Synthesis and Cytotoxic Evaluation of Novel Benzimidazole Fused Condensed Thienopyrimdines Derivatives

Author(s): S. Kaliraj, Muthu K. Kathiravan*

Journal Name: Current Bioactive Compounds

Volume 16 , Issue 2 , 2020

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Graphical Abstract:


Background: Cancer is a major health problem acting as a global killer and one of the leading causes of death. Most cancer chemotherapeutic drugs currently in clinical use are to kill malignant tumour cells by inhibiting some of the mechanisms implied in cellular division. Thienopyrimidines occupy a special position among the fused pyrimidines, along with other pyrimidines containing an annelated five membered hetero aromatic ring; forms a significant class of drugs which exhibit an array of various biological activities. One of the important current anticancer agent gefitinib acts as tyrosine kinase inhibitors is a quinazoline derivative. The thieno[2,3-d]pyrimidine ring system, is considered as a bioisostere of quinazoline moiety and have attracted great attention due to their broad bioactivities, including antitumor.

Methods: Novel thienopyrimidine derivatives were synthesized by cyclization of thiophene o-amino esters with lactam salts such as pyrrolidin-2-one, piperidin-2-one and caprolactam by treating using phosphorous oxychloride. The next set of compounds thieno[2,3-d]pyrimidin-4(3H)-one were synthesised by Niementowski condensations between 2-aminothiophene carboxylate and formamide under reflux condition, followed by its chlorination in good yield. Microwave Fusion of 4-chlorothieno[2,3-d] pyrimidines with o-phenylenediamine afforded target compounds. The target compounds were tested on MCF-7 and HEK293 cell line.

Results: The synthesized thirty compounds structures were established by IR, 1H NMR and Mass spectroscopy. The synthesized compounds were obtained in the good yield ranging from 45-70%. The synthesized compounds were subjected to cytotoxicity studies. Among the twenty compounds only one compound showed moderate activity. One of the compound 2c bearing acetyl group had IC50 48.93 μM. However decrease in the size of the lactam ring from six to five member ring or increase to seven member ring resulted in the loss of activity. The IC50 value of 5a was found to be 70.86μg/ml. The compound 5i have more cytotoxic action among the series.

Conclusion: A series of thirty compounds belonging to novel pyyrolo, pyrido and benzimidazole fused thienopyrimidines were synthesized, characterized and were evaluated for their in vitro cytotoxicity. The compounds bearing bulky group such as terbutyl group and chloro substitution had the best activity. In conclusion, these structures seems to have biological properties and further investigation on this group could provide a lead.

Keywords: Condensed thienopyrimidines, niementowski, cytotoxicity, anticancer chemotherapies, pyrimidine, antihistaminic.

Johnstone, T.C.; Park, G.Y.; Lippard, S.J. Understanding and improving platinum anticancer drugs--phenanthriplatin. Anticancer Res., 2014, 34(1), 471-476.
[PMID: 24403503]
Hemdan, M.M.; Abd El-Mawgoude, H.K. Synthesis and antimicrobial evaluation of Thieno[2,3-d]-pyrimidine, Thieno[2′,3′:4,5]pyrimido [1,2-a][1,3,5]triazine, Thieno[2,3-d]-1,3-thiazine and 1,2,4-Triazole Systems. Chem. Pharm. Bull. (Tokyo), 2015, 63(10), 812-818.
[] [PMID: 26423038]
Fayeda, A.A.; Amr, A.E.G.E.; Omar, M.A.A.; Mostafa, E.E. Synthesis and antimicrobial activity of some new substituted pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidinone derivatives. Russ. J. Bioorganic Chem., 2014, 40(3), 308-313.
Rashad, A.E.; Shamroukh, A.H.; Abdel-Megeid, R.E.; Mostafa, A.; el-Shesheny, R.; Kandeil, A.; Ali, M.A.; Banert, K. Synthesis and screening of some novel fused thiophene and thienopyrimidine derivatives for anti-avian influenza virus (H5N1) activity. Eur. J. Med. Chem., 2010, 45(11), 5251-5257.
[] [PMID: 20828882]
Rashad, A.E.; Ali, M.A. Synthesis and antiviral screening of some thieno[2,3-d]pyrimidine nucleosides. Nucleosides Nucleotides Nucleic Acids, 2006, 25(1), 17-28.
[] [PMID: 16440982]
Shishoo, C.J.; Shirsath, V.S.; Rathod, I.S.; Patil, M.J.; Bhargava, S.S. Design, synthesis and antihistaminic (H1)activity of some condensed 2-(substituted)arylaminoethylpyrimidin-4(3H)-ones. Arzneimittelforschung, 2001, 51(3), 221-231.
[PMID: 11304938]
Hafez, H.N.; Hussein, H.A.; El-Gazzar, A.R.B.A. Synthesis of substituted thieno[2,3-d]pyrimidine-2,4-dithiones and their S-glycoside analogues as potential antiviral and antibacterial agents. Eur. J. Med. Chem., 2010, 45(9), 4026-4034.
[] [PMID: 20691339]
Santagati, M.; Modica, M.; Santagati, A.; Russo, F.; Spampinato, S. Synthesis of aminothienopyrimidine and thienotriazolopyrimidine derivatives as potential anticonvulsant agents. Pharmazie, 1996, 51(1), 7-11.
[PMID: 8999439]
Toche, R.B.; Nikam, P. Synthesis and evaluation of antimicrobial and antitubercular activity of arylidene hydrazines of indenothieno[2,3-d]pyrimidine. Chem. Biol. Interact., 2015, 5(4), 246.
Pan, F.J.; Wang, S.B.; Liu, D.C.; Gong, G.H.; Quan, Z.S. Synthesis of 4-Phenylthieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine-5(4H)-one derivatives and evaluation of their anti-inflammatory activity. Lett. Drug Des. Discov., 2016, 13, 141-148.
Rizk, O.H.; Shaaban, O.G.; El-Ashmawy, I.M. Design, synthesis and biological evaluation of some novel thienopyrimidines and fused thienopyrimidines as anti-inflammatory agents. Eur. J. Med. Chem., 2012, 55, 85-93.
[] [PMID: 22835720]
Rashad, A.E.; Mahmoud, A.E.; Ali, M.M. Synthesis and anticancer effects of some novel pyrazolo[3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells. Eur. J. Med. Chem., 2011, 46(4), 1019-1026.
[] [PMID: 21315495]
Al-Taisan, K.M.; Al-Hazimi, H.M.; Al-Shihry, S.S. Synthesis, characterization and biological studies of some novel thieno[2,3-d]pyrimidines. Molecules, 2010, 15(6), 3932-3957.
[] [PMID: 20657418]
Elrazaz, E.Z.; Serya, R.A.T. Ismail, N.S.M.; El Ella, D.A.A.; Abouzid, K.A.M. Thieno [2, 3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents. Future. J. Pharm. Sci., 2015, 21, 33-41.
Saddik, A.A. El- Dean, K.; Adel, M.; El-Sokary, G.H.; Hassan, K.M.; Abbady, M.S.; Ismail, I.A.; Saber, S.H. Synthesis and Cytotoxicity of Some Thieno [2, 3‐d]pyrimidine Derivatives. J. Chin. Chem. Soc. (Taipei), 2017, 64, 87-93.
Kandeel, M.M.; Refaat, H.M.; Kassab, A.E.; Shahin, I.G.; Abdelghany, T.M. Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives. Eur. J. Med. Chem., 2015, 90(90), 620-632.
[] [PMID: 25499930]
Bendagude, R.D. Kondawar, M.S. Synthesis and Molecular Modeling Studies of Novel 2, 4-Disubstituted-1, 5-Diphenyl-1-H-Imidazole Derivatives as Potential Anti-Tubercular Agents. Curr. Bioact. Compd., 2017, 13(3), 244-258.
Kathiravan, M.K.; Shishoo, C.J.; Kumar, K.G.; Roy, S.K.; Mahadik, K.R.; Kadam, S.S.; Jain, K.S. Synthesis and antihyperlipidemic activity of some novel condensed 2-chloroalkyl-4-chloro/hydroxy-5,6-disubstituted pyrimidines. Arzneimittelforschung, 2007, 57(9), 599-606.
[PMID: 17966759]
Kathiravan, M.K.; More, K.D.; Raskar, V.K.; Jain, K.S.; Maheshwar, M.; Gadhwe, S.; Jain, D.P.; Nagras, M.A.; Phoujdar, M.S. Synthesis and antihyperlipidemic activity of novel condensed 2-fluoromethylpyrimidines. Med. Chem. Res., 2013, 22, 4286-4292.
Phoujdar, M.S.; Kathiravan, M.K.; Bariwal, J.B.; Shah, A.K.; Jain, K.S. Microwave-Based Synthesis of Novel Thienopyrimidine Bioisosteres of Gefitinib. Tetrahedron Lett., 2008, 49, 1269-1273.
Dudhe, P.B.; Jain, K.S.; Raskar, V.K.; Deodhe, A.S.; Patel, J.G.; Phoujdar, M.S.; Kathiravan, M.K. Synthesis and biological evaluation of novel condensed pyrimidinylmethylsulfinylbenzimidazoles as antiulcer agent. Med. Chem. Res., 2013, 22, 3719-3727.
Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger, K. 2-(diethylamino)thieno1,3ŏxazin-4-ones as stable inhibitors of human leukocyte elastase. J. Med. Chem., 1999, 42(26), 5437-5447.
[] [PMID: 10639285]
Puterova, Z.; Krutosikova, A.; Vegh, D. Gewald reaction: Synthesis, properties and applications of substituted 2-aminothiophenes. ARKIVOC, 2010, 2010(1), 209-246.
Sabnis, R.W.; Rangnekar, D.W.; Sonawane, N.D. 2‐aminothiophenes by the gewald reaction. J. Heterocycl. Chem., 1999, 36(2), 333-345.
Hashash, M.A.A.E.; Soliman, A.Y.; Shamy, I.E.E. Synthesis and antimicrobial evaluation of some annelated phthalazine derivatives and acyclo C-nucleosides from 1-chloro-4-(2,4,6-trimethylphenyl) phthalazine precursor. Turk. J. Chem., 2012, 36, 347-366.
Huangyong, L.; Changshui, C.; Shengzhen, X.; Xiufang, C. Synthesis and bioevaluation of thieno[2,3-d]pyrimidinone derivatives as potential tumor cell growth inhibitors. J. Chem., 2013, 2016, 1-6.
Bozorov, Kh.A.; Mamadalieva, N.Z.; Elmuradov, B.Zh.; Triggiani, D.; Egamberdieva, D.; Tiezzi, A.; Aisa, H.A.; Shakhidoyatov, Kh.M. Synthesis of substituted thieno[2,3-d]pyrimidin-4-ones and their testing for evaluation of cytotoxic activity on mammalian cell models. J. Chem., 2013, 2013, 1-6.
Ke, S.; Shi, L.; Cao, X.; Yang, Q.; Liang, Y.; Yang, Z. Heterocycle-functional gramine analogues: solvent- and catalyst-free synthesis and their inhibition activities against cell proliferation. Eur. J. Med. Chem., 2012, 54, 248-254.
[] [PMID: 22647218]
Kumar, R.R.; Ramesh, R.; Małecki, J.G. Versatile coordination ability of thioamide ligand in Ru(II) complexes: Synthesis, computational studies, in vitro anticancer activity and apoptosis induction. New J. Chem., 2017, 41, 9130-9141.

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Article Details

Year: 2020
Published on: 22 April, 2020
Page: [133 - 141]
Pages: 9
DOI: 10.2174/1573407214666180808124802
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