SYNTHESIS OF NEW SUBSTITUTED 3-(1,2,4-OXADIAZOL-5-YL)-THIENO[3,2-E][1,2,3]TRIAZOLO[1,5-A]PYRIMIDIN-5(4H)-ONES VIA AZIDE DOMINO REACTIONS
DOI:
https://doi.org/10.15421/jchemtech.v31i1.273476Keywords:
thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine, 1,2,4-oxadiazol-5-yl)acetonitriles, azide, domino reaction, anticancer activityAbstract
Fused polyheterocyclic compounds related to thieno[2,3-d]pyrimidines are a widely-used class of heterocycles in medicinal chemistry and have attracted considerable interest as potential anticancer agents. In the current article, the substituted (1,2,4-oxadiazol-5-yl)acetonitriles were implemented in convenient domino reactions with 2-azidothiophene-3-carboxylates for the straightforward synthesis of 3-(1,2,4-oxadiazol-5-yl)-thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones. The 1,2,4-oxadiazole motif was selected to be conjugated with thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine core because several (1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-5-amines recently was found as promising antitrypanosomal activity, which is often tied to cytotoxicity against cancer cells. The reaction proceeds at room temperature in a short time with base catalysis and no chromatographic purification of products is required. High purity products were isolated by simple filtration. The synthesized compounds were screened for anticancer activity in the 60 cancer cell panel in NCI. In general, selected 3-(1,2,4-oxadiazol-5-yl)thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones did not show significant antitumor activity. The highest activity was demonstrated by compound 3b, which inhibited the growth of 27% of LOX IMVI melanoma cells at a concentration of 10-5 M.
References
Ali, E. M., Abdel-Maksoud, M. S., Oh, C. H. (2019). Thieno[2,3-d]pyrimidine as a promising scaffold in medicinal chemistry: Recent advances. Bioorg. Med. Chem., 27(7), 1159–1194. https://doi.org/10.1016/j.bmc.2019.02.044
Wilding, B., Klempier, N. (2017). Newest Developments in the Preparation of Thieno[2,3-d]pyrimidines. Org. Prep. Proced. Int., 49(3), 183–215. https://doi.org/10.1080/00304948.2017.1320513
Abdelmoniem, A. M., Ghozlan, S. A., Abdelwahab, H. M., Abdelhamid, I. A. (2019). 2‐Cyano‐N‐(thiophen‐2‐yl)acetamide in Heterocyclic Synthesis: Synthesis and Antibacterial Screening of Novel Pyrido[1,2‐a]thieno[3,2‐e]pyrimidine‐2‐carboxylate Moieties. J. Heterocycl. Chem., 56(9), 2637–2643. https://doi.org/10.1002/jhet.3676
Mahmoud, M. R., Abu El-Azm, F. S., Ismail, M. F., Hekal, M. H., Ali, Y. M. (2018). Synthesis and antitumor evaluation of novel tetrahydrobenzo[4′,5′]thieno[3′,2′:5,6] pyrimido[1,2-b]isoquinoline derivatives. Synth. Commun., 48(4), 428–438. https://doi.org/10.1080/00397911.2017.1406520
Maloney, D. J., Waterson, A. G., Bantukallu, G. R., Brimacombe, K. R., Christov, P., Dang, V. Darley-Usmar, C. V., Hu, X., Jadhav, A., Jana, S., Kim, K. (2016). WO Patent No. 2016109559 (A2).
Ivashchenko, A. A., Ivashchenko, A. V., Savchuk, N. F. (2009). WO Patent No. 2009093934 (A2).
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. Y., Kim, J,, Han, S.-J., Kim, T.-H., Cechetto, J., Nam, J., Ahn, S., Sommer, P., Liuzzi, M., No, Z., Lee, J. (2013). Synthesis and biological evaluation of triazolothienopyrimidine derivatives as novel HIV-1 replication inhibitors. Bioorg. Med. Chem. Lett., 23(1), 153–157. https://doi.org/10.1016/j.bmcl.2012.10.134
Shyyka, O., Pokhodylo, N., Finiuk, N., Matiychuk, V., Stoika, R., Obushak, M. (2018). Anticancer Activity Evaluation of New Thieno[2,3-d]pyrimidin-4(3H)-ones and Thieno[3,2-d]pyrimidin-4(3H)-one Derivatives. Sci. Pharm., 86(3), 28. https://doi.org/10.3390/scipharm86030028
Shyyka, O. Y., Pokhodylo, N. T., Palchykov, V. A., Finiuk, N. S., Stoika, R. S., Obushak, M. D. (2020). Cage-like amines in the green protocol of transannular thieno[2,3-d]pyrimidinone formation as promising anticancer agents. Chem. Heterocycl. Compd., 56, 793–799. https://doi.org/10.1007/s10593-020-02732-2
Shyyka, O. Ya., Pokhodylo, N. T., Finiuk, N. S. (2019). Anticancer activity evaluation of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines and thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine derivatives. Biopolym. Cell, 35(2), 321–330. http://dx.doi.org/10.7124/bc.000A0F
Renyu, Q., Yuchao, L., Kandegama, W. M., Qiong, C., Guangfu, Y. (2018). Recent applications of triazolopyrimidine-based bioactive compounds in medicinal and agrochemical chemistry. Mini Rev. Med. Chem., 18(9), 781–793. https://doi.org/10.2174/1389557517666171101112850
Singh, P. K., Choudhary, S., Kashyap, A., Verma, H., Kapil, S., Kumar, M., Arora, M., Silakari, O. (2019). An exhaustive compilation on chemistry of triazolopyrimidine: A journey through decades. Bioorg. Chem., 88, 102919. https://doi.org/10.1016/j.bioorg.2019.102919
Brand, S., Ko, E. J., Viayna, E., Thompson, S., Spinks, D., Thomas, M., Sandberg, L., Francisco, A. F., Jayawardhana, S., Smith, V. C., Jansen, C., De Rycker, M., Thomas, J., MacLean, L., Osuna-Cabello, M., Riley, J., Scullion, P., Stojanovski, L., Simeons, F. R. C., Epemolu, O., Shishikura, Y., Crouch, S. D., Bakshi, T. S., Nixon, C. J., Reid, I. H., Hill, A. P., Underwood, T. Z., Hindley, S. J., Robinson, S. A., Kelly, J. M., Fiandor, J. M., Wyatt, P. G., Marco, M., Miles, T. J., Read, K. D., Gilbert, I. H. (2017). Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi. J. Med. Chem., 60(17), 7284–7299. https://doi.org/10.1021/acs.jmedchem.7b00463
Yang, Z., Shen, M., Tang, M., Zhang, W., Cui, X., Zhang, Z., Pei, H., Li, Y., Hu, M., Bai, P., Chen, L. (2019). Discovery of 1,2,4-oxadiazole-Containing hydroxamic acid derivatives as histone deacetylase inhibitors potential application in cancer therapy. Eur. J. Med. Chem., 178, 116–130. https://doi.org/10.1016/j.ejmech.2019.05.089
Caneschi, W., Enes, K. B., de Mendonça, C. C., de Souza Fernandes, F., Miguel, F. B., da Silva Martins, J., Le Hyaric, M.; Pinho, R. R.; Duarte, L. M.; Leal de Oliveira, M. A.; Dos Santos, H. F.; Paz Lopes, M. T.; Dittz, D.; Silva, H.; Costa Couri, M. R. (2019). Synthesis and anticancer evaluation of new lipophilic 1,2,4 and 1,3,4-oxadiazoles. Eur. J. Med. Chem., 165, 18–30. https://doi.org/10.1016/j.ejmech.2019.01.001
Mohammadi-Khanaposhtani, M., Ahangar, N., Sobhani, S., Masihi, P. H., Shakiba, A., Saeedi, M., Akbarzadeh, T. (2019). Design, synthesis, in vivo, and in silico evaluation of new coumarin-1, 2, 4-oxadiazole hybrids as anticonvulsant agents. Bioorg. Chem., 89, 102989. https://doi.org/10.1016/j.bioorg.2019.102989
De, S. S., Khambete, M. P., Degani, M. S. (2019). Oxadiazole scaffolds in anti-tuberculosis drug discovery. Bioorganic Med. Chem. Lett., 29(16), 1999–2007. https://doi.org/10.1016/j.bmcl.2019.06.054
Pokhodylo, N. T. (2015). Multicomponent and domino reactions leading to 1,2,3-triazoles. Chemistry of 1,2,3-triazoles. In W. Dehaen, V. A. Bakulev (Eds.), Topics in Heterocyclic Chemistry, (vol. 40, Chemistry of 1,2,3-triazoles, рр. 269-324). Switzerland: Springer International Publishing. https://doi.org/10.1007/7081_2014_122
Westerlund, C. (1980). The synthetic utility of heteroaromatic azido compounds. Part VI. Preparation of some 1H‐1,2,3‐triazolo[1,5‐a]thieno[3,2‐d] pyrimidines. J. Heterocycl. Chem., 17(8), 1765–1769. https://doi.org/10.1002/jhet.5570170826
Lauria, A., Patella, C., Abbate, I., Martorana, A., Almerico, A. M. (2013). An unexpected Dimroth rearrangement leading to annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines with potent antitumor activity. Eur. J. Med. Chem., 65, 381–388. https://doi.org/10.1016/j.ejmech.2013.05.012
Ivachtchenko, A. V., Golovina, E. S., Kadieva, M. G., Koryakova, A. G., Kovalenko, S. M., Mitkin, O. D., Okun, I. M., I. Ravnyeyko, M., Tkachenko S. E., Zaremba, O. V. (2010). Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists. Bioorg. Med. Chem., 18(14), 5282–5290. https://doi.org/10.1016/j.bmc.2010.05.051
Anderson, M. O., Zhang, J., Liu, Y., Yao, C., Phuan, P. W., Verkman, A. S. (2012). Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B. J. Med. Chem., 55(12), 5942–5950. https://doi.org/10.1021/jm300491y
Pokhodylo, N. T., Matiychuk, V. S., Obushak, N. D. (2009). Synthesis of a new heterocyclic system–pyrido[3',2':4,5]thieno-[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine. Chem. Heterocycl. Compd., 45(7), 881–883. https://doi.org/10.1007/s10593-009-0338-z
Lauria, A., Diana, P., Barraja, P., Almerico, A. M., Cirrincione, G., Dattolo, G. (2000). Pyrrolo[3,4‐e][1,2,3]triazolo[1,5‐a]pyrimidine and pyrrolo[3,4‐d][1,2,3]triazolo[1,5‐a]pyrimidine. New tricyclic ring systems of biological interest. J. Heterocycl. Chem., 37(4), 747–750. https://doi.org/10.1002/jhet.5570370413
Lauria, A., Diana, P., Barraja, P., Montalbano, A., Cirrincione, G., Dattolo, G., Almerico, A. M. (2002). New tricyclic systems of biological interest. Annelated 1,2,3-triazolo[1,5-a]pyrimidines through domino reaction of 3-azidopyrroles and methylene active nitriles. Tetrahedron, 58(48), 9723–9727. https://doi.org/10.1016/S0040-4020(02)01245-0
Lauria, A., Patella, C., Diana, P., Barraja, P., Montalbano, A., Cirrincione, G., Dattolo, G., Almerico A. M. (2003). A New Tetracyclic Ring System of Biological Interest. Indolo[3,2-e]-[1,2,3]triazolo[1,5-a]pyrimidines through Domino Reactions of 2-Azidoindole. Heterocycles, 60(12), 2669–2675. https://doi.org/10.3987/COM-03-9877
Lauria, A., Patella, C., Diana, P., Barraja, P., Montalbano, A., Cirrincione, G., Dattolo G., Almerico, A. M. (2006). A synthetic approach to new polycyclic ring system of biological interest through domino reaction: indolo[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine. Tetrahedron Lett., 47(13), 2187–2190. https://doi.org/10.1016/j.tetlet.2006.01.112
Lauria, A., Patella, C., Dattolo, G., Almerico, A. M. (2008). Design and Synthesis of 4-Substituted Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine Derivatives with Antitumor Activity. J. Med. Chem., 51(7), 2037–2046. https://doi.org/10.1021/jm700964u
Khan, M. A., Freitas, A. C. C. (1980). Fused pyrazolopyrimidines. I. Pyrazolo[4,3‐e]‐v‐triazolo[1,5‐a]pyrimidine. A new heterocyclic system. J. Heterocycl. Chem., 17(7), 1603–1604. https://doi.org/10.1002/jhet.5570170751
Lauria, A., Abbate, I., Patella, C., Gambino, N., Silvestri, A., Barone, G., Almerico, A. M. (2008). Pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine: a new ring system through Dimroth rearrangement. Tetrahedron Lett., 49(35), 5125–5128. https://doi.org/10.1016/j.tetlet.2008.06.104
Paula Freitas, A., Fernanda, M., Proença, J. R. P., Booth, B. L. (1995). Synthesis of 5‐azido‐4‐cyanoimidazole and its reaction with active methylene compounds. J. Heterocycl. Chem., 32(2), 457–462. https://doi.org/10.1002/jhet.5570320212
L'abbé, G., Godts, F., Toppet, S. (1985a). Synthesis of 5‐Diazomethyl Substituted V‐Triazolo[4,5‐d]Pyrimidines. Bull. Soc. Chim. Belg., 94(7), 441–447. https://doi.org/10.1002/bscb.19850940702
L'abbé, G., Godts, F., Toppet, S. (1985b). Diazoimine–triazole equilibrium in fused 1,2,3-triazolo[1,5-a]pyrimidines. J. Chem. Soc., Chem. commun., (9), 589–590. https://doi.org/10.1039/C39850000589
L'abbé, G., Godts, F., Toppet, S., Meervelt, L. V., King, G. S. (1987). Synthesis and Crystal Structure of Bis[1,2,3]Triazolo[1,5‐a:4′,5′‐d] Pyrimidin‐9‐Ones. Bull. Soc. Chim. Belg., 96(8), 587–593.: https://doi.org/10.1002/bscb.19870960805
Pokhodylo, N. T., Shyyka, O. Y., Obushak, M. D. (2014). Facile and efficient one-pot procedure for thieno[23-e][1,2,3]triazolo[1,5-a]pyrimidines preparation. Synth. Commun., 44(7), 1002–1006. https://doi.org/10.1080/00397911.2013.840729
Pokhodylo, N. T., Shyyka, O. Y., Savka, R. D., Obushak, M. D. (2010). Novel selected tandem transformations of the amino and carbonyl/nitrile groups in the Gewald thiophenes. Phosphorus, Sulfur, and Silicon, 185(10), 2092–2100. https://doi.org/10.1080/10426500903496739
Pokhodylo, N. T., Shyyka, O. Y., Tupychak, M. A., Obushak, M. D. (2018). Selectivity in domino reaction of ortho-carbonyl azides with malononitrile dimer leading to [1,2,3]triazolo[1,5-a]pyrimidines. Chem. Heterocycl. Compd., 54, 209–212. https://doi.org/10.1007/s10593-018-2256-4
Pokhodylo, N. T., Shyyka, O. Y. (2017). New cascade reaction of azides with malononitrile dimer to polyfunctional [1,2,3]triazolo[4,5-b]pyridine. Synth. Commun., 47(11), 1096–1101. https://doi.org/10.1080/00397911.2017.1313427
Tupychak, M. A., Shyyka, O. Y., Pokhodylo, N. T., Obushak, M. D. (2020). Nitrileimines as an alternative to azides in base-mediated click [3+2]cycloaddition with methylene active nitriles. RSC Adv., 10(23), 13696–13699. https://doi.org/10.1039/D0RA01417F
Shoemaker, R. H. (2006). The NCI60 human tumour cell line anticancer drug screen. Nat. Rev. Cancer., 6(10), 813–823. https://doi.org/10.1038/nrc1951
Grever, M. R., Schepartz, S. A., Chabner, B. A. (1992). The National Cancer Institute: cancer drug discovery and development program. Semin. Oncol.. 19(6), 622–638.
Monks, A., Scudiero, D., Skehan, P., Shoemaker, R., Paull, K., Vistica, D., Hose, C., Langley, J., Cronise, P., Vaigro-Wolff, A., Gray-Goodrich, M., Campbell, H., Mayo, J., Boyd M. (1991). Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 83(11), 757–766, https://doi.org/10.1093/jnci/83.11.757
Boyd, M. R., Paull, K. D. (1995). Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev. Res., 34(2), 91–109. https://doi.org/10.1002/ddr.430340203
![The substituted (1,2,4-oxadiazol-5-yl)acetonitriles were implemented in convenient domino reactions with 2-azidothiophene-3-carboxylates for the straightforward synthesis of 3-(1,2,4-oxadiazol-5-yl)-thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones. The reaction proceeds at room temperature in a short time with base catalysis and no chromatographic purification of products is required. High purity products were isolated by simple filtration. The synthesized compounds were screened for anticancer activity in the 60 cancer cell panel in NCI.](http://chemistry.dnu.dp.ua/public/journals/112/submission_273476_311627_coverImage_en_US.jpg)
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