A Review on Synthesis, Anticancer and Antiviral Potentials of Pyrimidine Derivatives

Author(s): Sanjiv Kumar , Aakash Deep , Balasubramanian Narasimhan* .

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 3 , 2019

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Abstract:

Background: Pyrimidine is the six membered heterocyclic aromatic compound similar to benzene and pyridine containing two nitrogen atoms at 1st and 3rd positions. Pyrimidine is present throughout nature in various forms and is the building blocks of numerous natural compounds from antibiotics to vitamins and liposacharides. The most commonly recognized pyrimidines are the bases of RNA and DNA, the most abundant being cytosine, thymine or uracil.

Results: Pyrimidine is a core structure in a wide variety of compounds that exhibits significant biological activity and also plays an important role in the drug discovery process. Various synthetic aspects indicated that pyrimidine derivatives are easy to synthesize and has diverse biological and chemical applications. The present review article aims to review the work reported on synthesis, anticancer and antiviral potentials of pyrimidine derivatives during new millennium.

Conclusion: It may be concluded that the fused pyrimidine derivatives enhanced the anticancer potential against different human cancer cell lines and antiviral potential against different human immunodeficiency virus (HIV), herpes simplex virus (HSV-1) etc, which created interest among the medicinal chemists in the pyrimidine skeleton in medicinal chemistry. Thus, a tremendous scope for research is present in this direction for investigating pyrimidine derivatives as lead molecules.

Keywords: Pyrimidine derivatives, synthesis, antiviral activity, anticancer activity, malignancy, human leukaemia.

[1]
Rani, J.; Kumar, S.; Saini, M.; Mundlia, J.; Verma, P.K. Biological potential of pyrimidine derivatives in a new era. Res. Chem. Intermed., 2016, 42, 6777-6804.
[2]
Cocco, M.T.; Congiu, C.; Onnis, V.; Piras, R. Synthesis and antitumor evaluation of 6-thioxo-, 6-oxo- and 2,4-dioxopyrimidine derivatives. Farmaco, 2001, 56(10), 741-748.
[3]
Meneghesso, S.; Vanderlinden, E.; Stevaert, A.; McGuigan, C.; Balzarini, J.; Naesens, L. Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus. Antiviral Res., 2012, 94(1), 35-43.
[4]
Anupama, B.; Dinda, S.C.; Prasad, Y.R.; Rao, A.V. Synthesis and antimicrobial activity of some new 2,4,6-trisubstituted pyrimidines. Int. J. Res. Pharm. Chem., 2012, 2(2), 231-236.
[5]
Tozkoparan, B.; Ertan, M.; Kelicen, P.; Demirdamar, R. Synthesis and anti-inflammatory activities of some thiazolo[3,2-a]pyrimidine derivatives. Farmaco, 1999, 54(9), 588-593.
[6]
Ashour, H.M.; Shaaban, O.G.; Rizk, O.H.; El-Ashmawy, I.M. Synthesis and biological evaluation of thieno [2′,3′:4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 2013, 62, 341-351.
[7]
Bhalgat, C.M.; Ali, M.I.; Ramesh, B.; Ramu, G. Novel pyrimidine and its triazole fused derivatives: synthesis and investigation of antioxidant and anti-inflammatory activity. Arab. J. Chem., 2014, 7, 986-993.
[8]
Kumar, D.; Khan, S.I.; Tekwani, B.L.; Ponnan, P.; Rawat, D.S. 4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies. Eur. J. Med. Chem., 2015, 89, 490-502.
[9]
El-Sayed, N.S.; El-Bendary, E.R.; El-Ashry, S.M.; El-Kerdawy, M.M.; El-Kerdawy, M.M. Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines. Eur. J. Med. Chem., 2011, 46(9), 3714-3720.
[10]
Abbas, S.E.; Abdel Gawad, N.M.; George, R.F.; Akar, Y.A. Synthesis, antitumor and antibacterial activities of some novel tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. Eur. J. Med. Chem., 2013, 65, 195-204.
[11]
Hafez, H.N.; El-Gazzar, A.B.A.; Al-Hussain, S.A.; Al-Hussain, S.A. Novel pyrazole derivatives with oxa/thiadiazolyl, pyrazolyl moieties and pyrazolo[4,3-d]-pyrimidine derivatives as potential antimicrobial and anticancer agents. Bioorg. Med. Chem. Lett., 2016, 26(10), 2428-2433.
[12]
Fares, M.; Abou-Seri, S.M.; Abdel-Aziz, H.A.; Abbas, S.E.S.; Youssef, M.M.; Eladwy, R.A. Synthesis and antitumor activity of pyrido [2,3-d]pyrimidine and pyrido[2,3-d] [1,2,4]triazolo[4,3-a]pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest. Eur. J. Med. Chem., 2014, 83, 155-166.
[13]
Hu, Y-G.; Wang, Y.; Du, S-M.; Chen, X-B.; Ding, M-W. Efficient synthesis and biological evaluation of some 2,4-diamino-furo[2,3-d]pyrimidine derivatives. Bioorg. Med. Chem. Lett., 2010, 20(21), 6188-6190.
[14]
Naresh Kumar, R.; Poornachandra, Y.; Nagender, P.; Mallareddy, G.; Ravi Kumar, N.; Ranjithreddy, P.; Ganesh Kumar, C.; Narsaiah, B. Synthesis of novel trifluoromethyl substituted furo[2,3-b]pyridine and pyrido[3,2′:4,5]furo[3,2-d]pyrimidine derivatives as potential anticancer agents. Eur. J. Med. Chem., 2016, 108, 68-78.
[15]
Huang, Y.Y.; Wang, L.Y.; Chang, C.H.; Kuo, Y.H.; Kaneko, K.; Takayama, H.; Kimura, M.; Juang, S.H.; Wong, F.F. One-pot synthesis and antiproliferative evaluation of pyrazolo[3,4-d]pyrimidine derivatives. Tetrahedron, 2012, 68, 9658-9664.
[16]
Mohareb, R.M.; Abbas, N.S.; Abdelaziz, M.A. Heterocyclic ring extension of androstenedione: synthesis and cytotoxicity of fused pyran, pyrimidine and thiazole derivatives. Steroids, 2014, 86, 45-55.
[17]
Nagarapu, L.; Vanaparthi, S.; Bantu, R.; Ganesh Kumar, C. Synthesis of novel benzo[4,5]thiazolo[1,2-a]pyrimidine-3-carboxylate derivatives and biological evaluation as potential anticancer agents. Eur. J. Med. Chem., 2013, 69, 817-822.
[18]
Song, X.J.; Shao, Y.; Dong, X.G. Microwave-assisted synthesis of some novel fluorinated pyrazolo[3,4-d]pyrimidine derivatives containing 1,3,4-thiadiazole as potential antitumor agents. Chin. Chem. Lett., 2011, 22, 1036-1038.
[19]
Prajapti, S.K.; Nagarsenkar, A.; Guggilapu, S.D.; Gupta, K.K.; Allakonda, L.; Jeengar, M.K.; Naidu, V.G.M.; Babu, B.N. Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine derivatives as potential cytotoxic agents. Bioorg. Med. Chem. Lett., 2016, 26(13), 3024-3028.
[20]
Tangeda, S.J.; Garlapati, A. Synthesis of new pyrrolo[2,3-d]pyrimidine derivatives and evaluation of their activities against human colon cancer cell lines. Eur. J. Med. Chem., 2010, 45(4), 1453-1458.
[21]
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.
[22]
Chen, P-J.; Yang, A.; Gu, Y-F.; Zhang, X-S.; Shao, K-P.; Xue, D-Q.; He, P.; Jiang, T.F.; Zhang, Q.R.; Liu, H.M. Synthesis, in vitro antimicrobial and cytotoxic activities of novel pyrimidine-benzimidazol combinations. Bioorg. Med. Chem. Lett., 2014, 24(12), 2741-2743.
[23]
Zhu, W.; Liu, Y.; Zhai, X.; Wang, X.; Zhu, Y.; Wu, D.; Zhou, H.; Gong, P.; Zhao, Y. Design, synthesis and 3D-QSAR analysis of novel 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives as potential antitumor agents. Eur. J. Med. Chem., 2012, 57, 162-175.
[24]
Guo, X.; Li, Y.; Tao, L.; Wang, Q.; Wang, S.; Hu, W.; Pan, Z.; Yang, Q.; Cui, Y.; Ge, Z.; Dong, L.; Yu, X.; An, H.; Song, C.; Chang, J. Synthesis and anti-HIV-1 activity of 4-substituted-7-(2′-deoxy-2′-fluoro-4′-azido-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues. Bioorg. Med. Chem. Lett., 2011, 21(22), 6770-6772.
[25]
Xu, X.; Wang, J.; Yao, Q. Synthesis and quantitative structure-activity relationship (QSAR) analysis of some novel oxadiazolo[3,4-d]pyrimidine nucleosides derivatives as antiviral agents. Bioorg. Med. Chem. Lett., 2015, 25(2), 241-244.
[26]
Rashad, A.E.; Hegab, M.I.; Abdel-Megeid, R.E.; Micky, J.A.; Abdel-Megeid, F.M.E. Synthesis and antiviral evaluation of some new pyrazole and fused pyrazolopyrimidine derivatives. Bioorg. Med. Chem., 2008, 16(15), 7102-7106.
[27]
Sari, O.; Roy, V.; Métifiot, M.; Marchand, C.; Pommier, Y.; Bourg, S.; Bonnet, P.; Schinazi, R.F.; Agrofoglio, L.A. Synthesis of dihydropyrimidine α,γ-diketobutanoic acid derivatives targeting HIV integrase. Eur. J. Med. Chem., 2015, 104, 127-138.
[28]
Hocková, D.; Holý, A.; Masojídková, M.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Synthesis and antiviral activity of 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy)ethoxy]pyrimidine and related compounds. Bioorg. Med. Chem., 2004, 12(12), 3197-3202.
[29]
Srivastav, N.C.; Mak, M.; Agrawal, B.; Tyrrell, D.L.J.; Kumar, R. Antiviral activity of 2,3′-anhydro and related pyrimidine nucleosides against hepatitis B virus. Bioorg. Med. Chem. Lett., 2010, 20(22), 6790-6793.
[30]
Tian, Y.; Du, D.; Rai, D.; Wang, L.; Liu, H.; Zhan, P.; De Clercq, E.; Pannecouque, C.; Liu, X. Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives. Bioorg. Med. Chem., 2014, 22(7), 2052-2059.
[31]
Lu, H-H.; Xue, P.; Zhu, Y-Y.; Ju, X-L.; Zheng, X-J.; Zhang, X.; Xiao, T.; Pannecouque, C.; Li, T-T.; Gu, S-X. Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR. Bioorg. Med. Chem., 2017, 25(8), 2491-2497.
[32]
Amblard, F.; Aucagne, V.; Guenot, P.; Schinazi, R.F.; Agrofoglio, L.A. Synthesis and antiviral activity of novel acyclic nucleosides in the 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series. Bioorg. Med. Chem., 2005, 13(4), 1239-1248.
[33]
Kim, J.; Kwon, J.; Lee, D.; Jo, S.; Park, D-S.; Choi, J.; Park, E.; Hwang, J.Y.; Ko, Y.; Choi, I.; Ju, M.K.; Ahn, J.; Kim, J.; Han, S-J.; Kim, T-H.; Cechetto, J.; Nam, J.; Ahn, S.; Sommer, P.; Liuzzi, M.; Lee, J. Serendipitous discovery of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine derivatives as novel HIV-1 replication inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(23), 5473-5477.


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Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [289 - 303]
Pages: 15
DOI: 10.2174/1573407214666180124160405
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