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
References
[1]
J. V. Ragavendran, D. Sriram, S. K. Patel et al., “Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore,” European Journal of Medicinal Chemistry, vol. 42, no. 2, pp. 146–151, 2007.
[2]
A. G. M. Fraga, C. R. Rodrigues, A. L. P. de Miranda, E. J. Barreiro, and C. A. M. Fraga, “Synthesis and pharmacological evaluation of novel heterotricyclic acylhydrazone derivatives, designed as PAF antagonists,” European Journal of Pharmaceutical Sciences, vol. 11, no. 4, pp. 285–290, 2000.
[3]
A. R. Todeschini, A. L. P. de Miranda, K. C. M. da Silva, S. C. Parrini, and E. J. Barreiro, “Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives,” European Journal of Medicinal Chemistry, vol. 33, no. 3, pp. 189–199, 1998.
[4]
G. A. Silva, L. M. M. Costa, F. C. F. Brito, A. L. P. Miranda, E. J. Barreiro, and C. A. M. Fraga, “New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives,” Bioorganic and Medicinal Chemistry, vol. 12, no. 12, pp. 3149–3158, 2004.
[5]
S. Gemma, G. Kukreja, C. Fattorusso et al., “Synthesis of N1-arylidene-N2-quinolyl- and N2-acrydinylhydrazones as potent antimalarial agents active against CQ-resistant P. falciparum strains,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 20, pp. 5384–5388, 2006.
[6]
G. Turan-Zitouni, Y. Blache, and K. Güven, “Synthesis and antimicrobial activity of some imidazo-[1,2-a]pyridine-2-carboxylic acid arylidenehydrazide derivatives,” Bollettino Chimico Farmaceutico, vol. 140, no. 6, pp. 397–400, 2001.
[7]
E. Gürsoy and N. Güzeldemirci-Ulusoy, “Synthesis and primary cytotoxicity evaluation of new imidazo[2,1-b]thiazole derivatives,” European Journal of Medicinal Chemistry, vol. 42, no. 3, pp. 320–326, 2007.
[8]
S. A. M. El-Hawash, A. E. Abdel Wahab, and M. A. El-Demellawy, “Cyanoacetic acid hydrazones of 3-(and 4)acetylpyridine and some derived ring systems as potential antitumor and anti-HCV agents,” Archiv der Pharmazie, vol. 339, no. 1, pp. 14–23, 2006.
[9]
A. G. Silva, G. Zapata-Sudo, A. E. Kummerle, C. A. M. Fraga, E. J. Barreiro, and R. T. Sudo, “Synthesis and vasodilatory activity of new N-acylhydrazone derivatives, designed as LASSBio-294 analogues,” Bioorganic and Medicinal Chemistry, vol. 13, no. 10, pp. 3431–3437, 2005.
[10]
M. T. Abdel-Aal, W. A. El-Sayed, and E. H. El-Ashry, “Synthesis and antiviral evaluation of some sugar arylglycinoylhydrazones and their oxadiazoline derivatives,” Archiv der Pharmazie, vol. 339, no. 12, pp. 656–663, 2006.
[11]
A. Monks, D. Scudiero, P. Skehan et al., “Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines,” Journal of the National Cancer Institute, vol. 83, no. 11, pp. 757–766, 1991.
[12]
A. M. Khalil, M. A. Berghot, and M. A. Gouda, “Synthesis and antibacterial activity of some new heterocycles incorporating phthalazine,” European Journal of Medicinal Chemistry, vol. 44, no. 11, pp. 4448–4454, 2009.
[13]
T. M. Abu Elmaati and F. M. A. El-Taweel, “Routes to pyrazolo[3,4-e][1,4]thiazepine, pyrazolo[1,5-a]pyrimidine and pyrazole derivatives,” Journal of the Chinese Chemical Society, vol. 50, no. 3, pp. 413–418, 2003.
[14]
H. Z. Shams, R. M. Mohareb, M. H. Helal, and A. E. Mahmoud, “Novel synthesis and antitumor evaluation of polyfunctionally substituted heterocyclic compounds derived from 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide,” Molecules, vol. 16, no. 1, pp. 52–73, 2011.
[15]
M. S. Al-Said, M. S. Bashandy, S. I. Al-Qasoumi, and M. M. Ghorab, “Anti-breast cancer activity of some novel 1,2-dihydropyridine, thiophene and thiazole derivatives,” European Journal of Medicinal Chemistry, vol. 46, no. 1, pp. 137–141, 2011.
[16]
A. A. Bekhit, H. T. Y. Fahmy, S. A. F. Rostom, and A. M. Baraka, “Design and synthesis of some substituted 1H-pyrazolyl-thiazolo[4,5-d]pyrimidines as anti-inflammatory-antimicrobial agents,” European Journal of Medicinal Chemistry, vol. 38, no. 1, pp. 27–36, 2003.
[17]
R. M. Scrowston, “Recent advances in the chemistry of benzo [b] thiophenes,” Advances in Heterocyclic Chemistry, vol. 29, pp. 171–249, 1981.
[18]
M. A. Gouda and A. A. Abu-Hashem, “Synthesis, characterization, antioxidant and antitumor evaluation of some new thiazolidine and thiazolidinone derivatives,” Archiv der Pharmazie, vol. 344, no. 3, pp. 170–177, 2011.
[19]
A. A. Fadda1, M. M. Mukhtar, and H. M. Refat, “Utility of activated nitriles in the synthesis of some new heterocyclic compounds,” American Journal of Organic Chemistry, vol. 2, no. 2, pp. 32–40, 2012.
[20]
G. H. Elgemeie, A. H. Elghandour, A. M. Elzanaty, and S. A. Ahmed, “Novel 1,3-dithiolan-2-ones using sodium α-cyanoketene dithiolates,” Synthetic Communications, vol. 36, no. 6, pp. 755–764, 2006.
