C, 65.51; H, 3.47; N, 8.04; S, 9.20. Found: C, 65.44; H, 3.59; N, 7.94; S, 9.38. MS: m/e 348 (M+, 18%). IR, υ: 3439-3312 (NH), 3056 (CH, aromatic), 1690, 1682 (2CO), 1665 (C=N), 1628 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.13 (s, 1H, thiazole H-5), 6.29 (s, 1H, coumarin H-4), 7.21 - 7.43 (m, 9H, C6H5, C6H4), 8.30 (s, 1H, D2O exchangeable, NH).

9) General procedure for the synthesis of the aryl hydrazone derivatives 15a-c

To a cold solution (0˚C - 5˚C) of compound 9 (2.43 g, 0.01 mol) in ethanol (40 mL) containing sodium acetate (2.50 g) any of the diazonium salts namely benzenediazonium chloride (14a) (0.01 mol) 4-chlorobenzene diazonium chloride (14b) (0.01 mol) or 4-methylbenzenediazonium chloride (14c) (0.01 mol) [prepared by the addition of sodium nitrite (0.70 g, 0.01 mol) to a cold solution (0-5 ˚C) of any of aniline (0.93 g, 0.01 mol), 4-chloroaniline (1.27 g, 0.01 mol) or 4-methylaniline (1.14 g, 0.01 mol) in concentrated hydrochloric acid (16 mL)] was added. The whole reaction mixture, in each case, was stirred at room temperature for 2 h and the formed solid product was collected by filtration.

10) 2-Oxo-N’-phenyl-2-((4-phenylthiazol-2-yl)amino)acetohydrazonoyl cyanide (15a)

Orange crystals from ethanol, yield 65% (2.24 g), m.p. 153˚C - 156˚C. Anal. Calculated for C18H13N5OS (347.39): C, 62.23; H, 3.77; N, 20.16; S, 9.23. Found: C, 62.41; H, 3.54; N, 20.08; S, 9.52. MS: m/e 347 (M+, 36%). IR, υ: 3452-3316 (2NH), 3053 (CH, aromatic), 2220 (CN), 1686 (CO), 1660 (C=N), 1626 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.12 (s, 1H, thiazole H-5), 7.24-7.38 (m, 10H, 2C6H5), 8.26, 8.30 (2s, 2H, D2O exchangeable, 2NH).

11) N’-(4-Chlorophenyl)-2-oxo-2-((4-phenylthiazol-2-yl)amino)acetohydra- zonoyl cyanide (15b)

Orange crystals from ethanol, yield 74% (2.82 g), m.p. 177˚C - 179˚C. Anal. Calculated for C18H12ClN5OS (381.84): C, 56.62; H, 3.17; N, 18.34; S, 8.40. Found: C, 56.82; H, 3.38; N, 18.51; S, 8.29. MS: m/e 381 (M+, 28%). IR, υ: 3458 - 3331 (2NH), 3056 (CH, aromatic), 2222 (CN), 1688 (CO), 1653 (C=N), 1628 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.18 (s, 1H, thiazole H-5), 7.22-7.41 (m, 9H, C6H5, C6H4), 8.28, 8.31 (2s, 2H, D2O exchangeable, 2NH).

12) 2-Oxo-2-((4-phenylthiazol-2-yl)amino)-N’-(p-tolyl)acetohydrazonoylcya- nide (15c)

Orange crystals from ethanol, yield 72% (2.59 g), m.p. 203˚C - 206˚C. Anal. Calculated for C19H15N5OS (361.42): C, 63.14; H, 4.18; N, 19.38; S, 8.87. Found: C, 62.97; H, 3.92; N, 19.26; S, 8.65. MS: m/e 361 (M+, 38%). IR, υ: 3471 - 3369 (2NH), 3055 (CH, aromatic), 2220 (CN), 1687 (CO), 1656 (C=N), 1629 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 2.69 (s, 3H, CH3), 6.17 (s, 1H, thiazole H-5), 7.24 - 7.45 (m, 9H, C6H5, C6H4), 8.26, 8.33 (2s, 2H, D2O exchangeable, 2NH).

13) General procedure for the synthesis of the pyran derivatives 17a-c

To a solution of compound 9 (2.43 g, 0.01 mol) in ethanol (30 mL) containing triethylamine (0.50 mL) malononitrile (0.66 g, 0.01 mol) and any of benzaldehyde (1.06 g, 0.01 mol), 4-chlorobenzaldehyde (1.40 g, 0.01 mol) or 4-methox- ybenzaldehyde (1.36 g, 0.01 mol) was added. The reaction mixture, in each case, was heated under reflux (78˚C) for 3 h then left to cool and the formed solid product was collected by filtration.

14) 2-Amino-4-phenyl-6-(4-phenylthiazol-2-yl)amino)-4H-pyran-3,5-dicar- bonitrile (17a)

Orange crystals from ethanol, yield 83% (3.29 g), m.p. 213˚C - 215˚C. Anal. Calculated for C22H15N5OS (397.45): C, 66.48; H, 3.80; N, 17.62; S, 8.07. Found: C, 66.73; H, 3.92; N, 17.94; S, 8.19. MS: m/e 397 (M+, 26%). IR, υ: 3462 - 3338 (NH, NH2), 3056 (CH, aromatic), 2221 (CN), 1662 (C=N), 1621 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 4.82 (s, 2H, D2O exchangeable, NH2), 6.14 (s, 1H, thiazole H-5), 6.28 (s, 1H, D2O exchangeable, NH), 6.49 (s, 1H, pyran H-4), 7.28-7.42 (m, 10H, 2C6H5).

15) 2-Amino-4-(4-chlorophenyl)-6-(4-phenylthiazol-2-yl)amino)-4H-pyran- 3,5-dicarbonitrile (17b)

Orange crystals from ethanol, yield 76% (3.27 g), m.p. 183˚C - 185˚C. Anal. Calculated for C22H14ClN5OS (431.90): C, 61.18; H, 3.27; N, 16.22; S, 7.42. Found: C, 61.28; H, 3.37; N, 16.49; S, 7.80. MS: m/e 431 (M+, 18%). IR, υ: 3462 - 3338 (NH, NH2), 3056 (CH, aromatic), 2222 (CN), 1659 (C=N), 1626 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 4.80 (s, 2H, D2O exchangeable, NH2), 6.17 (s, 1H, thiazole H-5), 6.26 (s, 1H, D2O exchangeable, NH), 6.49 (s, 1H, pyran H-4), 7.22 - 7.48 (m, 9H, C6H5, C6H4).

16) 2-Amino-6-(4-phenylthiazol-2-yl)amino)-4-(p-tolyl)-4H-pyran-3,5-dicar- bonitrile (17c)

Orange crystals from ethanol, yield 68% (2.90 g), m.p. 97˚C - 99˚C. Anal. Calculated for C23H17N5O2S (427.48): C, 64.62; H, 4.01; N, 16.38; S, 7.50. Found: C, 64.80; H, 4.26; N, 16.60; S, 7.44. MS: m/e 427 (M+, 33%). IR, υ: 3462 - 3338 (NH, NH2), 3055 (CH, aromatic), 2220 (CN), 1655 (C=N), 1628 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 3.77 (s, 3H, CH3), 4.81 (s, 2H, D2O exchangeable, NH2), 6.19 (s, 1H, thiazole H-5), 6.28 (s, 1H, D2O exchangeable, NH), 6.46 (s, 1H, pyran H-4), 7.24 - 7.45 (m, 9H, C6H5, C6H4).

17) General procedure for the synthesis of the pyran derivatives 18a-c

To a solution of compound 9 (2.43 g, 0.01 mol) in ethanol (30 mL) containing triethylamine (0.50 mL) ethyl cyanoacetate (1.13 g, 0.01 mol) and any of benzaldehyde (1.06 g, 0.01 mol), 4-chlorobenzaldehyde (1.40 g, 0.01 mol) or 4-me- thoxybenzaldehyde (1.36 g, 0.01 mol) was added. The reaction mixture, in each case, was heated under reflux (78˚C) for 6 h then left to cool and the formed solid product was collected by filtration.

18) 2-Hydroxy-4-phenyl-6-(4-phenylthiazol-2-yl)amino)-4H-pyran-3,5-dicar- bonitrile (18a)

Orange crystals from ethanol, yield 70% (2.79 g), m.p. 228˚C - 230˚C. Anal. Calculated for C22H14N4O2S (398.44): C, 66.32; H, 3.54; N, 14.06; S, 8.05. Found: C, 66.88; H, 3.51; N, 14.14; S, 8.40. MS: m/e 398 (M+, 19%). IR, υ: 3560 - 3328 (NH, OH), 3056 (CH, aromatic), 2223 (CN), 1660 (C=N), 1626 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.16 (s, 1H, thiazole H-5), 6.46 (s, 1H, pyran H-4), 6.49 (s, 1H, D2O exchangeable, NH),7.29 - 7.36 (m, 10H, 2C6H5), 10.20 (s, 1H, D2O exchangeable, OH).

19) 4-(4-Chlorophenyl)-2-hydroxy-6-(4-phenylthiazol-2-yl)amino)-4H-py- ran-3,5-dicarbonitrile (18b)

Yellow crystals from ethanol, yield 80% (3.46 g), m.p. 220˚C - 223˚C. Anal. Calculated for C22H13ClN4O2S (432.88): C, 61.04; H, 3.03; N, 12.94; S, 7.41. Found: C, 61.42; H, 3.02; N, 12.83; S, 7.83. MS: m/e 432 (M+, 20%). IR, υ: 3560 - 3328 (NH, OH), 3054 (CH, aromatic), 2220 (CN), 1659 (C=N), 1624 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 6.13 (s, 1H, thiazole H-5), 6.47 (s, 1H, pyran H-4), 6.6 (s, 1H, D2O exchangeable, NH), 7.23 - 7.47 (m, 9H, C6H5, C6H4), 10.22 (s, 1H, D2O exchangeable, OH).

20) 2-Hydroxy-6-(4-phenylthiazol-2-yl)amino)-4-(p-tolyl)-4H-pyran-3,5-di- carbonitrile (18c)

Orange crystals from ethanol, yield 72% (3.08 g), m.p. 234˚C - 237˚C. Anal. Calculated for C23H16N4O3S (428.46): C, 64.47; H, 3.76; N, 13.08; S, 7.48. Found: C, 64.43; H, 3.91; N; 13.22; S, 7.86. MS: m/e 428 (M+, 20%). IR, υ: 3560 - 3328 (NH, OH), 3056 (CH, aromatic), 2223 (CN), 1652 (C=N), 1623 (C=C). 1H NMR (DMSO-d6, 200 MHz): δ = 3.79 (s, 3H, CH3), 6.16 (s, 1H, thiazole H-5), 6.27 (s, 1H, D2O exchangeable NH), 6.48 (s, 1H, pyran H-4), 7. 28 - 7.41 (m, 9H, C6H5, C6H4), 10.18 (s, 1H, D2O exchan- geable, OH).

21) General procedure for the synthesis of the pyrimidine derivatives 19a-c

To a solution of compound 9 (2.43 g, 0.01 mol) in ethanol (30 mL) containing triethylamine (0.50 mL) thiourea (0.76 g, 0.01 mol) and any of benzaldehyde (1.06 g, 0.01 mol), 4-chlorobenzaldehyde (1.40 g, 0.01 mol) or 4-methoxybenzal- dehyde (1.36 g, 0.01 mol) was added. The reaction mixture, in each case, was heated under reflux (78˚C) for 6 h then left to cool and the formed solid product was collected by filtration.

22) 6-Phenyl-4-(4-phenylthiazol-2-yl)amino)-2-thioxo-1,2-dihydropyrimi- dine-5-carbonitrile (19a)

Orange crystals from ethanol, yield 66% (2.55 g), m.p. 162˚C - 165˚C. Anal. Calculated for C20H13N5S2 (387.48): C, 61.99; H, 3.38; N, 18.07; S, 16.55. Found: C, 62.32; H, 3.49; N; 18.33; S, 16.19. MS: m/e 387 (M+, 25%). IR, υ: 3480 - 3337 (2NH), 3054 (CH, aromatic), 2220 (CN), 1663 (C=N), 1629 (C=C), 1205 (C=S). 1H NMR (DMSO-d6, 200 MHz): δ = 6.18 (s, 1H, thiazole H-5), 6.28 (s, 1H, D2O exchangeable, NH), 7.29 - 7.36 (m, 10H, 2C6H5), 8.24 (s, 1H, D2O exchangeable, NH).

23) 6-(4-Chlorophenyl)-4-(4-phenylthiazol-2-yl)amino)-2-thioxo-1,2-dihy- dropyrimidine-5-carbonitrile (19b)

Yellow crystals from ethanol, yield 75% (3.15 g), m.p. 133˚C - 135˚C. Anal. Calculated for C20H12ClN5S2 (421.93): C, 56.93; H, 2.87; N, 16.60; S, 15.20. Found: C, 56.73; H, 2.99; N; 16.83; S, 15.69. MS: m/e 421 (M+, 28%). IR, υ: 3487 - 3346 (2NH), 3056 (CH, aromatic), 2223 (CN), 1656 (C=N), 1628 (C=C), 1221 (C=S). 1H NMR (DMSO-d6, 200 MHz): δ = 6.14 (s, 1H, thiazole H-5), 6.6 (s, 1H, D2O exchangeable, NH), 7.21 - 7.49 (m, 9H, C6H5, C6H4), 8.25 (s, 1H, D2O exchangeable, NH).

24) 6-(4-Methoxyphenyl)-4-(4-phenylthiazol-2-yl)amino)-2-thioxo-1,2-dihy- dropyrimidine-5-carbonitrile (19c)

Orange crystals from ethanol, yield 68% (2.83 g), m.p. 177˚C - 179˚C. Anal. Calculated for C21H15N5OS2 (417.51): C, 60.41; H, 3.62; N, 16.77; S, 15.36. Found: C, 60.52; H, 3.79; N; 16.55; S, 15.26. MS: m/e 417 (M+, 15%). IR, υ: 3480 - 3329 (2NH), 3054 (CH, aromatic), 2221 (CN), 1658 (C=N), 1622 (C=C), 1205 (C=S). 1H NMR (DMSO-d6, 200 MHz): δ = 3.74 (s, 3H, CH3), 6.16 (s, 1H, thiazole H-5), 6.36 (s, 1H, D2O exchangeable, NH), 7.23 - 7.46 (m, 9H, C6H5, C6H4), 8.23 (s, 1H, D2O exchangeable, NH).

25) 4-Amino-3-phenyl-N-(4-phenylthiazol-2-yl)amino)-2-thioxo-2,3-dihy- drothiazole-5-carboxamide (20)

To a solution of compound 9 (2.43 g, 0.01 mol) in ethanol (30 mL) containing triethylamine (0.50 mL), elemental sulfur (0.32 g, 0.01 mol) and phenylisothiocyanate (1.35 g, 0.01 mol) were added. The reaction mixture, in each case, was heated under reflux (78˚C) for 6 h then left to cool then poured onto ice/water containing few drops of hydrochloric acid and the formed solid product was collected by filtration.

Orange crystals from ethanol, yield 50% (2.05 g), m.p. 164˚C - 167˚C. Anal. Calculated for C19H14N4OS3 (410.54): C, 55.59; H, 3.44; N, 13.65; S, 23.43. Found: C, 55.73; H, 3.83; N; 13.83; S, 23.44. MS: m/e 410 (M+, 35%). IR, υ: 3475 - 3342 (NH, NH2), 3056 (CH, aromatic), 1688 (CO), 1655 (C=N), 1623 (C=C), 1230 (C=S). 1H NMR (DMSO-d6, 200 MHz): δ = 4.34 (s, 2H, D2O exchangeable NH2), 6.19 (s, 1H, thiazole H-5), 7. 23 - 7.46 (m, 10H, 2C6H5), 8.39 (s, 1H, D2O exchan- geable, NH).

4. Biological Activity

4.1. In Vitro Cytotoxic Assay

4.1.1. Chemicals

Fetal bovine serum (FBS) and L-glutamine, were purchased from Gibco Invitrogen Co. (Scotland, UK). RPMI-1640 medium was purchased from Cambrex (New Jersey, USA). Dimethyl sulfoxide (DMSO), doxorubicin, penicillin, streptomycin and sulforhodamine B (SRB) were purchased from Sigma Chemical Co. (Saint Louis, USA).

4.1.2. Cell cultures

Were obtained from the European Collection of cell Cultures (ECACC, Salisbury, UK) and human gastric cancer (NUGC and HR), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), human breast cancer (MCF), nasopharyngeal carcinoma (HONE1) and normal fibroblast cells (WI38) were kindly provided by the National Cancer Institute (NCI, Cairo, Egypt). They grow as monolayer and routinely maintained in RPMI-1640 medium supplemented with 5% heat inactivated FBS, 2 mM glutamine and antibiotics (penicillin 100 U/mL, streptomycin 100 lg/mL), at 37˚C in a humidified atmosphere containing 5% CO2. Exponentially growing cells were obtained by plating 1.5 ´ 105 cells/mL for the seven human cancer cell lines including cells derived from 0.75 ´ 104 cells/mL followed by 24 h of incubation. The effect of the vehicle solvent (DMSO) on the growth of these cell lines was evaluated in all the experiments by exposing untreated control cells to the maximum concentration (0.5%) of DMSO used in each assay.

The heterocyclic compounds, prepared in this study, were evaluated according to standard protocols for their in vitro cytotoxicity against six human cancer cell lines including cells derived from human gastric cancer (NUGC), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), human breast cancer (MCF), nasopharyngeal carcinoma (HONE1) and a normal fibroblast cells (WI38). All of IC50 values were listed in Table 1. Some heterocyclic compounds was observed with significant cytotoxicity against most of the cancer cell lines tested (IC50 = 10 - 1000 nM). Normal fibroblasts cells (WI38) were affected to a much lesser extent (IC50 > 10,000 nM). The reference compound used is the CHS-828 which is a pyridyl cyanoguanidine anti-tumor agent.

4.2. Structure Activity Relationship

It is clear from Table 1 that most of the tested compounds showed high cytotoxicity against the six cancer cell line. The thiazole derivative 3 showed moderate cytotoxicity against the six cancer cell lines. Acetylation of compound 3 to give the N-acetyl derivative 3 did not give a remarkable difference in activity compared with the original thiazole 3. Reaction of compound 3 with phenylisothiocyanate to give the N-phenylthiourea derivative 7 showed also moderate potency. Similarly, the N-cyanoacetyl derivative 9 showed moderate potency against the six cancer cell lines. However, the reaction of compound 9 with any of the aromatic aldehydes gave the arylidene derivatives 11a-c. It is obvious that compound 11b (X = Cl) showed the highest potency among such series of compounds. On the other hand, 11c (X = OCH3) showed high potency against only NUGC cell lines and moderate potency against the other cell lines. The reaction of compound 9 with any of the diazonium salts 14a-c gave the aryl hydrazone derivatives 15a-c. Compound 15b with the electronegative Cl group showed the highest cytotoxicity among the three compounds. The multicomponent reactions of compound 9 with any of the aromatic aldehydes 10a-c and malononitrile gave the pyran derivatives 17a-c. It is obvious from Table 1 that compounds 17b and 17c showed high potency against the six cancer cell lines. However compound 17a showed high potency against NUGC, DLDI, HA22T, HEPG2and HONE1 cell lines and low potency against MCF cell lines. On the other hand, for the pyran derivatives 18a-c it is clear from Table 1 that compound 18a (X = H) showed high potency against DLDI, HEPG2 and MCF cell lines with IC50’s 368, 224 and 310 nM and 18b showed high potency against HONE1 cell line with IC50 666 nM. For the pyrimidine derivatives 19a-c, compound 19c with X = OCH3 showed high potency against NUGC, DLDI, HA22,

Table 1. Cytotoxicity of novel derivatives against a variety of cancer cell lines [IC50b (nM)].

aNUGC, gastric cancer, DLDI, colon cancer, HA22T, liver cancer, HEPG2, liver cancer; HONEI, nasopharyngeal carcinoma; HR, gastric cancer; MCF, breast cancer; WI38, normal fibroblast cells.

and MCF cell lines. Finally, the thiazole derivative 20 showed high potency against the six cancer cell lines. Its high potency is attributed to the presence of high content of N and S together with the phenyl moiety through the molecule.

5. Conclusions

A series of new heterocyclic compounds with the thiazole nucleus were synthesized and characterized. Their cytotoxicity against six cancer cell lines was measured and the results showed that compounds 11b, 11c, 15b, 17a, 17b, 17c, 19c and 20 were the most potent compounds among the synthesized compounds. The 2-amino-4-(4-chlorophenyl)-6-(4-phenylthiazol-2-yl)-4H-pyran-3, 5-dicarbonitrile (17b) showed the maximum cytotoxicity among the synthesized compounds towards the six cancer cell lines.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Hamed, F. , Mohamed, A. and Abouzied, A. (2017) The Uses of 2-Amino-4-Phenylthiazole in the Synthesis of Coumarin, Pyran, Pyridine and Thiazole Derivatives with Antitumor Activities. Open Access Library Journal, 4, 1-14. doi: 10.4236/oalib.1103526.

References

[1] Bharti, S.K., Nath, G., Tilak, R. and Singh, S.K. (2010) Synthesis, Anti-Bacterial and Anti-Fungal Activities of Some Novel Schiff Bases Containing 2,4-Disubstituted Thiazole Ring. European Journal of Medicinal Chemistry, 45, 651–660.
https://doi.org/10.1016/j.ejmech.2009.11.008
[2] Yang, B.V., Weinstein, D.S., Doweyko, L.M., Gong, H., Vaccaro, W., Huynh, T., Xiao, H.-Y., Doweyko, A.M., Mckay, L., Holloway, D.A., Somerville, J.E., Habte, S., Cunningham, M., McMahon, M., Townsend, R.,, Shuster, D., Dodd, J.H., Nadler, S.G. and Barrish, J.C. (2010) Dimethyl-Diphenyl-Propanamide Derivatives as Nonsteroidal Dissociated Glucocorticoid Receptor Agonists. Journal of Medicinal Chemistry, 53, 8241-8251.
https://doi.org/10.1021/jm100957a
[3] Spector, F.C., Liang, L., Giordano, H., Sivaraja, M. and Peterson, M.G. (1998) Inhibition of Herpes Simplex Virus Replication by a 2-Amino Thiazole via Interactions with the Helicase Component of the UL5-UL8-UL52 Complex. Journal of Virology, 72, 6979-6987.
[4] Diego, G.C., Frederic, D., Feng, T.-S., Nchinda, A., Younis, Y., White, K.L., Wu, Q., Ryan, E., Burrows, J., Waterson, D., Witty, J.M., Wittlin, S., Charman, S.A. and Chibale, K. (2011) Novel Orally Active Antimalarial Thiazoles. Journal of Medicinal Chemistry, 54, 7713-7719.
https://doi.org/10.1021/jm201108k
[5] Bell, F.W., Cantrell, A.S., Högberg, M., Jaskunas, S.R., Johansson, N.G., Jordan, C.L., Kinnick, M.D., Lind, P., Morin Jr, J.M., Noréen, R., Oberg, B., Palkoeitz, J.A., Parrish, C.A., Pranc, P., Sahiberg, C., Ternansky, R.J., Vasileff, R.T., Vrang, L., West, S.J., Zhang, H. and Zhou, X.-X. (1995) Phenethylthiazolethiourea (PETT) Compounds, a New Class of HIV-1 Reverse Transcriptase Inhibitors. 1. Synthesis and Basic Structure-Activity Relationship Studies of PETT Analogs. Journal of Medicinal Chemistry, 38, 4929-4936.
https://doi.org/10.1021/jm00025a010
[6] Fink, B.E., Mortensen, D.S., Stauffer, S.R., Aron, Z.D. and Katzenellenbogen, J.A. (1999) Novel Structural Templates for Estrogen-Receptor Ligands and Prospects for Combinatorial Synthesis of Estrogens. Cell Chemical Biology, 6, 205-219.
https://doi.org/10.1016/s1074-5521(99)80037-4
[7] Matteo, B., Colin, P.L., Angelica, M. and Caberlotto, L. (2010) Synthesis and Structure-Activity Relationship of N-(3-Azabicyclo[3.1.0]Hex-6-ylMethyl)-5-(2-Pyridinyl)-1,3-Tthiazol-2-Amines Derivatives as NPY Y5 Antagonists. Bioorganic and Medicinal Chemistry Letters, 20, 4741-4744.
https://doi.org/10.1016/j.bmcl.2010.06.140
[8] Tilburg, E.W.V., Van der Klein, P.A.M., Groote, M.D., Beukers, M.W. and Jzerman, A.P.I. (2001) Substituted 4-Phenyl-2-(Phenylcarboxamido)-1,3-Thiazole Derivatives as Antagonists for the AdenosineA1 Receptor. Bioorganic and Medicinal Chemistry Letters, 11, 2017-2019.
https://doi.org/10.1016/S0960-894X(01)00356-0
[9] Bhoga, U. (2007) Novel Synthetic Approach to N-aryl-4-(3-Pyridyl)Thiazol-2-Amine and Analogues Using HMCM-41 as Catalyst, and Their Biological Evaluation as Human Platelet Aggregation Inhibitors. European Journal of Medicinal Chemistry, 42, 1144-1150.
https://doi.org/10.1016/j.ejmech.2007.01.016
[10] Wilson, K.J., Illig, C.R., Subasinghe, N. and Spurlino, J. (2001) Synthesis of Thiophene-2 -Carboxamidines Containing 2-Aminothiazoles and Their Biological Evaluation as Urokinase Inhibitors. Bioorganic and Medicinal Chemistry Letters, 11, 915-918.
https://doi.org/10.1016/S0960-894X(01)00102-0
[11] Zhang, W.T., Ruan, J.L., Wu, P.F., Jiang, F.-C., Zhang, L.-N., Fang, W., Chen, X.-L., Wang, Y., Cao, B.-S., Chen, G.-Y., Zhu, Y.-J., Gu, J. and Chen, J.-G. (2009) Design, Synthesis, and Cytoprotective Effect of 2-Aminothiazole Analogues as Potent Poly (ADP-Ribose) Polymerase-1 Inhibitors. Journal of Medicinal Chemistry, 52, 718-725.
https://doi.org/10.1021/jm800902t
[12] Gebeyehu, G., Marquez, V.E., Cott, A.V., Cooney, D.A., Kelley, J.A., Jayaram, H.N., Ahluwalia, G.S., Dion, R.L., Wilson, Y.A. and Johns, D.G. (1985) Ribavirin, Tiazofurin, and Selenazofurin: Mononucleotides and Nicotinamide Adenine Dinucleotide Analogues. Synthesis, Structure, and Interactions with IMP Dehydrogenase. Journal of Medicinal Chemistry, 28, 99-105.
https://doi.org/10.1021/jm00379a018
[13] Sekhiguchi, A., Nishina, A., Kimura, H., Fukumoto, R.-H., Kanoh, K., Ishihara, H. and Koketsu, M. (2005) Superoxide Anion-Scavenging Effect of 2-Amino-1, 3-Selenazoles. Chemical and Pharmaceutical Bulletin, 53, 1439-1442.
https://doi.org/10.1248/cpb.53.1439
[14] Koketsua, M., Ishihara, H., Wu, W., Murakami, K. and Saiki, I. (1999) 1,3-Selenazine Derivatives Induce Cytotoxicity and DNA Fragmentation in Human HT-1080 Fibrosarcoma Cells. European Journal of Pharmaceutical Sciences, 9, 157-161.
https://doi.org/10.1016/S0928-0987(99)00058-5
[15] Hantzsch, A. and Weber, J.H. (1887) Ueber Verbindungen des Thiazols (Pyridins der Thiophenreihe). Berichte der deutschen chemischen Gesellschaft, 20, 3118-3132.
https://doi.org/10.1002/cber.188702002200

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.