Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells

Dina Abed Bakhotmah

doi:doi:10.11648/j.ajhc.20190504.11

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Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells

Dina Abed Bakhotmah

Published in American Journal of Heterocyclic Chemistry (Volume 5, Issue 4)

Received: 27 August 2019 Accepted: 10 September 2019 Published: 11 October 2019

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Abstract

Synthesis of several new diphenyl-1',2',4'-triazin-3'-yl barbituric acid are described. The method involves addition reaction of isocyanate and isothiocyanate and 3-amino-5,6-diphenyl-1,2,4-triazine (1) to give N1,N3-disubstituted urea 2 and N1,N3-disubstituted thioureas 3 and 4 respectively. Further, ring closure reactions with malonate ester give barbituric acid 5 and thiobarbituric acid 6 and 7. The Presence of the active methylene in the skeleton of compound 5-7 at C-5 are deduced by condensation with pyridine-4-carboxyladehyde to give barbituric and thiobarbituric acids (8-10). Further fluoroacylation of compounds 5-7, afforded 1-(cyclohexyl/methyl/phenyl)-3-(5',6'-diphenyl-1',2',4'-triazin-3'-yl)-5-(trifluoracetyl)-5H-barbituric/thiobarbituric acids (11-13). Synthesis compounds of the series 5-(trifluoroacetyl) barbituric acid (11) and 5-(trifluoroacetyl) thiobarbituric acids (12 and 13) were able to inhibit activity of CDK2 in a biochemical assay with IC50 values comparable to olomoucine. In addition, a pyridine side chain at C-5 (compound 9 and 10) significantly decreases CDK2 inhibitory activity.

Published in	American Journal of Heterocyclic Chemistry (Volume 5, Issue 4)
DOI	10.11648/j.ajhc.20190504.11
Page(s)	76-80
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2019. Published by Science Publishing Group

Keywords

Barbituric, Thiobarbituric, 1,2,4-triazine, CDK2, Malonate Ester, Trifluoroacylation

References

[1]	C. Schiffer, (2007). BCR-ABL tyrosine kinase inhibitors for chronic myeloge-nous leukemia. N. Engl. J. Med. 357, 258-265.
[2]	P. Cohen, (2002). Protein kinases—the major drug targets of the twenty-firstcentury? Nat. Rev. Drug Discov. 1, 309–315.
[3]	V. Miduturu, X. Deng, N. Kwiatkowski, W. Yang, L. Brault, P. Filippakopoulos, E. Chung, Q. Yang, J. Schwaller, S. Knapp, R. King, J. Lee, S. Herrgard, P. Zarrinkar, N. Gray, (2011). High-Throughput Kinase Profiling: A More Efficient Approach toward the Discovery of New Kinase Inhibitors, Chemistry & Biology, 18 (7), 868-879, doi.org/10.1016/j.chembiol.2011.05.010.
[4]	B. Mathew, J. Suresh, D. Vinod., (2012). Antitumor activity of 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted-phenylprop-2-en-1-ylidene]pyrimidine2,4,6(1H,3H,5H)-triones against Dalton’s ascetic lymphoma in mice. Med Chem Res 22: 3911-3917.
[5]	T. Venkatesh, Y. Bodke, R. Kenchappa and S. Venkatesh, (2016). Synthesis, Antimicrobial and Antioxidant Activity of Chalcone Derivatives Containing Thiobarbitone Nucleus. Med chem (Los Angeles), 6 (7), 440-448. DOI: 10.4172/2161-0444.1000383.
[6]	D. Bakhotmah, R. Abdel-Rahman, (2016), A Review on the Synthesis and Chemistry of Bioactive Pyrazolines Bearing 1,2,4-Triazine Moieties, Mini-Reviews in Organic Chemistry, 13, 62-77. 13 (1): 62-77.
[7]	R. Abdel-Rahman, M. Makki, T. Ali, M. Ibrahim, (2015), 1,2,4-Triazine chemistry Part IV: Synthesis and chemical behavior of 3-functionalized 5,6-diphenyl-1,2,4-triazines towards some nucleophilic and electrophilic reagents, J. Heterocyclic chem. 52: 1595-1607.
[8]	A. Bazgir, M. Khanaposhtani and A. Soorki, (2008), One-pot synthesis and antibacterial activities of pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-dione derivatives. Bioorganic and medicinal chemistry letters, 18, 5800-5803.
[9]	M. Masoud, M. Awad, M. Shaker, M. El-Tahawy, (2010), The role of structural Chemistry in the inhibitive performance of some aminopyrimidines on the corrosion of steel, Corrosion Science, 52 (7), 2387-96.
[10]	R. Abdel-Rahman, M. Makki, M. Ali, M. Ibrahim, (2013), 1,2,4-Triazine Chemistry Part III: Synthetic Strategies to Functionalized Bridgehead Nitrogen Heteroannulated 1,2,4-Triazine Systems and Their Regiospecific and Pharmacological Properties. Current Organic Chemistry, 10, 136-160.
[11]	R. Abdel-Rahman, K. El-mahdy, (2012), Biological Evaluation of Pyramidpyrimidines as Multi-Targeted Small Molecule Inhibitors and Resistance Modifying Agents. Heterocycles, 85, 2391-2414. doi.org/10.3987/REV-12-745.
[12]	B. Vinosha, S. Perumal, S. Renuga, A. Almansour, (2012) A facile domino protocol for the stereoselective synthesis of trans-2,3-dihydrobenzofurans and cis-5, 6-dihydrofuro[2,3-d]pyrimidines, Tetrahedron Letters, 53, 962-966.
[13]	L. Ma, S. Li, H. Zheng, J. Chen, L. Lin, X. Ye, Z. Chen, Q. Xu, T. Chen and J. Yang, (2011), Synthesis and biological activity of novel barbituric and thiobarbituric acid derivatives against non-alcoholic fatty liver disease. European journal of medicinal chemistry, 46 (6): 2003-10. doi: 10.1016/j.ejmech.2011.02.033.
[14]	M. Palmer, P. Preston and M. F. Stevens, The Mass Spectra of 1,2,4-Triazines and Related Compounds. Organic Mass Spectrometry Organic Mass Spectrometry 1971, 5, 1085-1092.
[15]	J. Hunt, T. Mitt, R. Borzilleri, J. Gullo-Brown, J. Fargnoli, B. Fink, W. C Han, S. Mortillo, G. Vite, B. Wautlet, T. Wong, C. Yu, X. Zheng, R. Bhide, (2004) Discovery of the pyrrolo[2,1-f][1,2,4]triazine nucleus as a new kinase inhibitor template. J Med Chem 47 (16): 4054-9.
[16]	T. Gucky, E. Řezníčková, P. Dzubak, Hajduch, K. Marian, (2010). ChemInform Abstract: Synthesis and Anticancer Activity of Some 1,5-Diaryl-3-(3,4,5-trihydroxyphenyl)-1H-pyrazolo[4,3-e][1,2,4]triazines, Monatsh Chem., 141: 709-714. 10.1007/s00706-010-0314-4.
[17]	A. Senderowicz, Inhibitors of cyclin-dependent kinase modulators for cancer therapyProgress in Drug Research (2005), Progress in Drug Research. 63, 183-206.

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APA Style

Dina Abed Bakhotmah. (2019). Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells. American Journal of Heterocyclic Chemistry, 5(4), 76-80. https://doi.org/10.11648/j.ajhc.20190504.11

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ACS Style

Dina Abed Bakhotmah. Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells. Am. J. Heterocycl. Chem. 2019, 5(4), 76-80. doi: 10.11648/j.ajhc.20190504.11

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AMA Style

Dina Abed Bakhotmah. Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells. Am J Heterocycl Chem. 2019;5(4):76-80. doi: 10.11648/j.ajhc.20190504.11

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@article{10.11648/j.ajhc.20190504.11,
  author = {Dina Abed Bakhotmah},
  title = {Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells},
  journal = {American Journal of Heterocyclic Chemistry},
  volume = {5},
  number = {4},
  pages = {76-80},
  doi = {10.11648/j.ajhc.20190504.11},
  url = {https://doi.org/10.11648/j.ajhc.20190504.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajhc.20190504.11},
  abstract = {Synthesis of several new diphenyl-1',2',4'-triazin-3'-yl barbituric acid are described. The method involves addition reaction of isocyanate and isothiocyanate and 3-amino-5,6-diphenyl-1,2,4-triazine (1) to give N1,N3-disubstituted urea 2 and N1,N3-disubstituted thioureas 3 and 4 respectively. Further, ring closure reactions with malonate ester give barbituric acid 5 and thiobarbituric acid 6 and 7. The Presence of the active methylene in the skeleton of compound 5-7 at C-5 are deduced by condensation with pyridine-4-carboxyladehyde to give barbituric and thiobarbituric acids (8-10). Further fluoroacylation of compounds 5-7, afforded 1-(cyclohexyl/methyl/phenyl)-3-(5',6'-diphenyl-1',2',4'-triazin-3'-yl)-5-(trifluoracetyl)-5H-barbituric/thiobarbituric acids (11-13). Synthesis compounds of the series 5-(trifluoroacetyl) barbituric acid (11) and 5-(trifluoroacetyl) thiobarbituric acids (12 and 13) were able to inhibit activity of CDK2 in a biochemical assay with IC50 values comparable to olomoucine. In addition, a pyridine side chain at C-5 (compound 9 and 10) significantly decreases CDK2 inhibitory activity.},
 year = {2019}
}

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TY  - JOUR
T1  - Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells
AU  - Dina Abed Bakhotmah
Y1  - 2019/10/11
PY  - 2019
N1  - https://doi.org/10.11648/j.ajhc.20190504.11
DO  - 10.11648/j.ajhc.20190504.11
T2  - American Journal of Heterocyclic Chemistry
JF  - American Journal of Heterocyclic Chemistry
JO  - American Journal of Heterocyclic Chemistry
SP  - 76
EP  - 80
PB  - Science Publishing Group
SN  - 2575-5722
UR  - https://doi.org/10.11648/j.ajhc.20190504.11
AB  - Synthesis of several new diphenyl-1',2',4'-triazin-3'-yl barbituric acid are described. The method involves addition reaction of isocyanate and isothiocyanate and 3-amino-5,6-diphenyl-1,2,4-triazine (1) to give N1,N3-disubstituted urea 2 and N1,N3-disubstituted thioureas 3 and 4 respectively. Further, ring closure reactions with malonate ester give barbituric acid 5 and thiobarbituric acid 6 and 7. The Presence of the active methylene in the skeleton of compound 5-7 at C-5 are deduced by condensation with pyridine-4-carboxyladehyde to give barbituric and thiobarbituric acids (8-10). Further fluoroacylation of compounds 5-7, afforded 1-(cyclohexyl/methyl/phenyl)-3-(5',6'-diphenyl-1',2',4'-triazin-3'-yl)-5-(trifluoracetyl)-5H-barbituric/thiobarbituric acids (11-13). Synthesis compounds of the series 5-(trifluoroacetyl) barbituric acid (11) and 5-(trifluoroacetyl) thiobarbituric acids (12 and 13) were able to inhibit activity of CDK2 in a biochemical assay with IC50 values comparable to olomoucine. In addition, a pyridine side chain at C-5 (compound 9 and 10) significantly decreases CDK2 inhibitory activity.
VL  - 5
IS  - 4
ER  -

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Author Information

Dina Abed Bakhotmah

Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

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APA Style

Dina Abed Bakhotmah. (2019). Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells. American Journal of Heterocyclic Chemistry, 5(4), 76-80. https://doi.org/10.11648/j.ajhc.20190504.11

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ACS Style

Dina Abed Bakhotmah. Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells. Am. J. Heterocycl. Chem. 2019, 5(4), 76-80. doi: 10.11648/j.ajhc.20190504.11

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AMA Style

Dina Abed Bakhotmah. Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells. Am J Heterocycl Chem. 2019;5(4):76-80. doi: 10.11648/j.ajhc.20190504.11

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@article{10.11648/j.ajhc.20190504.11,
  author = {Dina Abed Bakhotmah},
  title = {Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells},
  journal = {American Journal of Heterocyclic Chemistry},
  volume = {5},
  number = {4},
  pages = {76-80},
  doi = {10.11648/j.ajhc.20190504.11},
  url = {https://doi.org/10.11648/j.ajhc.20190504.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajhc.20190504.11},
  abstract = {Synthesis of several new diphenyl-1',2',4'-triazin-3'-yl barbituric acid are described. The method involves addition reaction of isocyanate and isothiocyanate and 3-amino-5,6-diphenyl-1,2,4-triazine (1) to give N1,N3-disubstituted urea 2 and N1,N3-disubstituted thioureas 3 and 4 respectively. Further, ring closure reactions with malonate ester give barbituric acid 5 and thiobarbituric acid 6 and 7. The Presence of the active methylene in the skeleton of compound 5-7 at C-5 are deduced by condensation with pyridine-4-carboxyladehyde to give barbituric and thiobarbituric acids (8-10). Further fluoroacylation of compounds 5-7, afforded 1-(cyclohexyl/methyl/phenyl)-3-(5',6'-diphenyl-1',2',4'-triazin-3'-yl)-5-(trifluoracetyl)-5H-barbituric/thiobarbituric acids (11-13). Synthesis compounds of the series 5-(trifluoroacetyl) barbituric acid (11) and 5-(trifluoroacetyl) thiobarbituric acids (12 and 13) were able to inhibit activity of CDK2 in a biochemical assay with IC50 values comparable to olomoucine. In addition, a pyridine side chain at C-5 (compound 9 and 10) significantly decreases CDK2 inhibitory activity.},
 year = {2019}
}

Copy | Download

TY  - JOUR
T1  - Synthesis of Barbituric and Thiobarbituric Acids Bearing 5,6-Diphenyl-1,2,4-Triazin-3-yl Moiety as CDK2 Inhibitors of Tumor Cells
AU  - Dina Abed Bakhotmah
Y1  - 2019/10/11
PY  - 2019
N1  - https://doi.org/10.11648/j.ajhc.20190504.11
DO  - 10.11648/j.ajhc.20190504.11
T2  - American Journal of Heterocyclic Chemistry
JF  - American Journal of Heterocyclic Chemistry
JO  - American Journal of Heterocyclic Chemistry
SP  - 76
EP  - 80
PB  - Science Publishing Group
SN  - 2575-5722
UR  - https://doi.org/10.11648/j.ajhc.20190504.11
AB  - Synthesis of several new diphenyl-1',2',4'-triazin-3'-yl barbituric acid are described. The method involves addition reaction of isocyanate and isothiocyanate and 3-amino-5,6-diphenyl-1,2,4-triazine (1) to give N1,N3-disubstituted urea 2 and N1,N3-disubstituted thioureas 3 and 4 respectively. Further, ring closure reactions with malonate ester give barbituric acid 5 and thiobarbituric acid 6 and 7. The Presence of the active methylene in the skeleton of compound 5-7 at C-5 are deduced by condensation with pyridine-4-carboxyladehyde to give barbituric and thiobarbituric acids (8-10). Further fluoroacylation of compounds 5-7, afforded 1-(cyclohexyl/methyl/phenyl)-3-(5',6'-diphenyl-1',2',4'-triazin-3'-yl)-5-(trifluoracetyl)-5H-barbituric/thiobarbituric acids (11-13). Synthesis compounds of the series 5-(trifluoroacetyl) barbituric acid (11) and 5-(trifluoroacetyl) thiobarbituric acids (12 and 13) were able to inhibit activity of CDK2 in a biochemical assay with IC50 values comparable to olomoucine. In addition, a pyridine side chain at C-5 (compound 9 and 10) significantly decreases CDK2 inhibitory activity.
VL  - 5
IS  - 4
ER  -

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