Modern Organic Chemistry Research

Download PDF (401.1 KB) PP. 112 - 123 Pub. Date: August 3, 2017

DOI: 10.22606/mocr.2017.23004

• Ehab Abdel-Latif^*
  Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt
• Eman M. Keshk
  
  Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt
• Ali Saeed
  
  Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt
• Abdel-Galil M. Khalil
  
  Department of Chemistry, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt

New heterocyclic scaffolds containing acetanilide moiety were synthesized as anticancer agents. The precursor N-(4-acetamidophenyl)-2-cyanoacetamide (3) was coupled smoothly with (un)substituted phenyl diazonium chlorides producing the hydrazones 4. Various 2-pyridones 6 were picked up through the treatment of 3 with different arylidene malononitriles. The precursor underwent reaction with phenyl isothiocyanate in DMF/KOH followed by in situ addition of several α-halogenated reagents afforded the corresponding thiazole derivatives 9 and 10. Heating of thiocarbamoyl scaffold 11 with chloroacetone and phenacyl chloride resulted in the formation of 5-substitutedthiophene-3-carboxamides 12. Condensation of the synthesized ketene N,S-acetal 13 with NH₂NH₂ furnished the corresponding pyrazole-4-carboxamide 14. The newly synthesized scaffolds were characterized by considering their spectral analyses and they evaluated for their in vitro anticancer activities to show promising results.

4-aminoacetanilide, hydrazones, 2-pyridones, thiazolidin-4-one, thiophene-3-carboxamides, anticancer activity.

[1] El-Gaml, K. M. (2015) Synthesis and antimicrobial evaluation of new polyfunctionally substituted heterocyclic compounds derived from 2-cyano-N-(3-cyanoquinolin-2-yl)acetamide. American Journal of Organic Chemistry, 5, 1–9.

[2] Darwish, E. S., Fattah, A. M. A., Attaby, F. A. and Al-Shayea, O. N. (2014) Synthesis and antimicrobial evaluation of some novel thiazole, pyridone, pyrazole, chromene, hydrazone derivatives bearing a biologically active sulfonamide moiety. International Journal of Molecular Sciences, 15, 1237–1254.

[3] Panchal, A. D., Kunjadia, P. D. and Patel, P. M. (2011) Synthesis and biological evaluation of chalcone derivatives linked triazoles. International Journal of Pharmaceutical Sciences and Drug Research, 3, 331–337.

[4] Alafeefy, A. M., Isik, S., Abdel-Aziz, H. A., Ashour, A. E., Vullo, D., Al-Jaber, N. A. and Supuran, C. T. (2013) Carbonic anhydrase inhibitors: Benzenesulfonamides incorporating cyanoacrylamide moieties are low nanomolar/subnanomolar inhibitors of the tumor-associated isoforms IX and XII. Bioorganic and Medicinal Chemistry, 21, 1396–1403.

[5] Arora, M., Saravanan, J., Mohan, S. and Bhattacharjee, S. (2013) Synthesis, characterization and antimicrobial activity of some Schiff bases of 2-amino-N-(p-acetamidophenyl carboxamido)-4,5,6,7-tetramethylene thiophenes. International Journal of Pharmacy and Pharmaceutical Sciences, 5, 315-319.

[6] Khokhani, K., Khatri, T. and Patel, P. (2013). One Pot Synthesis of bioactive novel cyanopyridones. Journal of the Korean Chemical Society, 57, 476–482.

[7] Fadda, A. A., Mukhtar, M. M. and Refat, H. M. (2012) Utility of activated nitriles in the synthesis of some new heterocyclic compounds. American Journal of Organic Chemistry, 2, 32–40.

[8] Al-Saadi, M. S., Faidallah, H. M. and Rostom, S. A. F. (2008) Synthesis and biological evaluation of some 2,4,5-trisubstituted thiazole derivatives as potential antimicrobial and anticancer agents. Archiv der Pharmazie -Chemistry in Life Sciences, 341, 424-434.

[9] Bondock, S., Rabie, R., Etman, H. A. and Fadda, A. A. (2008) Synthesis and antimicrobial activity of some newheterocycles incorporating antipyrine moiety. European Journal of Medicinal Chemistry, 43, 2122-2129.

[10] Bondock, S., Khalifa, W. and Fadda, A. A. (2007) Synthesis and antimicrobial evaluation of some new thiazole,thiazolidinone and thiazoline derivatives starting from 1-chloro-3,4-dihydronaphthalene-2-carboxaldehyde.European Journal of Medicinal Chemistry, 42, 948-954.

[11] Karegoudar, P., Karthikeyan, M. S., Prasad, D. J., Mahalinga, M., Holla, B. S. and Kumari, N. S. (2008)Synthesis of some novel 2,4-disubstituted thiazoles as possible antimicrobial agents. European Journal ofMedicinal Chemistry, 43, 261-267.

[12] Chandanshive, J. Z., Pedro, B. G., Tiznado, W., Bonini, B. F., Caballero, J. and Femoni, C. (2012) 1,3-Dipolarcycloaddition of nitrile imines with α,β-unsaturated lactones, thiolactones and lactams: Synthesis of ring-fusedpyrazoles. Tetrahedron, 68, 3319-3328.

[13] Bekhit, A. A. and Aziem T. A. (2004) Design, synthesis and biological evaluation of some pyrazole derivativesas anti-inflammatory-antimicrobial agents. Bioorganic and Medicinal Chemistry, 12, 1935–1945.

[14] El-Emary, T. and El-Mohsen, S. (2012) Multi-component one-pot synthesis and antimicrobial activities of 3-methyl-1,4-diphenyl-7-thioxo-4,6,8,9-tetrahydro-pyrazolo[5,4-b]pyrimidino[5,4-e]pyridine-5-one and relatedderivatives. Molecules, 17, 14464–14483.

[15] Abu-Hashem, A. A., Gouda, M. A. and Badria, F. A. (2010) Synthesis of some newpyrimido[2',1':2,3]thiazolo[4,5-b]quinoxaline derivatives as anti-inflammatory and analgesic agents. EuropeanJournal of Medicinal Chemistry, 45, 1976–1981.

[16] Gouda, M. A., Berghot, M. A., Abd El-Ghani, G. E. and Khalil, A. M. (2010). Synthesis and antimicrobialactivities of some new thiazole and pyrazole derivatives based on 4,5,6,7-tetrahydrobenzothiophene moiety.European Journal of Medicinal Chemistry, 45, 1338–1345.

[17] Khalil, A. M., Berghot, M. A. and Gouda M. A. (2009) Synthesis and antibacterial activity of some new thiazoleand thiophene derivatives. European Journal of Medicinal Chemistry, 44, 4434–4440.

[18] Gouda, M. A., Berghot, M. A., Shoeib, A. I. and Khalil, A. M. (2010) Synthesis and antimicrobial of certainnew thiazolidinone, thiazoline and thiophene derivatives. Phosphorus, Sulfur, and Silicon and the RelatedElements, 185, 1455–1462.

[19] Gouda, M. A. and Abu-Hashem A. A. (2011) Synthesis, characterization, antioxidant and antitumor evaluationof some new thiazolidine and thiazolidinone derivatives. Archiv der Pharmazie - Chemistry in Life Sciences, 11,170–177.

[20] Wilby, M. J. and Hutchinson P. J. (2004) The pharmacology of chlormethiazole: A potential neuroprotectiveagent. CNS Drug Reviews, 10, 281–294.

[21] Harnett, J. J., Roubert, V., Dolo, C., Charnet, C., Spinnewyn, B., Cornet, S., Rolland, A., Marin, J. G., Bigg, D.and Chabrier, P. E. (2004) Phenolic thiazoles as novel orally-active neuroprotective agents. Bioorganic andMedicinal Chemistry Letters, 14, 157–160.

[22] Lesyk, R., Zimenkovsky, B., Atamanyuk, D., Jensen, F., Kononowicz, K. K. and Gzella, A. (2006) Anticancerthiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety. Synthesis, cytotoxicity, physico-chemical properties,and computational studies. Bioorganic and Medicinal Chemistry, 14, 5230–5240.

[23] Kashfi, K. (2009) Anti-inflammatory agents as cancer therapeutics. Advances in pharmacology, 57, 31–89.

[24] Modiya, P. R. and Patel, C. N. (2012) Synthesis and screening of antibacterial and antifungal activity of 5-chloro-1,3-benzoxazol-2(3H)-one derivatives. Organic and Medicinal Chemistry Letters, 2, 29.

[25] Al-Said, M. S., Ghorab, M. M. and Nissan, Y. M. (2012) Dapson in heterocyclic chemistry, part VIII: Synthesis,molecular docking and anticancer activity of some novel sulfonylbiscompounds carrying biologically active 1,3-dihydropyridine, chromene and chromenopyridine moieties. Chemistry Central Journal, 6, 64.

[26] Dragovich, P. S., Prins, T. J., Zhou, R., Brown, E. L., Maldonado, F. C., Fuhrman, S. A., Zalman, L. S.,Tuntland, T., Lee, C. A. and Patick, A. K. (2002) Structure-based design, synthesis, and biological evaluation ofirreversible human rhinovirus 3C protease inhibitors. Part 6: Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics. Journal of Medicinal. Chemistry, 45, 1607–1623.

[27] Dragovich, P. S., Prins, T. J. Zhou, R., Johnson, T. O., Brown, E. L., Maldonado, F. C., Fuhrman, S. A., Zalman, L. S., Patick, A. K. and Matthews, D. A. (2002) Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. Part 7: Structure–activity studies of bicyclic 2-pyridone-containing peptidomimetics. Bioorganic and Medicinal Chemistry Letters, 12, 733–738.

[28] Ye, D., Zhang, Y., Wang, F., Zheng, M., Zhang, X., Luo, X., Shen, X., Jiang, H. and Liu, H. (2010) Novel thiophene derivatives as PTP1B inhibitors with selectivity and cellular activity. Bioorganic and Medicinal Chemistry, 18, 1773-1782.

[29] Kulandasamy, R., Adhikari, A. V. and Stables, J. P. (2009) A new class of anticonvulsants possessing 6 Hz activity: 3,4-Dialkyloxy thiophene bishydrazones. European Journal of Medicinal Chemistry, 44, 4376–4384.

[30] Khalil, A. M., Berghot, M. A., Ghada E. A. and Gouda, M. A. (2010), Synthesis and antimicrobial evaluation of some new thiophene derivatives. European Journal of Medicinal Chemistry, 40, 1658-1669.

[31] Ronad, P. M., Noolvi, M. N., Sapkal, S., Dharbhamulla, S. and Maddi, V. S. (2010) Synthesis and antimicrobial activity of 7-(2-substitutedphenylthiazolidinyl)-benzopyran-2-one derivatives. European Journal of Medicinal Chemistry, 45, 85-89.

[32] Borges, F., Roleir, F., Santana, L. and Uriare E. (2005) Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Current Medicinal Chemistry, 12, 887-916.

[33] Fadda, A. A., Berghot, M. A., Amer, F. A., Badway, D. S. and Bayoumy, N. M. (2012) Synthesis and antioxidant and antitumor activity of novel pyridine, chromine, thiophene and thiazoles derivatives. Archiv der Pharmazie, 435, 378–385.

[34] Fadda, A. A. and Youssif, E. H. E. (2011) Synthesis of some new chromene derivatives. Synthetic Communications, 41, 677-694.

[35] El-Shafei, A., Fadda, A. A., Abdel-Gawad, I. I. and Youssif, E. H. E. (2009) Stereospecificity of Diels–Alder reactions validated using ab initio calculations: Synthesis of novel coumarin and phenanthridine derivatives. Synthetic Communications, 39, 2954-2972.

[36] Lahtchev, K. L. Batovska, D. I., Parushev, St. P., Ubiyvovk, V. M. and Sibirny, A. A. (2008) Antifungal activity of chalcones: A mechanistic study using various yeast strains. European Journal of Medicinal Chemistry, 43, 2220-2228.

[37] Tim, M. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65, 55-63.

[38] Francois, D. and Rita, L. (1986) Rapid colorimetric assay for cell growth and survival: Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. Journal of Immunological Methods, 89, 271-277.

[39] Helena, J. M., Nader, N. H., Micheal, A. B., David, H. G., Mary, J. S., Kerri, A. S., Kevin, B., Ruth, H., Stephen, G., Mohanraj, D., Gerald, A. S., Vikas, P. S., Donald, W. K. and Ralph, R. W. (1998). Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature, 394, 287-291.