Synthesis and anti-tumor evaluation of novel hydrazide and hydrazide-hydrazone derivatives

Open access


The reaction of cyclopentanone with cyanoacetylhydrazine gave 2-cyano-2-cyclopentylideneacetohydrazide (1). Treatment of compound 1 with elemental sulphur in the presence of triethylamine afforded 2-amino-5,6-dihydro- -4H-cyclopenta[b]thiophene-3-carbohydrazide (2), which in-turn formed the corresponding intermediate diazonium salt. The latter was coupled with either ethyl cyanoacetate or ethyl acetoacetate to form 2-cyano-2-(3-(hydrazinecarbonyl)- 5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)hydrazono) acetate (3) and ethyl 2-(2-(3-(hydrazinecarbonyl)-5,6-dihydro- 4H-cyclopenta[b]thiophen-2-yl)hydrazono)-3-oxobutanoate (4), respectively. On the other hand, the reaction of compound 1 with either benzaldehyde or acetophenone afforded N’-benzylidene-2-cyano-2-cyclopentylideneacetohydrazide (7) and 2-cyano-2-(2-cyclopentylidene)phenylacetohydrazide (10), respectively. Moreover, compound 1 was used to synthesize 2-cyano-2-cyclopentylidene- N'-(arylthiazol-2(3H)-ylidene)acetohydrazides (6a,b), 2-(2-benzylidenecyclopentylidene)-2-cyanoacetohydrazide (8), 2-amino-N'-benzylidene-5,6-dihydro-4H- -cyclopenta[b]thiophene-3-carbohydrazide (9), 2-cyano- -2-(2-(2-phenylhydrazono)cyclopentylidene)acetohydrazide (11), N'-(1-chloropropan-2-ylidene)-2-cyano-2-cyclopentylideneacetohydrazide (12), and 2-cyclopentylidene-3- -(3,5-disubstituted-1H-pyrazol-1-yl)-3-oxopropanenitriles (13a,b) through its reaction with the respective reagents. Antitumor evaluation of the newly synthesized compounds against the three human tumor cells lines, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) showed that some of the described compounds exhibited higher inhibitory effects towards the three tumor cell lines than the reference compound doxorubicin.

  • 1. S. K. Bharti, G. Nath, R. Tilak and S. K. Singh, Synthesis, anti-bacterial and anti-fungal activities of some novel Schiff bases containing 2,4-disubstituted thiazole ring, Eur. J. Med. Chem. 45 (2010) 651-660; DOI: 10.1016/j.ejmech.2009.11.008.

  • 2. C. Loncle, J. M. Brunel, N. Vidal, M. Dherbomez and Y. Letourneux, Synthesis and antifungal activity of cholesterol-hydrazone derivatives, Eur. J. Med. Chem. 39 (2004) 1067-1071; DOI: 10.1016/ j.ejmech.2004.07.005.

  • 3. S. P. Garoufalias, N. Pouli, P. Marakos and A. C. Ladas, Synthesis, antimicrobial and antifungal activity of some new 3-substituted derivatives of 4-(2,4-dichlorophenyl)-5-adamantyl-1H-1,2,4- -triazole, Farmaco 57 (2002) 973-977; DOI: 10.1016/S0014-827X(02)01273-9.

  • 4. P. Vicini, F. Zani, P. Cozzini and I. Doytchinova, Hydrazones of 1,2-benzisothiazole hydrazides: synthesis, antimicrobial activity and QSAR investigations, Eur. J. Med. Chem. 37 (2002) 553-567; DOI: 10.1016/S0223-5234(02)01378-8.

  • 5. F. D. Popp, Potential anticonvulsant. XII. Anticonvulsant activity of some aldehyde derivatives, Eur. J. Med. Chem. 24 (1989) 313-316; DOI: 10.1016/0223-5234(89)90016-0.

  • 6. S. K. Sridhar, S. N. Pandeya, J. P. Stables and R. Atmakuru, Anticonvulsant activity of hydrazones, Schiff and Mannich bases of isatin derivatives, Eur. J. Pharm. Sci. 16 (2002) 129-132; DOI: 10.1016/S0928-0987(02)00077-5.

  • 7. S. G. Küçükgüzel, S. Rollas, I. Küçükgüzel and M. Kiraz, Synthesis and antimycobacterial activity of some coupling products from 4-aminobenzoic acid hydrazones, Eur. J. Med. Chem. 34 (1999) 1093-1100; DOI: 10.1016/S0223-5234(99)00129-4.

  • 8. B. K. Kaymakçýoǧlu and S. Rollas, Synthesis, characterization and evaluation of antituberculosis activity of some hydrazones, Farmaco 57 (2002) 595-599; DOI: 10.1016/S0014-827X(02)01255-7.

  • 9. S. G. Küçükgüzel, A. Mazi, F. Sahin, S. Öztürk and J. P. Stables, Synthesis and biological activities of diflunisal hydrazide-hydrazones, Eur. J. Med. Chem. 38 (2003) 1005-1013; DOI: 10.1016/ j.ejmech.2003.08.004.

  • 10. A. R. Todeschini, A. L. P. de Miranda, K. C. M. da Silva, S. C. Parrini and E. Barreiro, Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives, Eur. J. Med. Chem. 33 (1998) 189-199; DOI: 10.1016/S0223-5234(98)80008-1.

  • 11. M. A. Gaston, L. R. S. Dias, A. C. C. Freitas, A. L. P. Miranda and E. J. Barreiro, Synthesis and analgesic properties of new 4-arylhydrazone 1H pyrazole[3,4-b]pyridine derivatives, Pharm. Acta Helv. 71 (1996) 213-219; DOI: 10.1016/0031-6865(96)00012-X.

  • 12. P. Melnyk, V. Leroux, C. Sergheraert and P. Grellier, Design, synthesis and in vitro antimalarial activity of an acylhydrazone library, Bioorg. Med. Chem. Lett. 16 (2006) 31-35; DOI: 10.1016/j.bmcl. 2005.09.058.

  • 13. N. Terzioglu and A. Gursoy, Synthesis and anticancer evaluation of some new hydrazone derivatives of 2,6-dimethylimidazo[2,1-b][1,3,4]thiadiazole-5-carbohydrazide, Eur. J. Med. Chem. 38 (2003) 781-786; DOI: 10.1002/chin.200401111.

  • 14. S. M. Sondhi, M. Dinodia and A Kumar, Synthesis, anti-inflammatory and analgesic activity evaluation of some amidine and hydrazone derivatives, Bioorg. Med. Chem. 14 (2006) 4657-4663; DOI: 10.1016/j.bmc.2006.02.014.

  • 15. C. Boga, L. Fiume, M. Baglioni, C. Bertucci, C. Farina, F. Kratz, M. Manerba, M. Naldi and G. Stefano, Characterisation of the conjugate of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin with lactosaminated human albumin by 13C NMR spectroscopy, Eur. J. Pharm. Sci.38 (2009) 262-269; DOI: 10.1016/j.ejps.2009.08.001.

  • 16. M. C. Garnett, Targeted drug conjugates: principles and progress, Adv. Drug Deliv. Rev. 53 (2001) 171-216; DOI: 10.1016/S0169-409X(01)00227-7.

  • 17. P. C. Rodrigues, K. Scheuermann, C. Stockmar, G. Maier, H. Fiebig, C. Unger, R. Mülhaupt and F. Kratz, Synthesis and in-vitro efficacy of acid-sensitive poly(ethylene glycol) paclitaxel conjugates, Bioorg. Med. Chem. Lett. 13 (2003) 355-360; DOI: 10.1016/S0960-894X(02)01002-8.

  • 18. O. I. El-Sabbagh and H. M. Rady, Synthesis of new acridines and hydrazones derived from cyclic â-diketone for cytotoxic and antiviral evaluation, Eur. J. Med. Chem. 44 (2009) 3680-3686; DOI: 10.1002/chin.200948062.

  • 19. H. Krakovicova, T. Etrych and K. Ulbrich, HPMA-based polymer conjugates with drug combination, Eur. J. Pharm. Sci. 37 (2009) 405-412; DOI: 10.1016/j.ejps.2009.03.011.

  • 20. H. Z. Zhang, J. Drewe, B. Tseng, S. Kasibhatla and S. X. Cai, Discovery and SAR of indole-2- -carboxylic acid benzylidene-hydrazides as a new series of potent apoptosis inducers using a cell-based HTS assay, Bioorg. Med. Chem. 12 (2004) 3649-3655; DOI: 10.1016/j.bmc.2004.04.017.

  • 21. P. Vicini, M. I. Incerti, P. L. Colla and R. Loddo, Anti-HIV evaluation of benzo[d]isothiazole hydrazones, Eur. J. Med. Chem. 44 (2009) 1801-1807; DOI: 10.1016/j.ejmech.2008.05.030.

  • 22. V. M. Rahman, S. Mukhtar, W. H. Ansari and G. Lemiere, Synthesis, stereochemistry and biological activity of some novel long alkyl chain substituted thiazolidin-4-ones and thiazan-4-one from 10- undecenoic acsid hydrazide, Eur. J. Med. Chem. 40 (2005) 173-184; DOI: 10.1016/j.ejmech.2004. 10.003.

  • 23. J. R. Dimmock, S. C. Vashishtha and J. P. Stables, Anticonvulsant properties of various acetylhydrazones, oxamoylhydrazones and semicarbazones derived from aromatic and unsaturated carbonyl compounds, Eur. J. Med. Chem. 35 (2000) 241-248; DOI: 10.1016/S0223-5234(00)00123-9.

  • 24. D. Kaushik, S. A. Khan, G. Chawla and S. Kumar, N'-[5-chloro-3-methyl-1-phenyl-1H-pyrazol- -4-yl)methylene]2/4-substituted hydrazide: Synthesis and anticonvulsant activity, Eur. J. Med. Chem. 45 (2010) 3943-3949; DOI: 10.1016/j.ejmech.2010.05.049.

  • 25. S. G. Küçükgüzel, A. Mazi, F. Sahin, S. Öztürk and J. Stables, Synthesis and biological activities of diflunisal hydrazide-hydrazones, Eur. J. Med. Chem. 38 (2003) 1005-1013. DOI: 10.1016/ j.ejmech.2003.08.004.

  • 26. Y. L. Xia, F. Chuan-Dong, B. X. Zhao, J. Zhao, D. S. Shin and J. Y. Miaom, Synthesis and structure- activity relationships of novel 1-arylmethyl-3-aryl-1H pyrazole-5-carbohydrazide hydrazone derivatives as potential agents against A549 lung cancer cells, Eur. J. Med. Chem. 43 (2008) 2347-2353; DOI: 10.1016/j.ejmech.2008.01.021.

  • 27. C. Menendez, A. Chollet, F. Rodriguez, C. Inard, M. R. Pasca, C. Lherbet and M. Baltas, Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents, Eur. J. Med. Chem. 52 (2012) 275-283; DOI: 10.1016/j.ejmech.2012.03.029.

  • 28. N. Özbek, S. Alyar and N. Karacan, Experimental and theoretical studies on methanesulfonic acid 1-methylhydrazide: Antimicrobial activities of its sulfonyl hydrazone derivatives, J. Mol. Struct. 938 (2009) 48-53; DOI: 10.1016/j.molstruc.2009.09.002.

  • 29. R. M. Mohareb and J. Schatz, Anti-tumor and anti-leishmanial evaluations of 1,3,4-oxadiazine, pyran derivatives derived from cross-coupling reactions of b-bromo-6H-1,3,4-oxadiazine derivatives, Bioorg. Med. Chem. 19 (2011) 2707-2713; DOI: 10.1016/j.bmc.2011.02.051.

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

Journal Information

IMPACT FACTOR 2016: 1.288
5-year IMPACT FACTOR: 1.600

CiteScore 2016: 1.55

SCImago Journal Rank (SJR) 2016: 0.353
Source Normalized Impact per Paper (SNIP) 2016: 0.854


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 16 16 16
PDF Downloads 6 6 6