European Journal of Chemistry 2011, 2(2), 214-222 | doi: | Get rights and content

Issue cover


Regioselective synthesis and biological evaluation of some novel thiophene-containing heterocyclic scaffolds as potential chemotherapeutic agents

Hatem Moustafa Gaber (1,*) , Mark Christopher Bagley (2)

(1) National Organization for Drug Control and Research (NODCAR), Cairo 12553, Egypt
(2) School of Chemistry, Cardiff University, Cardiff, CF10 3AT, U.K.
(*) Corresponding Author

Received: 24 Feb 2011 | Accepted: 29 Mar 2011 | Published: 30 Jun 2011 | Issue Date: June 2011


In the reaction of 2-amino-3-carbethoxythiophene derivative 2b with hydrazine hydrate the respective aminocarbohydrazide 3 was isolated. Treatment of the latter product with carbon disulfide in alkaline medium caused a heterocyclization to give 1,3,4-oxadiazole-2-thione 5 rather than 3-amino-2-thioxothieno[2,3-d]pyrimidin-4-one 4, which could be obtained on treatment of carbohydrazide 3 with thiourea. The structure of products 4 and 5 was proved by spectroscopic methods and chemical transformations. Derivatization led to two novel series of condensed and uncondensed thiophenes, which were of significant interest for biological study. Since compound 4 contains two adjacent reactive functional groups, it reacted readily with different electrophilic reagents to provide a series of thieno[2,3-d]pyrimidin-4-one derivatives with annelated bridgehead nitrogen heterocycles 8-11, whereas a second series of 3-heteroaryl-substituted thiophenes 13-17 was obtained by thioamide functionalization in 1,3,4-oxadiazole derivative 5 using various chemical reagents. The new thiophene-based derivatives were evaluated for their preliminary antimicrobial activity against a representative panel of Gram-positive and Gram-negative bacteria as well as fungi strains. The compounds tested displayed different levels of inhibitory effects, with the assays carried out on two pathogenic bacteria and two pathogenic fungi. Of these compounds, the monocyclic aminothiophene derivative 15 showed the highest effect on pathogenic bacteria, while the tricyclic condensed thiophene derivative 8 was observed to have the same inhibitory effect against pathogenic mould (Aspergillus flavus) as the reference drug Amphotericin B. For those derivatives belonging to first series of condensed thiophenes with annelated bridgehead nitrogen heterocycles, it has been observed that the antibacterial effect was in general found to be significantly higher than the corresponding uncondensed analogues. Although most of the condensed and uncondensed thiophenes under investigation showed generally remarkable in vitro antibacterial activity, unfortunately, no significant antifungal activity was observed with any of the compounds tested except for 8. Surprisingly, compound 8 displayed an excellent effect on fungus (A. flavus) on the one hand, whereas the lowest effect on bacteria on the other. The attachment of a triazolothiadiazine moiety to a thiophene ring could be considered as a promising strategy for the development of new therapeutic antibacterial agents related to the aminothiophene system.2_2_214_222_800


Thienopyrimidinone; Cyclocondensation; Cyclodesulfurization; Hydrazinolysis; Alkylation; Antimicrobial activity

Full Text:

PDF    Open Access

DOI: 10.5155/eurjchem.2.2.214-222.411

Links for Article

| | | | | | |

| | | | | | |

| | | |

Related Articles

Article Metrics

icon graph This Abstract was viewed 1674 times | icon graph PDF Article downloaded 1855 times



[1]. Banu Babür, Nermin Ertan
Part 1: Synthesis and visible absorption spectra of some new monoazo dyes derived from ethyl 2-amino-4-(4′-substitutedphenyl)thiophenes
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy  131, 319, 2014
DOI: 10.1016/j.saa.2014.04.042

[2]. Jun Ki Kim, Hwan Jung Lim, Kyung Chae Jeong, Seong Jun Park
One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates
Beilstein Journal of Organic Chemistry  14, 243, 2018
DOI: 10.3762/bjoc.14.16

[3]. Yahia Mabkhot, Fatima Alatibi, Nahed El-Sayed, Salim Al-Showiman, Nabila Kheder, Abdul Wadood, Abdur Rauf, Saud Bawazeer, Taibi Hadda
Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses
Molecules  21(2), 222, 2016
DOI: 10.3390/molecules21020222

[4]. Fatih Çelik, Yasemin Ünver
1,2,4-Triazole derivative containing thiophen ring: Comparison of theoretical IR and NMR data with experimental
Journal of the Indian Chemical Society  99(6), 100455, 2022
DOI: 10.1016/j.jics.2022.100455

[5]. L. V. Klyba, N. A. Nedolya, E. R. Sanzheeva, O. A. Tarasova
Mass Spectra of New Heterocycles. XVII. Main Fragmentation Routes of Molecular Ions of 4-Alkoxy-5-amino-3-methylthiophene-2-carbonitriles under Electron and Chemical Ionization
Russian Journal of Organic Chemistry  54(8), 1184, 2018
DOI: 10.1134/S1070428018080110

[6]. Ibragimdjan Аbdugafurov Azizovich, Fazliddin Qirgizov Bakhtiyarovich, Ilhom Оrtikov Sobirovich
Synthesis of 1,2,3-triazole derivatives based on propargyl ester of a saturated single-basic carbonic acid and para-azidobenzoic acid
European Journal of Chemistry  12(1), 13, 2021
DOI: 10.5155/eurjchem.12.1.13-17.2035

[7]. G.H. Elgemeie, K.A. Ahmed, E.A. Ahmed, M.H. Helal, D.M. Masoud
Synthesis of novel tetrasubstituted thiophenes based dye using sodium a-cyanoketene dithiolates as starting materials
Pigment & Resin Technology  44(6), 339, 2015
DOI: 10.1108/PRT-12-2014-0117

[8]. Xiaohui Zhang, Depeng Li, Jianzhong Qin, Yaozhong Xu, Kedong Ma
Synthesis of 4-thio-5-(2′′-thienyl)uridine and cytotoxicity activity against colon cancer cells in vitro
RSC Advances  6(74), 70099, 2016
DOI: 10.1039/C6RA14356C

[9]. Л.В. Клыба, Н.А. Недоля, Е.Р. Санжеева, О.А. Тарасова
Журнал органической химии  (8), 1173, 2018
DOI: 10.7868/S0514749218080113

[10]. Vilija Kederienė, Indrė Jaglinskaitė, Paulina Voznikaitė, Jolanta Rousseau, Patrick Rollin, Algirdas Šačkus, Arnaud Tatibouët
Mild Copper-Catalyzed, l-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate
Molecules  26(22), 6822, 2021
DOI: 10.3390/molecules26226822

[11]. Anupam Anupam, Mohammed Al-Bratty, Hassan Ahmad Alhazmi, Shamim Ahmad, Supriya Maity, Md Shamsher Alam, Waquar Ahsan
Synthesis and biological evaluation of triphenyl-imidazoles as a new class of antimicrobial agents
European Journal of Chemistry  9(4), 369, 2018
DOI: 10.5155/eurjchem.9.4.369-374.1785


[1]. Weinberg, E. D. Antifungal agents. In Burger's Medicinal Chemisrty and Drug Discovery, fifth ed., Wiley-Interscience: New York, 1996; Vol. 2, pp. 637-652.

[2]. Petrov, O.; Gerova, M.; Petrova, K.; Ivanova, Y. J. Heterocyclic Chem. 2009, 46, 44-48.

[3]. Wildfeuer, A.; Seidl, H. P.; Paule, I.; Haberreiter, A. Mycoses 1998, 41, 309-319.

[4]. Daidone, G.; Maggio, B.; Schillaci, D. Pharmazie 1990, 45, 441-442.

[5]. Franchini, C.; Muraglia, M.; Corbo, F.; Florio, M. A.; Mola, A. D.; Rosato, A.; Matucci, R.; Nesi, M.; Bambeke, F. V.; Vitali, C. Arch. Pharm. Chem. Life Sci. 2009, 342, 605-613.

[6]. Pinto, E.; Queiroz, M.-J. R. P.; Vale-Silva, L. A.; Oliveira, J. F.; Begouin, A.; Begouin, J.-M.; Kirsch, G. Bioorg. Med. Chem. 2008, 16, 8172-8177.

[7]. Daniel, V. P.; Murukan, B.; Kumari, B. S.; Mohanan, K. Spectrochim. Acta A 2008, 70A, 403-410.

[8]. Ghorab, M. M.; Amin, N. E.; El Gaby, M. S. A.; Taha, N. M. H.; Shehab, M. A.; Faker, I. M. I. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 2918-2928.

[9]. Darwish, E. S. Molecules 2008, 13, 1066-1078.

[10]. Queiroz, M. J. R. P.; Ferreira, I. C. F. R.; De Gaetano, Y.; Kirsch, G.; Calhelha, R. C.; Estevinho, L. M. Bioorg. Med. Chem. 2006, 14, 6827-6831.

[11]. Carrillo-Munoz, A. J.; Giusiano, G.; Ezkurra, P. A.; Quindos, G. Expert Rev. Anti-Infect. Ther. 2005, 3, 333-342.

[12]. Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.; Bahekar, R. H. Eur. J. Med. Chem. 2003, 38, 89-100.

[13]. El-Sharief, A. M. Sh.; Micky, J. A. A.; Shmeiss, N. A. M. M.; El-Gharieb, G. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 439-451.

[14]. El-Sherbeny, M. A.; El-Ashmawy, M. B.; El-Subbagh, H. I.; El-Emam, A. A.; Badria, F. A. Eur. J. Med. Chem. 1995, 30, 445-449.

[15]. Gaber, H. M.; Bagley, M. C. ChemMedChem 2009, 4, 1043-1050.

[16]. Filichev, V. V.; Gaber, H.; Olsen, T. R.; Jørgensen, P. T.; Jessen, C. H.; Pedersen, E. B. Eur. J. Org. Chem. 2006, 17, 3960-3968.

[17]. Gaber, H. M.; Elgemeie, G. E. H.; Ouf, S. A.; Sherif, S. M. Heteroat. Chem. 2005, 16, 298-307.

[18]. Gewald, K.; Schinke, E.; Boettcher, H. Chem. Ber. 1966, 99, 94-100.

[19]. Perrissin, M.; Duc, C. L.; Narcisse, G.; Bakri-Logeais, F.; Huguet, F. Eur. J. Med. Chem. 1980, 15, 563-565.

[20]. Hallas, G.; Choi, J.-H. Dyes Pigments 1999, 40, 99-117.

[21]. Koebel, R. F.; Needham, L. L.; Blanton, Jr., C. D. J. Med. Chem. 1975, 18, 192-194.

[22]. Tormyshev, V. M.; Trukhin, D. V.; Rogozhnikova, O. Y.; Mikhalina, T. V.; Troitskaya, T. I.; Flinn, A. Synlett 2006, 16, 2559-2564.

[23]. Gewald, K.; Gruner, M.; Hain, U.; Sueptitz, G. Monatsh. Chem. 1988, 119, 985-992.

[24]. Bauer, A. W.; Kirby, W. W. M.; Sherris, J. C.; Turck, M. Am. J. Clin. Pathol. 1966, 45, 493-496.

[25]. Pfaller, M. A.; Burmeister, L.; BartlettGhorab, M. A.; Rinaldi, M. G. J. Clin. Microbiol. 1988, 26, 1437-1441.
PMid:3049651 PMCid:266638

[26]. National Committee for Clinical Laboratory Standards, Method for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard, fourth ed. NCCLS Document M7-A4, Wayne, PA, USA, 1997.

[27]. Wu, L.; Pan, J.; Thoroddsen, V.; Wysong, D. R.; Blackman, R. K.; Bulawa, C. E.; Gould, A. E.; Ocain, T. D.; Dick, L. R.; Errada, P.; Dorr, P. K.; Parkison, T.; Wood, T.; Kornitzer, D.; Weussman, Z.; Willis, I. M. Eukaeyotic Cell 2003, 2, 256-264.
PMid:12684375 PMCid:154847

[28]. Ainsworth, C. J. Am. Chem. Soc. 1956, 78, 4475-4478.

[29]. Aboraia, A. S.; Abdel-Rahman, H. M.; Mahfouz, N. M.; El-Gendy, M. A. Bioorg. Med. Chem. 2006, 14, 1236-1246.

[30]. Abdel-Rahman, H. M.; Hussein, M. A. Arch. Pharm. Chem. Life Sci. 2006, 339, 378-387.

[31]. Küçükgüzel, İ.; Küçükgüzel, Ş. G.; Rollas, S.; Ötük-Saniş, G.; Özdemir, O.; Bayrak, İ.; Altuğ, T.; Stables, J. P. Farmaco 2004, 59, 893-901.

[32]. Oruç, E. E.; Koçyigit-Kaymakçioglu, B.; Oral, B.; Altunbas-Toklu, H. Z.; Kabasakal, L.; Rollas, S. Arch. Pharm. Chem. Life Sci. 2006, 339, 267-272.

[33]. Güzeldemirci, N. U.; Küçükbasmaci, Ö. Eur. J. Med. Chem. 2010, 45, 63-68.

[34]. Küçükgüzel, İ.; Küçükgüzel, Ş. G.; Rollas, S.; Kiraz, M. Bioorg. Med. Chem. Lett. 2001, 11, 1703-1707.

[35]. Gürsoy, A.; Demirayak, Ş.; Cesur, Z.; Reisch, J.; Ötük, G. Pharmazie 1990, 45, 246-250.

[36]. Rollas, S.; Kalyoncuoğlu, N.; Sur-Altiner, D.; Yeğenoğlu, Y. Pharmazie 1993, 48, 308-309.

[37]. Cho, N. S.; Kim, G. N.; Parkanyi, C. J. Heterocyclic Chem. 1993, 30, 397-401.

[38]. Elmoghayar, M. R. H.; Ghali, E. A.; Ramiz, M. M. M.; Elnagdi, M. H. Liebigs Ann. Chem. 1985, 10, 1962-1968.

[39]. Bartels-Keith, J. R.; Burgess, M. T.; Stevenson, J. M. J. Org. Chem. 1977, 42, 3725-3731.

[40]. Pappalardo, S.; Bottino, F.; Tringali, C. J. Org. Chem. 1987, 52, 405-412.

[41]. Ram, V. J.; Mishra, L.; Pandey, N. H.; Kushwaha, D. S. J. Heterocyclic Chem. 1990, 27, 351-355.

[42]. Ergenc, N.; Ilhan, E.; Ötük, G. Pharmazie 1992, 47, 59-60.

[43]. Shaker, R. M.; Mahmoud, A. F.; Abdel-Latif, F. F. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 397-406.

[44]. Sandström, J.; Wennerbeck, I. Acta Chem. Scand. 1966, 20, 57-71.

[45]. Still, I. W. J.; Plavac, N.; McKinnon, D. M.; Chauhan, M. S. Can. J. Chem. 1976, 54, 280-289.

[46]. Still, I. W. J.; Plavac, N.; McKinnon, D. M.; Chauhan, M. S. Can. J. Chem. 1976, 54, 1660-1664.

[47]. El-Essawy, F. A.; Khattab, A. F.; Abdel-Rahman, A. A. H. Monatsh. Chem. 2007, 138, 777-785.

[48]. Nawrocka, W.; Zimecki, M. Arch. Pharm. Pharm. Med. Chem. 1997, 330, 399-405.

[49]. Britsun, V. N.; Esipenko, A. N.; Kudryavtsev, A. A.; Lozinskii, M. O. Russ. J. Org. Chem. 2005, 41, 1333-1336.

[50]. Gogol, P. C.; Kataky, J. C. S. Heterocycles 1990, 31, 2147-2152.

[51]. Ilango, K.; Valentina, P. Eur. J. Chem. 2010, 1, 50-53.

[52]. Golgolab, H.; Lalezari, I.; Hosseini-Gohari, L. J. Heterocyclic Chem. 1973, 10, 387-390.

[53]. Ibrahim, D. A. Eur. J. Med. Chem. 2009, 44, 2776-2781.

[54]. Anwar, H. F.; Metwally, N. H.; Gaber, H.; Elnagdi, M. H. J. Chem. Research 2005, 1, 29-31.

[55]. Vainilavicius, P.; Smicius, R.; Jakubkiene, V.; Tumkevicius, S. Monatsh. Chem. 2001, 132, 825-831.

[56]. Elkholy, Y. M.; Ali, K. A.; Farag, A. M. J. Heterocyclic Chem. 2006, 43, 1183-1188.

[57]. Almasirad, A.; Vousooghi, N.; Tabatabai, S. A.; Kebriaeezadeh, A.; Shafiee, A. Acta Chim. Slov. 2007, 54, 317-324.

[58]. Salyers, A. A.; Whitt, D. D. Bacterial Pathogenesis: A Molecular Approach; second ed., ASM Press: Washington, D. C., USA, 2002, pp. 539. ISBN 1-55581-171-X.

[59]. Curran, J. P.; Al-Salihi, F. L. Pediatrics 1980, 66, 285-290.

[60]. Saraceno, J. L.; Phelps, D. T.; Ferro, T. J.; Futerfas, R.; Schwartz, D. B. Chest 1997, 112, 541-548.

[61]. Cowan, M. M. Clin. Microbiol. Rev. 1999, 12, 564-582.
PMid:10515903 PMCid:88925

[62]. Bozkurt, M. K.; Ozçelik, T.; Saydam, L.; Kutluay, L. Kulak Burun Bogaz Ihtis. Derg. 2008, 18, 53-55.

[63]. Di Santo, R.; Tafi, A.; Costi, R.; Botta, M.; Artico, M.; Corelli, F.; Forte, M.; Caporuscio, F.; Angiolella, L.; Palamara, A. T. J. Med. Chem. 2005, 48, 5140-5153.

How to cite

Gaber, H.; Bagley, M. Eur. J. Chem. 2011, 2(2), 214-222. doi:10.5155/eurjchem.2.2.214-222.411
Gaber, H.; Bagley, M. Regioselective synthesis and biological evaluation of some novel thiophene-containing heterocyclic scaffolds as potential chemotherapeutic agents. Eur. J. Chem. 2011, 2(2), 214-222. doi:10.5155/eurjchem.2.2.214-222.411
Gaber, H., & Bagley, M. (2011). Regioselective synthesis and biological evaluation of some novel thiophene-containing heterocyclic scaffolds as potential chemotherapeutic agents. European Journal of Chemistry, 2(2), 214-222. doi:10.5155/eurjchem.2.2.214-222.411
Gaber, Hatem, & Mark Christopher Bagley. "Regioselective synthesis and biological evaluation of some novel thiophene-containing heterocyclic scaffolds as potential chemotherapeutic agents." European Journal of Chemistry [Online], 2.2 (2011): 214-222. Web. 2 Oct. 2022
Gaber, Hatem, AND Bagley, Mark. "Regioselective synthesis and biological evaluation of some novel thiophene-containing heterocyclic scaffolds as potential chemotherapeutic agents" European Journal of Chemistry [Online], Volume 2 Number 2 (30 June 2011)

The other citation formats (EndNote | Reference Manager | ProCite | BibTeX | RefWorks) for this article can be found online at: How to cite item

DOI Link:

CrossRef | Scilit | GrowKudos | Researchgate | Publons | ScienceGate | scibey | Scite | Lens | OUCI

WorldCat Paperbuzz | LibKey Citeas | Dimensions | Semanticscholar | Plumx | Kopernio | Zotero | Mendeley

ZoteroSave to Zotero MendeleySave to Mendeley

European Journal of Chemistry 2011, 2(2), 214-222 | doi: | Get rights and content


  • There are currently no refbacks.

Copyright (c)

© Copyright 2010 - 2022  Atlanta Publishing House LLC All Right Reserved.

The opinions expressed in all articles published in European Journal of Chemistry are those of the specific author(s), and do not necessarily reflect the views of Atlanta Publishing House LLC, or European Journal of Chemistry, or any of its employees.

Copyright 2010-2022 Atlanta Publishing House LLC. All rights reserved. This site is owned and operated by Atlanta Publishing House LLC whose registered office is 2850 Smith Ridge Trce Peachtree Cor GA 30071-2636, USA. Registered in USA.