New Approaches for the Use of Acetoacetanilide in the Synthesis of Thiophenes and Their Fused Derivatives with Anti-Tumor Activity

DOI: 10.4236/oalib.1101089   PDF        1,267 Downloads   1,656 Views  


Acetoacetanilide derivatives 1a-c reacted with either malnonitrile or ethyl cyanoacetate and elemental sulfur to give the thiophene derivatives 3a-f. The reactivity of 3a towards some chemical reagents to give thiophene, theino[2,3-b]pyridine, thieno[2,3-c]pyrimidine and coumarin derivatives was studied. The anti-tumor 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 compounds 8a, 8b and 14 exhibit higher inhibitory effects towards the three tumor cell lines than the positive control doxorubicin.

Share and Cite:

Mohareb, R. , Sherif, S. , Wardakhan, W. and Abouzied, A. (2014) New Approaches for the Use of Acetoacetanilide in the Synthesis of Thiophenes and Their Fused Derivatives with Anti-Tumor Activity. Open Access Library Journal, 1, 1-16. doi: 10.4236/oalib.1101089.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Mohanakrishnan, A.K., Amaladass, P. and Clement, J.A. (2007) Synthesis of End-Blocked Thienyl Oligomers Incorporating Benzo[c]thiophene. Tetrahedron Letters, 48, 779-784.
[2] Ferreira, I.C., Queiroz, M.J. and Kirsch, G. (2003) Tandem Palladium-Catalyzed Borylation and Suzuki Coupling (BSC) to Thienocarbazole Precursors. Tetrahedron Letters, 44, 4327-4343.
[3] Queiroz, M.J., Ferreir, I.C., Gaetano, Y.D., Kirsch, G., Calhelha, R.C. and Estevinho, L.M. (2006) Synthesis and Antimicrobial Activity Studies of Ortho-Chlorodiarylamines and Heteroaromatic Tetracyclic Systems in the Benzo[b]thiophene Series. Bioorganic & Medicinal Chemistry, 14, 6827-6848.
[4] Sall, D.J., Briggs, S.L., Chirgadze, N.Y., Clawson, D.K., Gifford-Moore, D.S., Klimkowski, V.J., McCowan, J.R., Smith, G.F. and Wikel, J.H. (1998) Dibasic Benzo[b]thiophene Derivatives as a Novel Class of Active Site Directed Thrombin Inhibitors. 2. Exploring Interactions at the Proximal (S2) Binding Site. Bioorganic & Medicinal Chemistry Letters, 8, 2527-2538.
[5] Lee, S., Lee, H., Yi, K.Y., Lee, B.H. and Cho, N.S. (2005) 4-Substituted(benzo[b]thiophene-2-carbonyl)guanidines as Novel Na+/H+ Exchanger Isoform-1 (NHE-1) Inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 2998-3001.
[6] Bastian, J.A., Chrigadze, N., Denny, M.L., Gifford-Moore, D.S., Sall, D.J., Smith, G.F. and Wikel, J.H. (1999) Diamino Benzo[b]thiophene Derivatives as a Novel Class of Active Site Directed Thrombin Inhibitors: 3. Enhancing Activity by Imposing Conformational Restriction in the C-4" Side Chain. Bioorganic & Medicinal Chemistry Letters, 9, 363-368.
[7] Wang, Y. and Burton, D.J. (2007) Site-Specific Preparation of 4-Substituted-6-fluoro(carboalkoxyl)benzo[b]furans and Benzo[b]thiophenes via Base-Catalyzed Cyclization of Enyne Derivatives. Journal of Fluorine Chemistry, 128, 1052-1057.
[8] Pinto, E., Queiroz, M.J., Vale-Silva, L.A., Oliveira, J.F., Begouin, A., Begouin, J.M. and Kirsch, G. (2008) Antifungal Activity of Synthetic Di(hetero)arylamines Based on the Benzo[b]thiophene Moiety. Bioorganic & Medicinal Chemistry, 16, 8172-8177.
[9] Eicher, T., Hauptman, S. and Speicher, A. (2003) The Chemistry of Heterocycles: Chapter 5, Five-Membered Heterocycles, Section 5.6 Thiophene. Wiley-VCH, New York.
[10] King, W.J. and Nord, F.F. (1949) Studies in the Thiophene Series. V. Wolff-Kishner Reductions. Journal of Organic. Chemistry, 14, 638-642.
[11] Wu, C., Decker, E.R., Blok, N., Bui, H., You, T.J., Wang, J., Bourgoyne, A.R., Knowles, V., Berens, K.L., Holland, G.W., Brock, T.A. and Dixon, R.A.F. (2004) Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET A Selective, and Orally Bioavailable Endothelin Antagonist 1. Journal of Medicinal Chemistry, 47, 1969-1986.
[12] Dure, K., Dubus, S., Ho, H.A., Levesque, I., Brunette, M., Corbeil, G., Boissinot, M., Boivin, G., Bergeron, M.G., Boudreau, D. and Leclerc, M. (2004) Fluorescent Polymeric Transducer for the Rapid, Simple, and Specific Detection of Nucleic Acids at the Zeptomole Level. Journal of the American Chemical Society, 126, 4240-4244.
[13] Rost, C., Karg, S., Riess, W., Loi, M.A., Murgia, M. and Muccini, M. (2004) Ambipolar Light-Emitting Organic Field-Effect Transistor. Applied Physics Letters, 85, 1613-1615.
[14] Vriezema, D.M., Hoogboom, J., Veloonia, K., Takazawa, K., Christianen, P.C.M., Maan, J.C., Rowan, A.E. and Nolte, R.J.M. (2003) Vesicles and Polymerized Vesicles from Thiophene-Containing Rod-Coil Block Copolymers. Angewandte Chemie International Edition, 42, 772-776.
[15] Yu, H., Pullen, A.E., Beuschel, M.G. and Swager, T.M. (2004) Charge-Specific Interactions in Segmented Conducting Polymers: An Approach to Selective Ionoresistive Responses. Angewandte Chemie International Edition, 43, 3700-3703.
[16] Sally, E. and Wenzel, M.D. (1998) New Approaches to Anti-Inflammatory Therapy for Asthma. The American Journal of Medicine, 104, 287-300.
[17] Angerer, E. and Erber, S. (1992) 3-Alkyl-2-phenylbenzo[b]thiophenes: Nonsteroidal Estrogen Antagonists with Mammary Tumor Inhibiting Activity. The Journal of Steroid Biochemistry and Molecular Biology, 41, 557-562.
[18] Malaisa, O., Neuprez, A. and Reginster, J.Y. (2008) Traitements non hormonaux de l’ostéoporose postménopausique. Gynécologie Obstétrique & Fertilité, 36, 815-822.
[19] Mohareb, R.M., Fleita, D.A. and Sakka, O.K. (2011) Novel Synthesis of Hydrazide-Hydrazone Derivatives and Their Utilization in the Synthesis of Coumarin, Pyridine, Thiazole and Thiophene Derivatives with Antitumor Activity. Molecules, 16, 16-27.
[20] Shams, H.Z., Mohareb, R.M., Helal, M.H. and Mahmoud, A.E. (2011) 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, 16, 52-73.
[21] Mohareb, R.M., El-Arab, E.E. and El-Sharkaway, K.A. (2009) The Reaction of Cyanoacetic Acid Hydrazide with 2-Acetylfuran: Synthesis of Coumarin, Pyridine, Thiophene and Thiazole Derivatives with Potential Antimicrobial Activities. Scientia Pharmaceutica, 77, 355-366.

comments powered by Disqus

Copyright © 2020 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.