Synthesis and structure elucidation of some novel thiophene and benzothiophene derivatives as cytotoxic agents

Mohareb, Rafat M.; Abdallah, Amira E. M.; Helal, Maher H. E.; Shaloof, Somiya M. H.

doi:10.1515/acph-2016-0005

Abstract

Attempting to produce cyclized systems with potential anti-proliferative activity, a series of novel thiophene and benzothiophene derivatives were designed and synthesized. The reactivity of the latter derivatives towards different chemical reagents was studied. Twenty-one compounds were synthesized and evaluated as anti-cancer agents. The results showed that ethyl 5-amino-3-(4-chlorostyryl)-4-cyanothiophene-2-carboxylate (5b), ethyl 5-amino-4-((4-methoxyphenyl)carbonyl)-3-methylhiophene-2-carboxylate (8c) and 5-3-(ethoxy-3-oxopropanamido)-3-methyl-4-(phenylcarbamoyl)thiophene-2-carboxylate (9) were the most active compounds towards three tumor cell lines – MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (CNS cancer) and a normal fibro-blast human cell line (WI-38) compared to the anti-proliferative effects of the reference control doxorubicin.

References

1. F. M. Moghaddam, M. R. Khodabakhshi and A. Latifkar, A one-pot multicomponent synthesis of polysubstituted thiophenes via the reactions of an isocyanide, α-haloketones, and β-ketodithioesters in water, Tetrahedron Lett.55 (2014) 1251–1254; DOI: 10.1016/j.tetlet.2014.01.014.10.1016/j.tetlet.2014.01.014
Search in Google Scholar
2. J. C. Lee, S. Kassis, S. Kumar, A. Badger and J. L. Adams, p38 Mitogen-activated protein kinase inhibitors-mechanisms and therapeutic potentials, Pharmacol. Ther.82 (1999) 389–397; DOI: 10.1016/S0163-7258(99)00008-X.10.1016/S0163-7258(99)00008-X
Search in Google Scholar
3. G. Zeni, C. W. Nogueira, D. O. Silva, P. H. Menezes, A. L. Braga, H. A. Stefani and J. B. T. Rocha, 2,5-Bis-(butyltelluro) thiophene as a convenient precursor for the synthesis of 2,5-bis-(acetylenic) thiophenes, Tetrahedron Lett.44 (2003) 685–688; DOI: 10.1016/S0040-4039(02)02659-X.10.1016/S0040-4039(02)02659-X
Search in Google Scholar
4. H. Z. Shams, M. H. Helal and F. A. Mohamed, A novel synthesis of polyfunctionally substituted pyrazolo [1,2-a]pyrazole, and thieno [3′,2′-3,4]pyrazolo [1,2-a]pyrazole systems, Phosphorus Sulfur Silicon174 (2001) 255–267; DOI: 10.1080/10426500108040250.10.1080/10426500108040250
Search in Google Scholar
5. Y. M. Loksha, A. A. El-Barbary, M. A. El-Badawi, C. Nielsen and E. B. Pedersen, Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as novel capravirine analogues, Bioorg. Med. Chem.13 (2005) 4209–4220; DOI: 10.1016/j.bmc.2005.04.024.10.1016/j.bmc.2005.04.024
Search in Google Scholar
6. J. M. Holmes, G. C. M. Lee, M. Wijono, R. Weinkam, L. A. Wheeler and M. E. Garst, Synthesis and carbonic anhydrase Inhibitory activity of 4-substituted 2-thiophenesulfonamides, J. Med. Chem.37 (1994) 1646–1651; DOI: 10.1021/jm00037a015.10.1021/jm00037a015
Search in Google Scholar
7. T. J. Luker, H. G. Beaton, M. Whiting, A. Mete and D. R. Cheshire, Palladium catalysedamination of electron deficient halothiophenes, Tetrahedron Lett.41 (2000) 7731–7735; DOI: 10.1016/S0040-4039(00)01307-1.10.1016/S0040-4039(00)01307-1
Search in Google Scholar
8. I. L. Pinto, R. L. Jarvest and H. T. Serafinowska, The synthesis of 5-alkoxy and 5-amino substituted thiophenes, Tetrahedron Lett.41 (2000) 1597–1600; DOI: 10.1016/S0040-4039(99)02338-2.10.1016/S0040-4039(99)02338-2
Search in Google Scholar
9. A. Mishra, C.-Q. Ma and P. Bäuerle, Functional oligothiophenes: Molecular design for multidimensional nanoarchitectures and their applications, Chem. Rev.109 (2009) 1141–1276; DOI: 10.1021/cr8004229.10.1021/cr800422919209939
Search in Google Scholar
10. H. E. Katz, Z. Bao and S. L. Gilat, Synthetic chemistry for ultrapure, processable and high-mobility organic transistor semiconductors, Acc. Chem. Res.34 (2001) 359–369; DOI: 10.1021/ar990114j.10.1021/ar990114j11352714
Search in Google Scholar
11. T. Noda, I. Imae, N. Noma and Y. Shirota, 5,5″-bis{4-[bis(4-methylphenyl)amino]phenyl}2, 2′:5′,2″-terthiophene and 5,5″′-bis{4-[Bis(4-methylphenyl)amino]phenyl}2, 2′:5′, 2″:5″, 2″′-quaterthiophene as a novel family of amorphous molecular materials, Adv. Mater.9 (1997) 239–241; DOI: 10.1002/adma.19970090311.10.1002/adma.19970090311
Search in Google Scholar
12. S. Kim, N. Dahal and T. Kesharwani, Environmentally benign process for the synthesis of 2,3-disubstituted benzo[b]thiophenes using electrophilic cyclization, Tetrahedron Lett.54 (2013) 4373–4376; DOI: 10.1016/j.tetlet.2013.05.139.10.1016/j.tetlet.2013.05.139
Search in Google Scholar
13. S.-J. Jeong, R. Higuchi, T. Miyamoto, M. Ono, M. Kuwano and S. F. Mawatari, Bryoanthrathiophene, a new antiangiogenic constituent from the bryozoan watersipora subtorquata (d’Orbigny, 1852), J. Nat. Prod.65 (2002) 1344–1345; DOI: 10.1021/np010577+.10.1021/np010577+
Search in Google Scholar
14. M. R. Bleavins, F. A. de la Iglesia, J. A. McCay, K. L. White, Jr., and A. E. Munson, Immunotoxico-logic studies with CI-959, a novel benzothiophene cell activation inhibitor, Toxicology98 (1995) 111–123; DOI: 10.1016/0300-483X(94)02985-4.10.1016/0300-483X(94)02985-4
Search in Google Scholar
15. H. Z. Shams, R. M. Mohareb, M. H. Helal and A. E. Mahmoud, Synthesis, structure elucidation, and biological evaluation of some fused and/or pendant thiophene, pyrazole, imidazole, thiazole, triazole, triazine, and coumarin systems based on cyanoacetic 2-[(benzoylamino)thioxomethyl] hydrazide, Phosphorus Sulfur Silicon182 (2007) 237–263; DOI: 10.1080/10426500600892776.10.1080/10426500600892776
Search in Google Scholar
16. L. Berrade, B. Aisa, M. J. Ramirez, S. Galiano, S. Guccione, L. R. Moltzau, F. O. Levy, F. Nicoletti, G. Battaglia, G. Molinaro, I. Aldana, A., Monge and S. Perez-Silanes, Novel benzo[b]thiophene derivatives as new potential antidepressants with rapid onset of action, J. Med. Chem.54 (2011) 3086–3090; DOI: 10.1021/jm2000773.10.1021/jm200077321469694
Search in Google Scholar
17. H. U. Bryant and W. H. Dere, Selective estrogen receptor modulators: an alternative to hormone replacement therapy, Proc. Soc. Exp. Biol. Med.217 (1998) 45–52; DOI: 10.3181/00379727-217-44204.10.3181/00379727-217-442049421206
Search in Google Scholar
18. R. Romagnoli, P. G. Baraldi, M. D. Carrion, C. L. Cara, D. Preti, F. Fruttarolo, M. G. Pavani, M. A. Tabrizi, M. Tolomeo, S. Grimaudo, A. Di Cristina, J. Balzarini, J. A. Hadfield, A. Brancale and E. Hamel, Synthesis and biological evaluation of 2- and 3-aminobenzo[b]thiophene derivatives as antimitotic agents and inhibitors of tubulin polymerization, J. Med. Chem.50 (2007) 2273–2277; DOI: 10.1021/jm070050f.10.1021/jm070050f17419607
Search in Google Scholar
19. Z.-F. Tao, L. A. Hasvold, J. D. Leverson, E. K. Han, R. Guan, E. F. Johnson, V. S. Stoll, K. D. Stewart, G. Stamper, N. Soni, J. J. Bouska, Y. Luo, T. J. Sowin, N.-H. Lin, V. S. Giranda, S. H. Rosenberg and T. D. Penning, Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as potent highly selective and orally bioavailable inhibitors of the human protooncogene proviral insertion site in moloney murine leukemia virus (PIM) kinases, J. Med. Chem.52 (2009) 6621–6636; DOI: 10.1021/jm900943h.10.1021/jm900943h19842661
Search in Google Scholar
20. Y. Loidreau, E. Deau, P. Marchand, M.-R. Nourrisson, C. Logé, G. Coadou, N. Loaëc, L. Meijer and T. Besson, Synthesis and molecular modelling studies of 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors, Eur. J. Med. Chem.92 (2015) 124–134; DOI: 10.1016/j.ejmech.2014.12.038.10.1016/j.ejmech.2014.12.03825549552
Search in Google Scholar
21. R. M. Mohareb, A. E. Mahmoud and M. A. Abdelaziz, New approaches for the synthesis of pyrazole, thiophene, thieno[2,3-b]pyridine, and thiazole derivatives together with their anti-tumor evaluations, Med. Chem. Res.23 (2014) 564–579; DOI: 10.1007/s00044-013-0664-7.10.1007/s00044-013-0664-7
Search in Google Scholar
22. A. Martorana, C. Gentile, U. Perricone, A. P. Piccionello, R. Bartolotta, A. Terenzi, A. Pace, F. Mingoia, A. M. Almerico and A. Lauria, Synthesis, antiproliferative activity, and in silico insights of new 3-benzoylamino-benzo[b]thiophene derivatives, Eur. J. Med. Chem.90 (2015) 537–546; DOI:10.1016/j.ejmech.2014.12.002.10.1016/j.ejmech.2014.12.00225486425
Search in Google Scholar
23. R. M. Mohareb, H. Z. Shams and S. I. Aziz, Novel synthesis of 4-(coumarin-3-yl)-1,3-thiazole, 2-(cou-marin-3-carbonyl)thieno(2,3-b)pyridine and 2-(coumarin-3-carbonyl)thiophene derivatives, Sulfur Lett.13 (1991) 101–110; DOI: 10.1002/chin.199238159.10.1002/chin.199238159
Search in Google Scholar
24. R. M. Mohareb, S. I. Aziz, N. I. A. Sayed and H. Z. Shams, Reactions of benzoyl isothiocyanate with active methylene reagents: A novel synthesis of thiophene, thiazoline and thieno [2,3-d]pyrimidine derivatives, J. Chin. Chem. Soc.39 (1992) 181–187; DOI: 10.1002/jccs.199200030.10.1002/jccs.199200030
Search in Google Scholar
25. R. M. Mohareb, H. Z. Shams and Y. M. Elkholy, The use of 4-phenyl-3-thiosemicarbazide in hetero-cyclic synthesis: novel synthesis of thiazole, pyrazole and 1,3,4-thiadiazine derivatives, Phosphorus Sulfur Silicon72 (1992) 93–102; DOI: 10.1002/chin.199319192.10.1002/chin.199319192
Search in Google Scholar
26. H. Z. Shams Y. M. Elkholy, N. S. Ibrahim and M. H. Elnagdi, Nitriles in organic synthesis: new routes for synthesis of pyridines and azinothiopyrans, J. Prakt. Chem.330 (1988) 817–819; DOI: 10.1002/prac.19883300521.10.1002/prac.19883300521
Search in Google Scholar
27. 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, Molecules16 (2011) 52–73; DOI: 10.3390/molecules16010052.10.3390/molecules16010052625915221187817
Search in Google Scholar
28. A. Monks, D. Scudiero, P. Skehan, R. Shoemaker, K. Paull, D. Vistica, C. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff, M. Gray-Goodrich, H. Campbell, J. Mayo and M. Boyd, Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines, J. Natl. Cancer Inst.83 (1991) 757–766; DOI: 10.1093/jnci/83.11.757.10.1093/jnci/83.11.7572041050
Search in Google Scholar
29. K. D. Paull, R. H. Shoemaker, L. Hodes, A. Monks, D. A. Scudiero, L. Rubinstein, J. Plowman and M. R. Boyd, Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and compare algorithm, J. Natl. Cancer Inst.81 (1989) 1088–1092; DOI: 10.1093/jnci/81.14.1088.10.1093/jnci/81.14.10882738938
Search in Google Scholar
30. L. H. Li and F. L. Yu, Transcriptional specificities of adriamycin, Biochem. Mol. Biol. Int.31 (1993) 879–887.
Search in Google Scholar

Synthesis and structure elucidation of some novel thiophene and benzothiophene derivatives as cytotoxic agents

Abstract

Paradigm

My account