Synthetic Approach for Substituted 3-Amino-1,2,4-Triazines and their Chemical Reactivity and Biological Properties

Author(s): Reda M. Abdel-Rahman, Mohammed A. Assiri, Ahmed M. Fouda, Tarik E. Ali*

Journal Name: Mini-Reviews in Organic Chemistry

Volume 17 , Issue 5 , 2020

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Graphical Abstract:


3-Amino-1,2,4-triazines are considered versatile compounds for its significance as building blocks in synthetic and pharmaceutical chemistry. The synthesis, chemical reactivity, and applications of substituted 1,2,4-triazines bearing an amino group were described in this review. The presence of the amino group at position 3 exhibited unique reactivities towards carbonitrile, carbonyl and isothiocyanate reagents. The reactions were divided into several categories, depending on the other substituents on the 1,2,4-triazine ring. In this review, relevant and appropriate applications of the synthesized, isolated, and condensed heterocycles derivatives were reported.

Keywords: 1, 2, 4-Triazines, pharmacological, reactivity, pharmaceutical chemistry, isothiocyanate reagents, synthesis.

Mohamed, K.S.; El-Sayed, E.H. Synthesis, characterization and antimicrobial evaluation of some novel fused pyrimido[1,2-b][1,2,4]triazine, triazino[2,3-a]quinazoline and imid-azo [1,2-b][1,2,4]triazine derivatives. Heterocycles, 2018, 96, 1897-1909.
Bakhotmah, D.A.; Alotaibi, F.A. Synthetic of some new fluorine compounds bearing 1,2,4- triazine moieties and the related heteropolycyclic nitrogen systems as pharmacological probes-overview. Int. J. Org. Chem. (Irvine), 2020, 10, 17-38.
Taibl, A. Synthesis and antifungal activity of some new fluorine substituted 4-thiazolidinone bearing 1,2,4-triazinione. Int. J. Org. Chem. (Irvine), 2018, 8, 170-175.
Makki, M.S.T.; Abdel-Rahman, R.M.; Alharbi, A.S. Synthetic approach for novel fluorine substituted α-aminophosphonic acids containing 1,2,4-triazin-5-one moiety as antioxidant agents. Int. J. Org. Chem. (Irvine), 2018, 8, 1-15.
Makki, M.S.T.; Abdel-Rahman, R.M.; Alharbi, A.S. Synthetic strategies, chemical reactivities and biological activities of 3-thioxo-1,2,4-triazin-5-ones and their derivatives. Mini Rev. Org. Chem., 2019, 16, 308-322.
Makki, M.S.T.; Bakhotmah, D.A.; Abdel-Rahman, R.M.; Aqlan, F.M. New route to synthesize fluorine substituents lamotrigine drug analogues as anti-inflammatory agents. Curr. Org. Synth., 2017, 14, 1-10.
Bakhotmah, D.A. Synthesis of novel α-aminoacids bearing 1,2,4-triazinone and steroidal moieties as enzymatic affect (cellobiase activity), Part I. Int. J. Chem., 2015, 7, 98-103.
Abdel-Rahman, R.M.; Abdel-Malik, M.S. Synthesis of some new 3,6-diheteroaryl-1,2,4-triazin-5-ones and their effect on amylolytic activity of some fungi. Pak. J. Sci. Ind. Res., 1990, 33, 142-147.
Abdel-Rahman, R.M. Chemistry of uncondensed 1,2,4-triazines, Part I. chemical reactivity of 5,6-diphenyl-1,2,4-triazin-3-yl containing active groups. Trends Heterocycl. Chem., 1999, 6, 126-133.
Abdel-Rahman, R.M. Chemistry of uncondensed 1,2,4-triazines, Part IV. Synthesis and chemistry of bioactive 3-amino-1,2,4-triazines and related compounds--an overview. Pharmazie, 2001, 56(4), 275-286.
[PMID: 11338663]
Abdel-Rahman, R.M.; Abdel-Monem, W.R. Chemical reactivity of 3-hydrazino-5,6-diphenyl- 1,2,4-triazine towards π–acceptors activated carbonitriles. Indian J. Chem., 2007, 46B, 838-846.
Abdel-Rahman, R.M. Role of uncondensed 1,2,4-triazine compounds and related heterobicyclic systems as therapeutic agents--a review. Pharmazie, 2001, 56(1), 18-22.
[PMID: 11210661]
Abdel-Rahman, R.M. Role of uncondensed 1,2,4-triazine derivatives as biocidal plant protection agents--a review. Pharmazie, 2001, 56(3), 195-204.
[] [PMID: 11265582]
Abdel-Rahman, R.M.; Makki, M.S.T.; Ali, T.E.; Ibrahim, M.A. 1,2,4-Triazine chemistry Part I: Orientation of cycliza-tion reactions of functionalized 1,2,4-triazine derivatives. Eur. J. Chem., 2010, 1, 236-245.
Abdel-Rahman, R.M.; Makki, M.S.T.; Ali, T.E.; Ibrahim, M.A. 1,2,4-Triazine chemistry Part III: Synthetic strategies functionalized bridgehead nitrogen heteroannulated 1,2,4-triazines system and their regiospecific and pharmacological properties. Curr. Org. Synth., 2013, 10, 136-160.
Abdel-Rahman, R.M.; Makki, M.S.T.; Ali, T.E.; Ibrahim, M.A. 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. Heterocycl. Chem., 2015, 52, 1595-1607.
Abdel-Rahman, R.M.; Saad, H.A. Synthesis and chemical behavior of 1,2,4-triazine derivatives bearing phosphorus amides as donor acceptors. Curr. Org. Synth., 2016, 13, 408-425.
Limanto, J.; Desmond, R.A.; Gauthier, D.R., Jr; Devine, P.N.; Reamer, R.A.; Volante, R.P. A regioselective approach to 5-substituted-3-amino-1,2,4-triazines. Org. Lett., 2003, 5(13), 2271-2274.
[] [PMID: 12816426]
Hirsch, J.; Petrakova, E.; Feather, M.S. The reaction of some dicarbonyl sugars with aminoguanidine. Carbohydr. Res., 1992, 232(1), 125-130.
[] [PMID: 1423344]
Matikainen, J.K.T.; Elo, H.O. A novel intramolecular cycliza-tion reaction: Facile solvent-free microscale synthesis suitable for rapid production of libraries of 3-amino-1,2,4-triazines and for combinatorial chemistry. Mikrochim. Acta, 2004, 146, 49-53.
Bartashevich, E.V.; Potemkin, V.A.; Beresnev, D.G.; Rusinov, G.L.; Chupakhin, O.N. Theoretical study of the formation of benzofurotriazines by reaction of 3-substituted 1,2,4-triazines and fused azolo[1,2,4]triazines with resorcinol. Russ. J. Gen. Chem., 2003, 73, 816-820.
Mohamed, K.S.; El-Sayed, E.H. Synthesis, characterization and antimicrobial evaluation of some novel fused pyrim-ido[1,2-b][1,2,4]-triazine, triazino[2,3-a] quinazoline and imidazo[1,2-b]-[1,2,4]triazine derivatives. Politics and Religion J., 2018, 8, 1897-1909.
Chupakhin, O.N.; Rusinov, G.L.; Itsikson, N.A.; Beresnev, D.G.; Fedorova, O.V.; Ovchinnikova, I.G. New 1,2,4-triazine-containing podands: Synthesis and properties. Russ. Chem. Bull. Inter. Ed., 2004, 53, 2308-2313.
Shchegolkov, E.V.; Khudina, O.G.; Ivanova, A.E.; Burgart, Ya.V.; Sadchikova, E.V.; Kravchenko, M.A.; Saloutin, V.I. Synthesis and tuberculostatic activity of some 1,2,4-triazines. Pharm. Chem. J., 2014, 48, 383-386.
Loev, B.; Goodman, M.M. The correct structure of the supposed 1,2,4-triazacycloöctatetranes. Tetrahedron Lett., 1968, 9, 789-794.
Abdel-Rahman, R.M.; Morsy, J.M.; Hanafy, F.; Amene, H.A. Synthesis of heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as anti-HIV and anticancer drugs: Part I. Pharmazie, 1999, 54(5), 347-351.
[PMID: 10368828]
Abdel-Rahman, R.M.; Morsy, J.M.; el-Edfawy, S.; Amine, H.A. Synthesis of some new heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as anti-HIV and anti-cancer drugs, Part II. Pharmazie, 1999, 54(9), 667-671.
[PMID: 10522270]
Abdel-Rahman, R.M.; Ismail, I.E. Synthesis and reactions of acetonitrile derivatives bearing 5,6-diphenyl-1,2,4-triazine-3-yl moiety. Indian J. Chem., 1993, 32, 526-529.
Abdel-Rahman, R.M.; Seada, M.; Fawzy, M.; el-Baz, I. Synthesis of some new thioethers of 1,2,4-triazine-3-hydrazones and assays for their anticancer and anti human immune virus activities. Farmaco, 1993, 48(3), 397-406.
[PMID: 8323671]
Abdel-Rahman, R.M.; Seada, M.; Fawzy, M.M. Synthesis and antimicrobial activity of some new 3,5-disubstituted pyrazolines containing 1,2,4-triazine moiety. Pak. J. Sci. Ind. Res., 1991, 34, 465-467.
Abdel-Rahman, R.M.; Ghareib, M. Synthesis and biological activities of some new 3-substituted -5,6-diphenyl-1,2,4-triazines. Indian J. Chem., 1987, 26B, 496-500.
Abdel-Rahman, R.M.; Morsy, J.M. Synthesis of 3-(1,2,4-triazin-3-yl)-1,2,4-triazine derivatives and their effect on cel-lobiase activity. Boll. Chim. Farm., 1999, 138, 176-185.
Abdel-Rahman, R.M. Synthesis of some more heterocyclic derivatives bearing 1,2,4-triazine moiety and their antibacterial activity. Pak. Sci. Ind. Res., 1989, 32, 240-245.
Agalou, S.; Karachalias, N.; Dawnay, A.B.; Thornalley, P.J. Reaction kinetics of the scavenging of α-oxoaldehydes by aminoguanidine under physiological conditions.Inter. Cong. Series; , 2002, pp. 513-515.
Lovelette, C.A. 1,2,4-Triazines. 2. A convenient one-pot procedure for the preparation of 3,5(2H,4H)-1,2,4-triazinedione (6-azauracil). J. Heterocycl. Chem., 1979, 16, 1649-1650.
Makki, M.S.T.; Abdel-Rahman, R.M.; Khan, K.A. Fluorine substituted 1,2,4-triazinones as potential anti-HIV-1 and CDK2 inhibitors. J. Chem., 2014,. 430573
Abdel-Rahman, R.M.; Angawi, R.F.; Al-Mehmadi, A.R. Syn-thesis and biological evaluation of fluorine substituted pyrazolo[4,3-e][1,2,4]triazines as purine analogues. J. Saudi Chem. Soc., 2017, 21, 495-503.
Youssef, M.S.K.; Atta, F.M.; Hassan, K.M.; Abbady, M.S. Synthesis and some reactions of 7‐methyl‐5‐phenyl‐5H‐pyrazolo[3,4‐e][1,2,4]triazine‐3‐thiol. J. Prakt. Chem., 1984, 326, 994-998.
Martel, R.R.; Demerson, C.A.; Humber, L.G.; Philipp, A.H. Etodolic acid and related compounds. Chemistry and antiinflammatory actions of some potent di- and trisubstituted 1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acids. J. Med. Chem., 1976, 19(3), 391-395.
[] [PMID: 1255663]
Tomchin, A.B.; Velezheva, V.S.; Shusta, E.B. Thiourea and thiosemicarbazide derivatives: Structure, transformations, and pharmacological activity. Part V. Antihypoxic and actoprotec-tor activity of imidazo[4,5-b]indole derivatives. Pharm. Chem. J., 1998, 32, 59-63.
Gladych, J.M.Z.; Hornby, R.; Hunt, J.H.; Jack, D.; Boyle, J.J.; Ferlauto, R.J.; Haff, R.F.; Kormendy, C.G.; Stanfield, F.J.; Stewart, R.C. Antiviral agents. 5H-as-Triazino(5,6-b) indoles. J. Med. Chem., 1972, 15(3), 277-281.
[] [PMID: 4333824]
Tomchin, A.B.; Uryupov, O.Y.; Smirnov, A.V. Thiourea and thiosemicarbazide derivatives structure transformation and pharmacological activity, Part III. Antihypxic activity of 1,2,4-triazino[5,6-b]indole derivatives. Pharm. Chem. J., 1997, 31, 632-637.
Kgokong, J.L.; Smith, P.P.; Matsabisa, G.M. 1,2,4-Triazino-[5,6b]indole derivatives: effects of the trifluoromethyl group on in vitro antimalarial activity. Bioorg. Med. Chem., 2005, 13(8), 2935-2942.
[] [PMID: 15781403]
Holla, B.S.; Udupa, K.V. Synthesis of novel 5-mercapto-s-triazolo[3,4-c]-as-triazino[5,6-b]indoles and their Mannich Bases. Heterocycles, 1991, 32, 1081-1088.
Tomchin, A.B.; Okovityi, S.V.; Velezheva, V.S.; Smirnov, A.V. Thiourea and thiosemicarbazide derivatives: Structure, transformations, and pharmacological activity. Hepatoprotective effect of triazino- and imidazoindoles. Pharm. Chem. J., 1998, 32, 362-369.
Kim, H.; Sablin, S.O.; Ramsay, R.R. Inhibition of monoamine oxidase A by β-carboline derivatives. Arch. Biochem. Biophys., 1997, 337(1), 137-142.
[] [PMID: 8990278]
Mizntani, M.; Yoshida, R.; Sanemitsu, Y. Novel herbicidal compounds: dimethylamino-4H-1,2,4-triazino[5,6-b]indoles. Agric. Biol. Chem., 1987, 51, 3177-3178.
Tomchin, A.B.; Uryupov, O.Y.; Zhukova, T.I.; Kuznetsova, T.A.; Kostycheva, M.V.; Smirnov, A.V. Thiourea and thio-semicarbazide derivatives structure transformation and phar-macological activity, Part II. Antihypxic activity of 1,2,4-triazino[5,6-b]indole derivatives. Pharm. Chem. J., 1997, 31, 125-133.
Monge, A.; Palop, J.; Ramiraz, C.; Font, M.; Fernandez, E. New 5H-1,2,4-triazino[5,6-b] indole and aminoindole deriva-tives: Synthesis and studies as inhibitors of blood platelet ag-gregation, anti hypertessive agents and thromboxane synthe-tase inhibitors. Eur. J. Med. Chem., 1991, 26, 179-188.
Pozharskii, A.F.; Nanavyan, M.; Kuz’menko, V.V. Formation of 3-Amino-1,2,4-triazines by Thermolysis of Condensed N-Amino-α-Azidoimidazoles. Mendeleev Commun., 1992, 2, 33-35.
Eid, M.M.; Kadry, A.M.; Hassan, R.A. Synthesis and reac-tions of some 6‐(2‐hydroxy‐1‐naphthyl)‐1,2,4‐triazines. J. Heterocycl. Chem., 1988, 25, 1117-1118.
Adger, B.; Rees, C.W.; Sale, A.A.; Storr, R.C. A new synthesis of 1,2,4-benzotriazines. J. Chem. Soc. Chem. Commun., 1971, 695a

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Year: 2020
Published on: 11 August, 2020
Page: [605 - 624]
Pages: 20
DOI: 10.2174/1570193X16666190724105040
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