Organic Chemistry International

Volume 2013 (2013), Article ID 259348, 9 pages

http://dx.doi.org/10.1155/2013/259348

Research Article

Utility of Activated Nitriles in the Synthesis of Novel Heterocyclic Compounds with Antitumor Activity

Asmaa S. Salman

Department of Chemistry, Faculty of Science, Al-Azhar University, Girls' Branch, Nasr City, Cairo, Egypt

Received 23 July 2013; Accepted 19 August 2013

Academic Editor: Joseph E. Saavedra

Copyright © 2013 Asmaa S. Salman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Reaction of cyanoacetic acid hydrazide (1) with 4-methoxyacetophenone and 4-chlorobenzaldehyde (2a,b) afforded the corresponding 2-cyanoacetohydrazide derivatives (3a,b) respectively. The latter compounds were utilized as a key intermediate for the synthesis of new heterocyclic compounds. Newly synthesized compounds were characterized by elemental analyses and spectral data. The antitumor evaluation of some newly synthesized compounds was screened in vitro against human breast cancer cell line (MCF-7).

1. Introduction

In many reports, hydrazide-hydrazones are considered to be good candidates for different pharmaceutical applications, where such compounds were considered to exert anticonvulsant [1], analgesic [2], anti-inflammatory [3], antiplatelet [4], antimalarial [5], antimicrobial [6], antitumoral [7, 8], vasodil-ator [9], and antiviral activity [10]. With the aim of obtaining new hydrazide-hydrazones with such wide spectrum of pharmaceutical applications, in this research, synthesis of a series of hydrazide-hydrazones and some of their heterocyclic transformations, followed by antitumor evaluations of newly synthesized products was done.

2. Experimental

All melting points were determined in open glass capillaries on a Gallenkamp apparatus and are uncorrected. IR spectra (cm⁻¹) were recorded on a Pye-Unicam spectrophotometer type 1200 using KBr discs. ¹H-NMR spectra were recorded on a Varian EM-390 (90 MHz) spectrometer using TMS as an internal standard and DMSO-d6 as a solvent. Chemical shifts were expressed in δ (ppm) values and mass spectra were determined on Finnigan Incos 500 (70 ev). Elemental analyses were determined using a Parkin-Elmer 240C Microanalyzer. The microanalyses were performed at the Microanalytical Unit, Faculty of Science, Cairo University.

2.1. General Procedure for Synthesis of 3a ,b

To a solution of 2-cyanoacetohydrazide (0. 99 g, 0.01 mol) in ethanol (20 mL), 4-methoxyacetophenone and/or p-chlorobenzaldehyde (0.01 mol) was added. The reaction mixture was heated under reflux for 2 h, then left to cool, and poured into ice/water. The obtained product was filtered, washed with water, and recrystallized from the appropriate solvent to give 3a,b.

2.1.1. Cyano-N′-[1-(4-methoxyphenyl)ethylidene]acetohydrazide (3a)

Yield, 75%; m.p. 186–188°C (ethanol); IR (KBr, cm⁻¹): 3204 (NH), 1675 (CO), 2256 (CN); ¹H NMR (DMSO: δ ppm): 2.23 (s, 3H, CH₃), 3.81 (s, 3H, OCH₃), 4.18 (s, 2H, CH₂), 10.90 (s, 1H, NH), 6.93–7.76 (m, 4H Ar–H); MS m/z (%): 231 (M⁺, 98.11), 216 (27.99), 191 (40.26), 163 (48.64), 148 (80.06), 134 (87.96), 121 (39.49), 119 (56.71), 92 (100). Anal. for C₁₂H₁₃N₃O₂ (231.25); Calcd.: C, 62.33; H, 5.67; N, 18.17. Found: C, 62.00; H, 5.33; N, 18.02%.

2.1.2. N′-[(4-Chlorophenyl)methylene]-2-cyanoacetohydrazide (3b)

Yield, 80%; m.p. 210–214°C (ethanol); IR (KBr, cm⁻¹): 3185 (NH), 1673 (CO), 2258 (CN); ¹H NMR (DMSO, δ ppm): 4.21 (s, 2H, CH₂), 11.82 (s, 1H, NH), 7.48–7.99 (m, 4H Ar–H), 8.16 (s, 1H, =CH); MS m/z (%): 221 (M⁺, 2.35), 153 (5.54), 138 (100), 126 (15.89), 76 (15.35). Anal. for C₁₀H₈Cl N₃O (221.64); Calcd.: C, 54.19; H, 3.64; Cl, 16.00; N, 18.96. Found: C, 54.00; H, 3.42; Cl, 15.82; N, 18.65%.

2.2. General Procedure for Synthesis of 4a ,b

To a mixture of 3a,b (0.01 mol), and salicylaldehyde (1.22 g, 0.01 mol) in ethanol (15 mL) were added few drops of TEA. The reaction was heated on water bath for 4 h and poured into ice water. The obtained product was filtered, washed with water, and recrystallized from the appropriate solvent to give 4a,b.

2.2.1. 2-Imino-N′-[1-(4-methoxyphenyl)ethylidene]-2H-chromene-3-carbohydrazide (4a)

Yield, 80%; m.p. 210–212°C (ethanol); IR (KBr, cm⁻¹): 3430, 3300 (2NH), 1671 (CO); ¹H NMR (DMSO, δ ppm): 3.80 (s, 3H, OCH₃), 2.48 (s, 3H, CH₃), 6.98–7.83 (m, 9H, Ar–H and C4-H coumarin), 9.27 (s, 1H, NH), 13.47 (s, 1H, NH); MS m/z (%): 335 (M⁺, 100), 320 (18.43), 148 (3.90), 145 (95.72), 134 (12.36). Anal. for C₁₉H₁₇ N₃O₃ (335.35); Calcd.: C, 68.05; H, 5.11; N, 12.53. Found: C, 68.00; H, 5.09; N, 12.23%.

2.2.2. N′-[(4-Chlorophenyl)methylene]-2-imino-2H-chromene-3-carbohydrazide(4b)

Yield, 75%; m.p. 170–172°C (ethanol); IR (KBr, cm⁻¹): 3422, 3310 (2NH), 1618 (CO); ¹H NMR (DMSO, δ ppm): 6.94–7.70 (m, 10H, Ar–H, C4-H coumarin and =CH), 9.00 (s, 1H, NH), 11.10 (s, 1H, NH); MS m/z (%): 324 (M⁺ −1, 1.54), 310 (3.73), 239 (32.03), 165 (100). Anal. for C₁₇H₁₂Cl N₃O₂ (325.74); Calcd.: C, 62.68; H, 3.71; Cl, 10.88; N, 12.90. Found: C, 62.38; H, 3.41; Cl, 10.52; N, 12.69%.

2.3. General Procedure for Synthesis of Arylidene Derivatives (5a–d)

A solution of 3a,b (0.01 mol) in ethanol (30 mL) was treated with 0.01 mol of aromatic aldehydes such as 4-methoxybenzaldehyde and/or 4-chlorobenzaldehyde and few drops of TEA. The reaction mixture was heated under reflux for 6 h. The reaction mixture was left to cool at room temperature and poured into ice/water containing few drops of hydrochloric acid, and the formed solid was collected by filtration and recrystallized from the appropriate solvent to give 5a–d.

2.3.1. 2-Cyano-3-(4-methoxyphenyl)-N′-[1-(4-methoxyphenyl)ethylidene]acrylohydrazide(5a)

Yield, 60%; m.p. 158–160°C (ethanol); IR (KBr, cm⁻¹): 3367 (NH), 2199 (CN), 1686 (CO); ¹H NMR (DMSO, δ ppm): 3.77 (s, 6H, 2OCH₃), 2.49 (s, 3H, CH₃), 6.91–8.17 (m, 9H, Ar–H and =CH proton), 10.10 (s, 1H, NH); Anal. for C₂₀H₁₉N₃O₃ (349.38; Calcd.: C, 68.75; H, 5.48; N, 12.03. Found: C, 68.55; H, 5.28; N, 12.00%.

2.3.2. N′-[(4-Chlorophenyl)methylene]-2-cyano-3-(4-methoxyphenyl)acrylohydrazide (5b)

Yield, 65%; m.p. 168–170°C (ethanol); IR (KBr, cm⁻¹): 3287 (NH), 2209 (CN), 1680 (CO); ¹H NMR (DMSO, δ ppm): 3.87 (s, 3H, OCH₃), 6.91–8.17 (m, 10H, Ar–H and =CH proton), 8.71 (s, 1H, NH); MS m/z (%): 339 (M⁺, 3.15), 201 (100), 186 (93.94), 158 (38.79). Anal. for C₁₈H₁₄Cl N₃O₂ (339.77); Calcd.: C, 63.63; H, 4.15; Cl, 10.43; N, 12.37. Found: C, 63.43; H, 4.00; Cl, 10.23; N, 12.00%.

2.3.3. 3-(4-Chlorophenyl)-2-cyano-N′-[1-(4-methoxyphenyl) ethylidene]acrylohydrazide (5c)

Yield, 50%; m.p. 148–150°C (ethanol); IR (KBr, cm⁻¹): 3313 (NH), 2211 (CN), 1636 (CO); ¹H NMR (DMSO; δ ppm): 3.78 (s, 3H, OCH₃), 2.50 (s, 3H, CH₃), 6.92–8.06 (m, 9H, Ar–H and =CH proton), 10.06 (br, 1H, NH); Anal. for C₁₉H₁₆ClN₃O₂ (353.80); Calcd.: C, 64.50; H, 4.56; Cl, 10.02; N, 11.88. Found: C, 64.33; H, 4.32; Cl, 10.00; N, 11.65%.

2.3.4. 3-(4-Chlorophenyl)-N′-[(4-chlorophenyl)methylene]-2-cyanoacrylohydrazide (5d)

Yield, 60%; m.p. 228–230°C (ethanol); IR (KBr, cm⁻¹): 3282 (NH), 2212 (CN), 1682 (CO); ¹H NMR (DMSO, δ ppm): 7.52–8.02 (m, 9H, Ar–H and =CH proton), 8.27 (s, 1H, =CH), 8.71 (s, 1H, NH). Anal. for C₁₇H₁₁Cl₂ N₃O (344.19); Calcd.: C, 59.32; H, 3.22; Cl, 20.60; N, 12.21. Found: C, 59.11; H, 3.10; Cl, 20.50; N, 12.01%.

2.4. General Procedure for Synthesis of Pyrazole-4-carbohydrazide (6a,b)

A mixture of 5a,b (0.01) and hydrazine hydrate (0.50 g, 0.01 mol, 95%) was refluxed for 6 h. After cooling, the formed solid was filtered, washed with water, and recrystallized from the appropriate solvent to give 6a,b.

2.4.1. 5-Amino-3-(4-methoxyphenyl)-N′-[1-(4-methoxyphenyl)ethylidene]-1H-pyrazole-4-carbohydrazide (6a)

Yield, 50%; m.p. 120–124°C (ethanol); IR (KBr, cm⁻¹): 3340, 333, 3210 (NH, NH₂), 1663 (CO); ¹H NMR (DMSO, δ ppm): 3.82 (s, 6H, 2OCH₃), 2.56 (s, 3H, CH₃), 6.99–7.84 (m, 8H, Ar–H), 8.13 (s, 1H, NH), 8.17 (br, 1H, NH), 6.86 (s, 2H, NH₂). Anal. for C₂₀H₂₁N₅O₃ (379.41); Calcd.: C, 63.31; H, 5.58; N, 18.46. Found: C, 63.00; H, 5.32; N, 18.31%.

2.4.2. 5-Amino-N′-[(4-chlorophenyl)methylene]-3-(4-methoxyphenyl)-1H-pyrazole-4-carbohydrazide (6b)

Yield, 55%; m.p. 140–142°C (ethanol); IR (KBr, cm⁻¹): 3417, 3307, 3287, (NH, NH₂), 1660 (CO); ¹H NMR (DMSO, δ ppm): 3.74 (s, 3H, OCH₃), 7.03–7.91 (m, 9H, Ar–H and =CH proton), 8.62 (s, 1H, NH), 8.71 (s, 1H, NH), 6.86 (s, 2H, NH₂); MS m/z (%): 369 (M⁺, 1.26), 280 (34.72), 267 (43.68), 134 (100). Anal. for C₁₈H₁₆Cl N₅O₂ (369.80); Calcd.: C, 58.46; H, 4.36; Cl, 9.59; N, 18.94. Found: C, 58.22; H, 4.21; Cl, 9.32; N, 18.75%.

2.5. 2-Amino-4-(4-chlorophenyl)-5-cyano-1-{[1-(4-methoxyphenyl)ethylidene]amino}-6-oxo-1,6-dihydropyridine-3-carboxamide (8)

To a solution of compound 3a (2.31 g, 0.01 mol) in 1,4-dioxane (30 mL) containing few drops of TEA, 3-(4-chlorophenyl)-2-cyanoacrylamide (2.06 g, 0.01 mol) was added. The reaction mixture was heated under reflux for 4 h, then poured into ice/water, and the solid obtained was recrystallized from ethanol to give 8. Yield, 85%; m.p. 258–260°C; IR (KBr, cm⁻¹): 3435, 3313, 3210, 3129 (2NH₂), 1671, 1660 (2CO), 2211 (CN); ¹H NMR (DMSO, δ ppm): 3.73 (s, 3H, OCH₃), 2.48 (s, 3H, CH₃), 7.45–7.82 (m, 8H, Ar–H), 6.92 (br, 2H, NH₂), 6.95 (br, 2H, NH₂); MS m/z (%): 435 (M⁺, 8.76), 383 (77.70), 282 (14.04). Anal. for C₂₂H₁₈Cl N₅O₃ (435.86); Calcd.: C, 60.62; H, 4.16; Cl, 8.13; N, 16.07%. Found: C, 60.42; H, 4.00; Cl, 8.00; N, 16.00%.

2.6. 5-(4-Chlorophenyl)-8-{[1-(4-methoxyphenyl)ethylidene]amino}-4,7-dioxo-2-(4-nitrophenyl)-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (9)

A mixture of compound 8 (4.35 g, 0.01 mol) and 4-nitrobenzaldehyde (0.01 mol) in ethanol (20 mL) with few drops of TEA was refluxed in oil bath with stirring for 10–12 h. The reaction mixture was cooled, and poured into ice/water and the solid obtained was recrystallized from ethanol to give 9. Yield, 50%; m.p. 190–192°C; IR (KBr, cm⁻¹): 3332 (NH), 1660, 1675 (2CO), 2212 (CN); ¹H NMR (DMSO, δ ppm): 3.83 (s, 3H, OCH₃), 2.50 (s, 3H, CH₃), 7.46–7.94 (m, 12H, Ar–H), 8.22 (br, 1H, NH). Anal. for C₂₉H₁₉ClN₆O₅ (566.95); Calcd.: C, 61.44; H, 3.38; Cl, 6.25; N, 14.82. Found: C, 61.21; H, 3.08; Cl, 6.00; N, 14.52%.

2.7. 5-(4-Chlorophenyl)-8-{[1-(4-methoxyphenyl)ethylidene]amino}-4,7-dioxo-2-thioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10)

To a stirred solution of 8 (4.35 g, 0.01 mol) in DMF (10 mL), carbon disulfide (0.76 mL, 0.01 mol) and NaOH (0.2 g, 0.005 mol) were added. The reaction mixture was stirred at room temperature for 6 h, then diluted with an equal volume of water, and treated with dilute HCl (pH 4). The separated solid product was filtered, washed with water, and recrystallized from DMF to give 10. Yield, 50%; m.p. 130–132°C; IR (KBr, cm⁻¹): 3332, 3188 (NH), 1660, 1668 (2CO), 2206 (CN), 1243 (C=S); ¹H NMR (DMSO, δ ppm): 3.83 (s, 3H, OCH₃), 2.51 (s, 3H, CH₃), 6.93–7.60 (m, 8H, Ar–H), 8.62 (br, 1H, NH), 8.50 (br, 1H, NH); MS m/z (%): 478 (M⁺ +1, 1.58), 270 (12.99), 229 (17.15), 143 (100). Anal. for C₂₃H₁₆ ClN₅O₃S (477.92); Calcd.: C, 57.80; H, 3.37; Cl, 7.42; N, 14.65; S, 6.71. Found: C, 57.50; H, 3.30; Cl, 7.25; N, 14.38; S, 6.52%.

2.8. General Procedure for Synthesis of 4,5,6,7-Tetrahydrobenzo[b]thiophene-2-carbohydrazide Derivatives (11a ,b)

To a solution of 3a,b (0.01 mol) in ethanol (20 mL) containing TEA (1 mL) and elemental sulfur (0.01 mol), cyclohexanone (0.01 mol) was added. The reaction mixture was heated under reflux for 3 h, then poured into ice/water. The formed solid product was collected by filtration and recrystallized from the appropriate solvent to give 11a,b.

2.8.1. 3-Amino-N′-[1-(4-methoxyphenyl)ethylidene]-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carbohydrazide (11a)

Yield; 70%; m.p. 118–120°C (pot.ether 60–80); IR (KBr, cm⁻¹): 3391, 3298, 3267 (NH, NH₂), 1698 (CO); ¹H NMR (DMSO, δ ppm): 3.80 (s, 3H, OCH₃), 2.51 (s, 3H, CH₃), 6.94–7.84 (m, 4H, Ar–H), 6.40 (br, 2H, NH₂), 10.40 (br, 1H, NH), 1.71–1.73 (m, 4H, 2CH₂), 2.19–2.44 (m, 4H, 2CH₂). Anal. for C₁₈H₂₁ N₃O₂S (343.44); Calcd.: C, 62.95; H, 6.16; N, 12.23; S, 9.34. Found: C, 62.65; H, 6.00; N, 12.00; S, 9.11%.

2.8.2. 3-Amino-N′-[(4-chlorophenyl)methylene]-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carbohydrazide (11b)

Yield, 85%; m.p. 110–112°C (ethanol); IR (KBr, cm⁻¹), 3425, 3298, 3267 (NH, NH₂), 1624 (CO); ¹H NMR (DMSO, δ ppm): 7.30–7.41 (m, 5H, Ar–H and =CH), 4.30 (br, 2H, NH₂), 8.42 (br, 1H, NH), 2.48–2.50 (m, 8H, 4CH₂). Anal. for C₁₆H₁₆ Cl N₃OS (333.83); Calcd.: C, 57.56; H, 4.83; Cl, 10.62; N, 12.59; S, 9.61. Found: C, 57.32; H, 4.52; Cl, 10.42; N, 12.41; S, 9.32%.

2.9. 2-Cyano-N′-[1-(4-methoxyphenyl)ethylidene]-2-(4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene)ethanehydrazide (14)

To a stirred suspension of finely powdered potassium hydroxide (0.01 mole) in dry DMF (10 mL), cyanoacetohydrazide (3a) (2.31 g, 0.01 mole) was added and continuous stirring was done for 30 min. Then phenylisothiocyanate (1.35 mL, 0.01 mol) was added slowly over the course of 10 min. After complete addition, stirring of the reaction mixture was done at room temperature for 12 h. Then ethyl chloroacetate (1.22 mL, 0.01 mole) was added to the reaction mixture and stirred for 6 h. The reaction mixture was poured into crushed ice. The resulting precipitate was filtrated off, dried, and recrystallized from ethanol/DMF to give 14. Yield, 85%; m.p. 264–266°C; IR (KBr, cm⁻¹), 3370 (NH), 1742, 1667 (2CO), 2184 (CN); ¹H NMR (DMSO, δ ppm): 3.79 (s, 3H, OCH₃), 2.43 (s, 3H, CH₃), 4.02 (s, 2H, C 4-2H-thiazolidinone), 6.94–7.76 (m, 9H, Ar–H), 9.83 (br, 1H, NH); MS m/z (%): 406 (M⁺, 41.28), 391 (13.87), 360 (11.96), 314 (10.32), 281 (33.41), 134 (100). Anal. for C₂₁H₁₈N₄O₃S (406.45); Calcd.: C, 62.05; H, 4.46; N, 13.78; S, 7.89. Found: C, 61.88; H, 4.22; N, 13.62; S, 7.55%.

2.10. 3-Anilino-2-cyano-N′-[1-(4-methoxyphenyl)ethylidene]-3-methylthio-acrylohydrazide (15)

Compound 15 was synthesized as mentioned for the synthesis of 14 but using dimethylsulfate instead of ethylchloroacetate; the resulting product was crystallized from ethanol to give 15.

Yield, 70%, m.p. 156–158°C; IR (KBr, cm⁻¹), 3374, 3318 (2NH), 1642 (CO), 2182 (CN); ¹H NMR (DMSO, δ ppm): 3.81 (s, 3H, OCH₃), 2.33 (s, 3H, CH₃), 2.51 (s, 3H, SCH₃), 6.94–7.82 (m, 9H, Ar–H), 10.11 (br, 1H, NH Ph), 11.00 (br, 1H, NH); MS m/z (%): 380 (M⁺, 25.28), 333 (53.86), 365 (1.83), 318 (7.81), 231 (2.55), 217 (40.63), 163 (55.56). Anal. for C ₂₀H₂₀ N₄O₂ S (380.46); Calcd.: C, 63.14; H, 5.30; N, 14.73; S, 8.43. Found: C, 63.00; H, 5.00; N, 14.52; S, 8.30%.

2.11. 5-Amino-3-anilino-N′-[1-(4-methoxyphenyl)ethylidene]-1H-pyrazole-4-carbohydrazide (16)

A mixture of 15 (3.80 g, 0.01 mol) and hydrazine hydrate (0.012 mol) in ethanol (30 mL) was heated under reflux for 3 h. and allowed to cool. The solid product obtained was filtered and recrystallized from ethanol to give 16. Yield, 55%; m.p. 122–125°C; IR (KBr, cm⁻¹): 3391, 3298, 3242 (NH, NH₂), 1641 (CO); ¹H NMR (DMSO, δ ppm): 3.77 (s, 3H, OCH₃), 2.27 (s, 3H, CH₃), 6.85–7.57 (m, 9H, Ar–H), 6.13 (s, 2H, NH₂), 8.00 (br, 1H, NH Ph), 8.20 (br, 1H, NHCO), 10.10 (br, 1H, NH); MS m/z (%): 364 (M⁺, 0.41), 348 (0.47), 318 (2.92), 281 (28.52), 267 (22.88), 256 (0.71), 201 (1.60), 148 (47.34), 134 (100). Anal. for C₁₉H₂₀ N₆O₂ (364.40); Calcd: C, 62.62; H, 5.53; N, 23.06. Found: C, 62.32; H, 5.23; N, 23.00%.

2.12. General Procedure for Synthesis of 3,3-Dimercaptoacrylohydrazide Derivatives (18a ,b)

To suspension of finely powdered potassium hydroxide (0.04 mol) in dry DMF (20 mL) at 0°C the cyanoacetohydrazide 3a,b (0.04 mol) was added for 30 min, carbon disulfide (3.04 mL, 0.04 mol) was added to the resulting mixture, stirring was continued for 12 h, and then hydrochloric acid (2 M, 20 mL was added dropwise, and stirring continued for additional 1 h. Then, the reaction mixture was poured into ice water. The solid product that formed was filtered off, dried, and recrystallized from the appropriate solvent to give 18a,b.

2.12.1. 2-Cyano-3,3-dimercapto-N′-[1-(4-methoxyphenyl)ethylidene]acrylohydrazide (18a)

Yield, 70%; m.p. 248–250°C (ethanol); IR (KBr, cm⁻¹): 3225 (NH), 1663 (CO); ¹H NMR (DMSO, δ ppm): 3.7 (s, 3H, OCH₃), 2.49 (s, 3H, CH₃), 6.97–7.95 (m, 4H, Ar–H), 10.26 (br, 1H, NHCO), 2.73 (s, 2H, 2SH); MS m/z (%): 306 (M⁺  −1, 3.66), 281 (1.93), 274 (8.92), 241 (5.42), 215 (6.25), 163 (22.05), 134 (100). Anal. for C₁₃H₁₃ N₃O₂S₂ (307.39); Calcd.: C, 50.79; H, 4.26; N, 13.67; S, 20.86%. Found: C, 50.45; H, 4.00; N, 13.32; S, 20.52%.

2.12.2. N′-[(4-Chlorophenyl)methylene]-2-cyano-3,3-dimercaptoacrylohydrazide (18b)

Yield: 75%; m.p. 190–192°C (ethanol); IR (KBr, cm⁻¹): 3333 (NH), 1673 (CO); ¹H NMR (DMSO, δ ppm): 8.16 (s, 1H, CH=N), 7.48–7.99 (m, 4H, Ar–H), 11.82 (br, 1H, NH CO), 2.48 (s, 2H, 2SH). MS m/z (%): 297 (M⁺, 4.75), 271 (3.86), 264 (4.55), 231 (3.45), 205 (4.63), 161 (26.97), 158 (4.02), 153 (16.19), 143 (11.75), 138 (100), 115 (8.28), 78 (51.02). Anal. for C₁₁H₈ClN₃OS₂ (297.78); Calcd.: C, 44.37; H, 2.71; Cl, 11.91; N, 14.11; S, 21.54%. Found: C, 44.00; H, 2.32; Cl, 11.66; N, 14.00; S, 21.22%.

2.13. General Procedure for Synthesis of Ethyl [2-Cyano-1-mercapto-3-oxoprop-1-enyl)thio]acetate Derivatives (19a ,b)

To a stirred suspension of finely powdered potassium hydroxide (0.02 mole) in dry DMF (10 mL), cyanoacetohydrazides, 3a,b, (0.01 mole) were added. The resulted mixture was cooled at 10°C in an ice bath; then (0.01 mol) carbon disulfide was added slowly over the course of 10 min. After complete addition, stirring of the reaction mixture was continued for 6 h Then ethyl chloroacetate (1.22, 0.01 mol) was added to the mixture and stirring continued for 3 h, then the mixture was poured into crushed ice and HCl; the resulting precipitate was filtrated off, dried, and recrystallized from the appropriate solvent to give 19a,b.

2.13.1. Ethyl [2-Cyano-1-mercapto-3-2-[1-(4-methoxyphenyl)ethylidene]hydrazino-3-oxoprop-1-enyl)thio]acetate (19a)

Yield, 70%; m.p. 236–240°C (ethanol); IR (KBr, cm⁻¹): 3331 (NH); 2216 (CN); ¹H NMR (DMSO δ ppm): 3.84 (s, 3H, OCH₃), 2.51 (s, 3H, CH₃), 7.02–7.94 (m, 4H, Ar–H), 11.28 (br, 1H, NH), 11.54 (br, 1H, SH), 1.03 (t, 3H, CH₃), 4.33 (s, 2H, CH₂), 4.12 (q, 2H, CH₂). Anal. for C₁₇H₁₉N₃ O₄S₂ (393.48); Calcd.: C, 51.86; H, 4.87; N, 10.68; S, 16.30. Found: C, 51.53; H, 4.52; N, 10.51; S, 16.00%.

2.13.2. Ethyl ({3-[2-(4-Chlorobenzylidene)hydrazino]-2-cyano-1-mercapto-3-oxoprop-1-enyl}thio)acetate (19b)

Yield, 65%; m.p. 148–150°C (ethanol); IR (KBr, cm⁻¹): 3359 (NH), 2360 (CN); ¹H NMR (DMSO; δ ppm): 7.38–7.65 (m, 4H, Ar–H), 8.27 (s, 1H, CH=C), 1.05 (t, 3H, CH₃), 4.22 (q, 2H, CH₂), 4.02 (s, 2H, CH₂), 9.07 (br, 1H, NH), 10.02 (br, 1H, SH). Anal. for C₁₅H₁₄Cl N₃O₃ S₂ (383.87); Calcd.: C, 46.93; H, 3.68; Cl, 9.24; N, 10.95; S, 16.71. Found: C, 46.73; H, 3.34; Cl, 9.00; N, 10.65; S, 16.45%.

2.14. General Procedure for Synthesis of 3,3-Bis(methylthio)acrylohydrazide Derivatives (20a ,    b)

Compounds 20a,b were synthesized as mentioned for synthesis of 19, but using dimethyl sulfate instead of ethyl chloroacetate, the resulting product was recrystallized from the appropriate solvent to give 20a,b.

2.14.1. 2-Cyano-N′-[(1-(4-methoxyphenyl)ethylidene]-3,3-bis(methylthio)-acrylohydrazide (20a)

Yield, 70%; m.p. 168–170°C (pot.ether 60–80/benzene): IR (KBr, cm⁻¹), 3203 (NH), 1681 (CO); ¹H NMR (DMSO, δ ppm): 3.78 (s, 3H, OCH₃), 2.49 (s, 3H, CH₃), 2.50 (s, 6H, 2SCH₃), 6.93–7.76 (m, 4H, Ar–H), 10.90 (br, 1H, NH CO). Anal. for C₁₅H₁₇N₃O₂S₂ (335.44); Calcd.: C, 53.71; H, 5.11; N, 12.53; S, 19.12. Found: C, 53.52; H, 5.00; N, 12.23; S, 19.00%.

2.14.2. N′-[(4-Chlorophenyl)methylene]-2-cyano-3,3-bis(methylthio)acrylohydrazide (20b)

Yield, 75%; m.p. 188–190°C (ethanol); IR (KBr, cm⁻¹), 3185 (NH), 1674 (CO); ¹H NMR (DMSO, δ ppm): 8.16 (s, 1H, CH=N), 7.48–7.99 (m, 4H, Ar–H), 11.82 (br, 1H, NH CO), 2.50 (s, 6H, 2SCH₃); MS m/z (%): 325 (M⁺, 10.74), 295 (17.07), 153 (5.49), 138 (100). Anal. for C₁₃H₁₂ClN₃OS₂ (325.83); Calcd.: C, 47.92; H, 3.71; Cl, 10.88; N, 12.90; S, 19.68. Found: C, 47.64; H, 3.42; Cl, 10.55; N, 12.65; S, 19.48%.

2.15. General Procedure for Synthesis of 5-Amino-3-methylthio-pyrazole-4-carbohydrazide (21 and 22)

A mixture of 20a (3.35 g, 0.01 mol), hydrazine hydrate, and/or 2-hydrazino-1,3-benzothiazole (1.89 g, 0.012 mol) in ethanol (30 mL) was heated under reflux for 3 hrs and allowed to cool. The solid product obtained was filtrate off and recrystallized from the appropriate solvent to give 21 and 22.

2.15.1. 5-Amino-N′-[1-(4-methoxyphenyl)ethylidene]-3-methylthio-pyrazole-4-carbohydrazide (21)

Yield, 65%; m.p. 120–122°C (ethanol); IR (KBr, cm⁻¹): 3392, 3300, 3243 (NH, NH₂); ¹H NMR (DMSO, δ ppm): 3.74 (s, 3H, OCH₃), 2.27 (s, 3H, CH₃), 2.50 (s, 3H, SCH₃), 6.85–7.56 (m, 4H, Ar–H), 6.13 (br, 2H, NH₂), 8.00 (br, 1H, NH), 10.10 (br, 1H, NH); MS m/z (%): 319 (M⁺, 0.81), 275 (1.24), 259 (1.44), 246 (4.66), 228 (4.80), 210 (3.20), 176 (16.37), 162 (44.23), 128 (24.43), 134 (100). Anal. for C₁₄H₁₇N₅O₂S (319.38); Calcd.: C, 52.65; H, 5.37; N, 21.93; S, 10.04. Found: C, 52.42; H, 5.21; N, 21.73; S, 10.00%.

2.15.2. 5-Amino-1-(1,3-benzothiazol-2-yl)-N′-[1-(4-methoxyphenyl)ethylidene]-3-methylthio-pyrazole-4-carbohydrazide (22)

Yield, 70%; m.p. 150–152°C (acetone); IR (KBr, cm⁻¹): 3392, 3300, 3243 (NH, NH₂); ¹H-NMR (DMSO, δ ppm): 3.76 (s, 3H, OCH₃), 2.23 (s, 3H, CH₃), 2.50 (s, 3H, SCH₃), 6.85–7.56 (m, 8H, Ar–H), 6.13 (s, 2H, NH₂), 10.44 (br, 1H, NH), 453 (M⁺ +1, 16.51), 420 (12.55), 342 (5.93), 267 (2.54), 253 (4.46), 235 (100), 237 (8.19). Anal. for C₂₁H₂₀N₆O₂S₂ (452.55); Calcd.: C, 55.73; H, 4.45; N, 18.57; S, 14.17. Found: C, 55.52; H, 4.12; N, 18.23; S, 14.00%.

2.16. Antitumor Activity

Antitumor activity was performed in Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt. Compounds 3a, 3b, 4a, 4b, 6a, 6b, 11b, 14, 15, 16, 18b, 19a, 19b, 21, and 22 were tested for their cytotoxicity in vitro, in comparison with doxorubicin (DXR) as a reference drug against human breast cancer cell line (MCF-7). MCF-7 cells (1 × 10⁴) were incubated with synthesized compounds at various concentrations of 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, and 50 μg/mL (incorporated with 10 μL DMSO) at 37°C for 48 h, and viable cells yield was determined by colorimetric method [11]. Experiments were carried out in triplicate, and results are reported in Table 1.

Table 1: In vitro anticancer screening of the synthesized compounds against human breast cancer cell line (MCF-7) at different concentration.

Compd. no.
Compound concentrations (μg/mL)

1.56 (μg/mL)
3.125 (μg/mL)
6.25 (μg/mL)
12.5 (μg/mL)
25 (μg/mL)
50 (μg/mL)
IC50 (μg/mL)

doxorubicin
30.86
21.18
17.22
11.74
6.55
3.24
0.426

3a
94.28
85.92
73.36
98.63
47.25
14.94
23.4

3b
94.76
89.14
80.92
67.48
54.3
22.38
28.4

4a
95.08
88.93
79.34
67.68
47.92
16.58
23.7

4b
98.48
93.07
87.12
72.35
51.94
27.19
27

6a
97.32
86.46
77.95
48.52
27.04
10.71
12.2

6b
100
97.68
89.73
73.48
51.42
19.17
26.1

11b
84.58
69.75
56.84
23.08
19.32
10.58
7.5

14
100
98.17
91.98
86.3
63.62
29.56
35

15
100
96.54
88.72
73.91
60.58
28.92
33.4

16
91.96
82.55
71.67
50.11
41.36
29.18
12.6

18b
96.98
93.14
76.92
68.45
59.73
31.08
33.5

19a
100
98.42
93.16
90.34
78.19
61.92
50

19b
89.34
81.9
69.79
53.41
38.18
26.87
15.3

21
93.81
88.94
79.22
63.75
16.28
9.64
16.1

22
80.36
69.42
61.87
56.39
41.81
18.26
18

IC50 value: corresponds to the concentration required for 50% inhibition of cell viability.

3. Results and Discussion

3.1. Synthesis

The Schemes 1–4 describe the synthesis of the target molecules. Condensation of cyanoacetic acid hydrazide (1) with 4-methoxyacetophenone and 4-chlorobenzaldehyde(2a,b) in hot 1,4-dioxane afforded hydrazone derivatives (3a,b). The structures of compounds (3a,b) were established on the basis of analytical and spectral data. IR spectrum of 3a showed bands at 3204 cm⁻¹ (NH), 2256 (CN), and 1675 (C=O). ¹H NMR spectrum of 3a showed the presence of a singlet at δ 2.23 ppm corresponding to CH₃ group, a singlet at δ 3.81 ppm for methoxy group, a singlet at 4.18 ppm for CH₂ group, and a singlet at δ 10.90 ppm for an NH group. Further evidence for the structures of 3a,b was obtained through studying their chemical reactivity through some chemical reagents. Thus, cyclocondensation of compounds 3a,b with salicylaldehyde in boiling ethanol and in the presence of a few drops of triethylamine (TEA) [12] afforded the corresponding 2H-chromene-3-carbohydrazide derivatives, 4a,b.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Condensed 3a,b with aryl aldehydes such as 4-methoxybenzaldehyde and/or 4-chlorobenzaldehyde [13] afforded the corresponding arylidene derivatives 5a–d. The structures of compounds 5a–d were based on analytical and spectral data (see Section 2). When compounds 5a,b reacted with hydrazine hydrate [14], they afforded the corresponding 1H-pyrazole-4-carbohydrazide derivatives, 6a,b. The structure of 6 was inferred from its ¹H NMR spectrum which appeared as new signals for NH₂ group (Scheme 1).

Reactivity of hydrazide-hydrazone derivative 3a toward cinnamonitrile derivative was studied [15]. Thus, the reaction of 3a with 3-(4-chlorophenyl)-2-cyanoacrylamide afforded the corresponding pyridinone derivative 8; the reaction took place through the intermediate 7. Treatment of pyridinone derivative 8 with 4-nitrobenzaldehyde in the presence of ethanol and catalytic amount of triethylamine (TEA) afforded the corresponding pyrido[2,3-d]pyrimidine- 6-carbonitrile derivative 9. On the other hand, 2-thioxo-pyrido[2,3-d]pyrimidine-6-carbonitrile 10 was obtained by cyclizing 8 with carbon disulfide in the presence of sodium hydroxide at room temperature [16] followed by acidification with diluted hydrochloric acid. Structures of new compounds were based on analytical and spectral data. Thus, the ¹H NMR spectrum of 8 showed the presence of a singlet at δ 6.92 and 6.95 corresponding to the two NH₂ groups. The IR spectrum of 10 displayed absorption bands at 3332, 3188 cm⁻¹ due to the 2NH function and 1243 cm⁻¹ due to C=S group.

Reaction of compounds 3a,b with cyclohexanone and elemental sulfur in the presence of TEA afforded the corresponding 4,5,6,7-tetrahydrobenzo[b]thiophene derivatives, 11a,b. Formation of 11 took place according to the similar reported reactions of cyclohexanone with methylene reagents and elemental sulfur [17]. Structure of compound 11 was based on analytical and spectral data (Scheme 2).

The active methylene moiety of 2-cyano-N′-[1-(4-methoxyphenyl)ethylidene]acetohydrazide (3a) allowed reacting with phenylisothiocyanate in dry N, N-dimethylformamide DMF containing catalytic amount of potassium hydroxide [18] yielding the nonisolable intermediate potassium sulfide salt 12, and then ethylchloroacetate was added affording 1,3-thiazolidinone derivative 14. Probably, the reaction mechanism is assumed to proceed via S-alkylation to give the intermediate 13 which was cyclized to the corresponding thiazolidinone derivatives 14. Elemental analyses and spectral data were in favor of these proposed 1,3-thiazolidinone structures. The IR spectrum of 14 showed absorption bands at 1742 cm⁻¹ due to thiazolidinone CO. The ¹H NMR spectrum showed signals in the region at δ 4.02 ppm corresponding to C4 protons of the thiazolidinone ring. On the other hand, treatment of the nonisolable potassium sulfide salt 12 with dimethylsulfate afforded 3-anilino-2-cyano-3-methylthio-acrylohydrazide 15. Cyclocondensation of the acrylohydrazide 15 with hydrazine hydrate in boiling ethanol afforded aminopyrazole derivative 16. The structure of 15 and 16 was identified as the reaction product on the basis of their elemental analysis and spectroscopic data. ¹H NMR spectrum of 15 displayed the following signals at δ 2.50 corresponding to the SCH₃ group, δ 10.10 corresponding to the NHPh group, and δ 11.60 corresponding to the NHCO group. IR spectrum of 16 showed the lacks of absorption band assignable to the CN group and the presence of a new absorption band at 3298, 3242 cm⁻¹ assignable to NH₂ group. Its ¹H NMR spectrum showed signals at δ 6.13 ppm corresponding to the NH₂ protons, another three singlet signals at δ 8.00, 8.20, and 10.10 ppm assignable to three NH protons (Scheme 3).

Reaction of compounds 3a,b with carbon disulfide in boiling DMF containing catalytic amount of potassium hydroxide afforded nonisolable intermediate potassium sulfide salts 17a,b. Treatment of the nonisolable potassium salts 17a,b with dilute hydrochloric acid [19] afforded the corresponding dithiol derivatives 18a,b. The structures of compounds 18a,b were based on both elemental analyses and spectral data. The ¹H NMR spectrum of 18a revealed signal at δ2.73 and 2.88 ppm for two SH protons and at δ10.50 ppm for NHCO proton. Moreover, Alkylation of dithiol derivatives 17a,b with ethylchloroacetate yielded the corresponding ethyl [2-cyano-1-mercapto-3-oxoprop-1-enyl) thio]acetate derivatives 19a,b [20]. The structures of 19a,b were supported on the basis of elemental analyses and spectral data. Ketene S,S-dithio-acetals derivatives 20a,b can be prepared by alkylation of dithiol derivatives 17a,b with dimethylsulfate. The structure of 20 was elucidated on the basis of the elemental analyses and spectral data. The IR spectrums of 20a showed the appearance of absorption band at 3203 for NH and 2256 cm⁻¹ for CN groups. ¹H NMR spectrum of 20b showed singlet signal at δ2.50 ppm for 6 protons of two similar methyl protons, while a singlet signal for the methylene protons disappeared.

Cyclocondensation of bis-(methylthio)acrylohydrazide derivative 20a with hydrazine derivatives such as hydrazine hydrate and 2-hydrazino-1,3-benzothiazole affords the corresponding 5-(methylthio) 1H-pyrazole-4-carbohydrazide 21 and 22, respectively. The structures of compounds 21 and 22 were as established and confirmed as the reaction product on the basis of their elemental analyses and spectral data. The IR spectrum of 21 showed absorption band at 3300, 3243 cm⁻¹ assignable for NH₂, in addition to disappearance of nitrile function signal. Its ¹H NMR spectrum revealed the presence of singlet signals at δ 6.13 ppm assignable to the NH₂ protons (Scheme 4).

3.2. Antitumor Activity

Some newly synthesized compounds 3a, 3b, 4a, 4b, 6a, 6b, 11b, 14, 15, 16, 18b, 19a, 19b, 21, and 22, screened in vitro against human breast cancer cell line (MCF-7), using doxorubicin (Doxo) as a reference drug. The results were compared to the antiproliferative effects of the reference control doxorubicin (Table 1, plotted in Figure 1). The results indicated that most compounds demonstrated substantial growth inhibitory effects against the human tumor cells at the tested concentrations. The antiproliferative activity of the test compounds against tumor cell lines may be arranged in a descending order due to measured concentration required to inhibit tumor cell proliferation by IC50 μg/mL which corresponds to the concentration required for 50% inhibition of cell viability. In general, compounds 11b, 6a, 16, 19b, 21, and 22 with IC50 values 7.5, 12.2, 12.6, 15.3, 16.1, and 18 μg/mL, respectively, showed significant activity on the tumor cell lines tested.

Figure 1: In vitro anticancer screening of the synthesized compounds against human breast cancer cell line (MCF-7).

4. Conclusions

In this work, cyanoacetylhydrazine (1) reacted with 4-methoxy-acetophenone and 4-chlorobenzaldehyde (2a,b) to afford the hydrazide-hydrazone derivatives, 3a,b. The latter was reacted with different reagents to give coumarin, pyridine, thiophene, and pyrazole derivatives. The antitumor evaluations of the newly synthesized products were carried out, showing that compound exhibited moderate activity.

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