SYNTHESIS OF BIOLOGICALLY IMPORTANT s-TRIAZINE BASED CHALCONESHTML Full Text
SYNTHESIS OF BIOLOGICALLY IMPORTANT s-TRIAZINE BASED CHALCONES
Anupama *1, Iram Khan 1 and Bhawani Singh 2
Department of Chemistry 1, Banasthali Vidyapith-304022, Rajasthan, India
Department of Pure & Applied Chemistry 2, University of Kota, Kota- 324005, India
ABSTRACT: A new series of s- triazine based chalcones have been synthesized by the temperature controlled reaction. The first substitution occurs at low temperatures (0°C), the second substitution at approximately at room temperature (25-30°C) and the third at elevated temperatures (70-100°C). This property allows substitution of three different neucleophiles onto the same triazine core which provides a vast array of possible triazine derivatives.
s-triazine, Chalcones, Substitution, Neucleophiles, Temperature
INTRODUCTION: Heterocyclic compounds are of immense significance due to their wide spectrum of pharmacodynamic applications. These compounds have attracted the attention of chemists and biologists due to their varied nature of physicochemical and pharmacological activities.1 The most widely studied application of heterocycles is in the preparation of biologically active and medicinally important molecules. Modern drug discovery focuses on the synthesis of specific biomolecular targets, which invariably contain a heterocyclic component.2-10 A key challenge in the synthesis of such targets continues to be the development of new pathways and improvement of existing pathways. Literature survey shows that synthesis of pyrazole and isoxazole derivatives has been a subject of consistent interest because of the wide applications of such heterocycles in the field of pharmaceutical as well as agrochemical industry.
The isoxazoles and pyrazoles are one of the key nitrogen and oxygen containing five-membered heterocycles that possess significant roles in the medicinal chemistry and have been reported to exhibit various pharmacological activities likes anti-viral2, anti-tumor3, anti-convulsant4, analgesic5, antioxidant6, anti-depressant7, herbicidal8, insecticidal9, fungicidal10, anti-bacterial11, anti-microbial12 cyclooxygenase inhibitory and anti-inflammatory13 activities. The isoxazoles and pyrrazoles have also been reported to possess crop protection properties or have some other industrial utility14. Various pharmacologically important isoxazoles with anti-diabetic, anti-parkinsonian, and anti-hypertensive activity have also been reported 15. Isoxazoles are unique in their chemical behaviour not only among heterocyclic compounds in general but also among the related azoles. Isoxazoles functionalized with an additional nitrogen-containing group have seen many applications16.
As the main study in the thesis centers around to incorporate in the s- triazine molecule the 1,5- benzodiazepine nucleus and other moieties and fragments which have the previous history of being biologically active, on this premise that their presence in tandem in a single molecular framework of this nucleus could contribute significantly to the biological efficacy in the resulting materials, in this context it seems necessary in the account to follow to present a brief review of biological aspects and the synthetic aspects of s-Traizines and 1.5-benzodiazepines.
The quest to develop more reliable and suitable drugs is always very fascinating and challenging. A number of drugs containing simple heterocyclic or a combination of different heterocyclic moieties have been in use since a long time. Among them 1,3,5-triazines represent a widely used lead structure with multitude of interesting applications in numerous fields. This simple molecule is well-known in organic chemistry and has been used in a variety of applications as its 2,4,6-mono-, di- or trisubstituted derivatives bearing different substituents. Nitrogen containing heterocycles reveals that these form important constituent of a wide variety of products with plethora of pharmacodynamic applications1-6.
s-Triazine are endowed with a wide array of useful pharmacological properties including microbial and anti-inflamatory properties. It was aimed in the present work first to substitute chlorine atoms at different temperature by different neucleophiles. In the synthetic strategies which were envisaged in the present work, the s-triazine molecule has been selected with this idea in mind, that this molecule on one hand was very biologically active and on other hand it could provide a tempelate to hold the three biologically active pharmacophores together in the same molecule.
Condensed heterocyclic systems containing imidazole, benzimidazole, oxadiazole, thiadiazole, pyarazole, isoxazole, pyrimidine, diazepine, oxazepine, thiazepine nuclei have attracted the attention of chemists, on account of the significant medicinal properties associated with them. In view of the prodigious range of activities of these compounds, it was considered worthwhile in the present work to undertake investigation on the synthesis of condensed nitrogen-sulfur heterocyclic systems containing above nuclei fused to the s-Triazine neuleus. It was hoped that synthesis of these condensed heteocyclic systems and evaluation of their biological properties would provide a rational approach to the study of structure activity relationship of these molecules.
The triazine structure is a heterocyclic ring, analogous to the six-membered benzene ring but with three carbons replaced by nitrogens. The three isomers of triazine are distinguished from each other by the positions of their nitrogen atoms, and are referred to as 1,2,3-triazine (1), 1,2,4-triazine (2), and 1,3,5-triazine (3) . Triazines are prepared from 2-azidocyclopropene through thermal rearrangement (1,2,3-triazine), from 1,2-dicarbonyl compound with amidrazone by condensation reaction (1,2,4-triazine) and from cyanic acid amide by trimerization (1,3,5-triazine).
Reports have shown that among s-triazine, atrazine, simazine, cyanuric chloride and propazine, are promising for derivatization. There are many nucleophiles that have potential to replace chlorine of cyanuric chloride. The chlorines of cyanuric chloride can be replaced in a stepwise process at different temperatures by different nucleophiles. The reactivity of three chlorine atoms in cyanuric chloride towards nucleophilic reagents decreases as substitution reaction proceeds. Cyanuric chloride has temperature-dependent differential reactivity for displacement of chlorides with neucleophiles during SNAr.
This process is used for the incorporation of various nucleophiles 47. As a general rule, which varies with the reactivity of the neucleophile chosen, the first substitution occurs at low temperatures (0°C), the second substitution at approximately at room temperature (25-30°C) and the third at elevated temperatures (70-100°C) (Fig. 1). This property allows substitution of three different neucleophiles onto the same triazine core which provides a vast array of possible triazine derivatives. In view of the impressive biological activities shown by cyanuric chloride, it was anticipated that incorporation of pyrimidine molecule to the cyanuric chloride neucleus could form the novel biologically relevant molecules with widespread applications as therapeutics. Claisen-Schmidt condensation and temperature controlled reactions played a crucial role in the establishment of variety of organic molecules of biological importance. Encouraged by the impressive bioactive profiles of s-triazine, together with pyrimidines, it was considered of interest in the present work to explore the possibility of incorporating these moieties together in the same molecule, on the premise that their presence in the same molecular framework could contribute significantly by providing an additive effect on the overall bioefficacy in the resulting materials.
Fig.-2: REMOVAL OF CHLORINE FROM S-TRIAZINE
In recent years, s-triazine compounds have been studied extensively and have been the subject of many reviews. s-Triazine derivatives possess biological activities such as anti-plasmodial, antitumor, anticancer, herbicidal, anti-inflammatory, antifungal, anti-protozoal, antimalarial, and anti-microbial. It clearly establish that s-triazine framework form an important structural core in many synthetic drugs. In addition to the interest in s-triazine as biologically active materials, these have also found important applications in material sciences.
Triazine based materials as electroluminescent devices, non-linear optics and fullerenes are some remarkable examples which have been reported in recent years. Triazines are also useful as chromophore groups in second-order optical materials. Some triazine family of compounds are used in pharmaceutical industry as coupling agents for the synthesis of peptide in solid phase as well as in solution and as side chain of antibiotics. Some of s-triazine such as hexamethylmelamine (HMM) and 2- amino-4- morpholino-s-triazine have been used clinically due to their antitumor properties13 to treat lung, breast and ovarian cancer respectively. Antiproliferative activity of the synthesized l,2,4-triazolo[1,5-a][1,3,5]triazines were evaluated against breast, colon and lung cancer cell lines.
The highest antiproliferative activity in the series was found for 2-(pyridine-3-yl)-7-(4-trifluoro methylphenyl)-6,7-dihydro[1,2,4] triazolo [1,5-a][1,3,5]triazin-5,6-diamine.14s-Triazine chemistry has undergone a revitalization recently due to the usefulness of melamine derivatives as precursors of a variety of oligomers, polymers, as scavenging resins, components of host—guest, superstructure assemblies and ligand scaffolds for catalysis, in medicinal chemistry, in encapsulation of anticancer drugs and reduction of its toxicity. 1, 3, 5-Triazine derivatives have proven their great potential in the rising area of material chemistry, both for their their 7r-interaction abilities, and for their aptitude to be involved in intricate H-bond networks. They have been found to possess Anti-cancer, Antifungal and Antibacterial, Anti-HIV, Anti- malarial, Antidepressant, Antihypertensive Antihistaminic, Diuretic and Anti-inflammatory activities.
Fig.-3: BIOLOGICALLY IMPORTANT S-TRIAZINE DERIVATIVES
2,4,6-Trisubstituted - (dimethylamino) - 1,3,5-triazine is an antitumor agent known as altretamine used in the treatment of ovarian cancer. Further reports have demonstrated a number of derivatives of 2-aryl amino-4-(4-methoxy anilino)-6-(4-chlorophenyl/phenyl hydrazido)-1,3,5-triazine having anti-bacterial activity. Another compound 4,6-bis-allylamino-1,3,5-triazin-2-yl derivative exhibits reverse acquired resistance to anti-cancer and anti-malarial agents.
1,3,5-Triazine-2,4,6-triamine is reacted with formaldehyde to from a very durable thermoset resin. Benzoguanamine (2,4-diamino-6-phenyl-1,3,5-triazine) is used to increase thermoset properties of alkyl, acrylic and formaldehyde resins. Triazines are also useful as chromophore groups in colorants and chlorine attached in triazine compounds undergo nucleophilic substitution reactions well with hydroxyl groups in cellulose fibers.
CONCLUSIONS: Triazine derivatives are very important class of compounds having versatile use. They are not only being used for treating various diseases but are also used for various different purposes like in formulating bactericide and fungicide, as preservatives in oil field applications. They are also used as disinfectant, industrial deodorant and biocide in water treatment. They have been used as bleaching agents.
ACKNOWLEDGEMENTS: The author is thankful to the Dean & Head of Department of Chemistry, Banasthali University for their kind support to carry out this project.
- Quirke J. M. E: Comprehensive Heterocyclic Chemistry. Pergamon Press: Oxford, 1984.
- Lee Y-S and Kim B. H: Heterocyclic nucleoside analogues: Design and synthesis of antiviral, modified nucleosides containing isoxazole heterocycles. Bioorganic & Medicinal Chemistry Letters 2002; 12: 1395-1397.
- Schmidtke M, Wutzler P, Zieger , Riabova, O. B and Makarov V: A New pleconaril and [(biphenyloxy)propyl]isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against pleconaril-resistant coxsackie virus B3. Antiviral Research. 2009; 81(1):56-63.
- Eddington D, Cox D. S, Roberts R. R, Butcher R. J, Edafiogho I. O, Stables J. P , Cooke N , Goodwin A. M , Smith C. A. and Scott K. R: Synthesis and anticonvulsant activity of enaminones 4. Investigations on isoxazole derivatives. European Journal of Medicinal Chemistry. 2002; 37(8): 635-648.
- Karabasanagouda, T.; Airody, V. A. and Girisha, M. Synthesis of some new pyrazolines and isoxazoles carrying 4-methylthiophenyl moiety as potential analgesic and anti-inflammatory agents. Indian Journal of Chemistry 2009, 48B, 430-437.
- Padmaja, A.; Payani, T.; Reddy, G. D. and Padmavathi, V. Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles, isoxazoles, pyrimidine and thioxopyrimidine derivatives. European Journal of Medicinal Chemistry 2009, 44(11), 4557-4566.
- Andrés, I.; Alcázar, J.; Alonso, J. M.; Alvarez, R. M.; Cid, J. M.; De Lucas, A. I.; Fernández, J.; Martı́nez, S.; Nieto, C.; Pastor, J.; Bakker, M. H.; Biesmans, I.; Heylen, L. I. and Megens, A. A. Synthesis of 3a,4-dihydro-3H-benzopyrano[4,3-c]isoxazoles, displaying combined 5-HT uptake inhibiting and α2-adrenoceptor antagonistic activities: A novel series of potential antidepressants. Bioorganic & Medicinal Chemistry Letters 2003, 13(16), 2719-2725.
- Zhou, Y. H.; Miao, W. R. and Chen, L. B. Synthesis and Herbicidal activities of 3-(substituted phenyl)isoxazole derivatives. Chinese Chemical Letters 2003, 14(9), 897-900.
- Upadhyay, A.; Gopal, M.; Srivastava, C. and Pandey, N. D. Isoxazole derivatives as a potential insecticide for managing Callosobruchus chinensis. Journal of Pesticide Science 2010, 35(4), 464-469.
- Kai, H.; Ichiba, T.; Ohtsuka, T.; Takase, A. and Masuko, M. Synthesis and fungicidal activities of (α-methoxybenzyl)isoxazoles. Journal of Pesticide Science 2000, 25, 240-246.
- Srinivas, A.; Nagaraj, A. and Reddy, S. Synthesis and in vitro study of a new class of methylene-bis-4,6-diarylbenzo[d]isoxazoles as potential antifungal agents. Journal of Heterocyclic Chemistry 2009, 46(3), 497-502.
- Dabholkar, V. V. and Ansari, F. Y. Synthesis and characterization of selected fused isoxazole and pyrazole derivatives and their antimicrobial activity. Journal of Serbian Chemical Society 2009, 74 (11), 1219-1228.
- Selvam, C.; Jachak, S. M.; Thilagavathi, R.; Chakraborti, A. K. Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents. Bioorganic & Medicinal Chemistry Letters 2005, 15(7), 1793-1797.
- Lang, S. A. and Lin, Y-I. In: K. T. Potts (Ed): Comprehensive Heterocyclic Chemistry, Pergamon Press, New York, 1984, Vol. 6, pp. 1-130.
- Kochetkov, N. K. and Sokolov, S. D. in: A. R. Katritzky (Ed.): Advances in Heterocyclic Chemistry, Academic Press, New York, 1963, Vol. 2, pp. 365-422.
- (a) Mirzaei, Y. R.; Balasubramaniam, T. N.; Lefler, B. J. and Natale, R. Selective lateral metalation and electrophilic quenching of c-4 functionalized isoxazoles. IX. Direct formation of the C-N bond utilizing an electrophilic nitrogen source Journal of Heterocyclic Chemistry 1990, 27(7), 2001-2004. (b) Balasubramaniam, T. N.; Mirzaei, Y. R.; Natale, N. R. Metalation and electrophilic quenching of C-4 functionalized isoxazoles; VIII. Preparation of derivatives of 5-thioalkylisoxazoles Synthesis 1990, 11, 1076-1079. (c) Mirzaei, Y. R.; 1,3,5-triazine derivatives as anti-microbial agents. Bioorganic & Medicinal Chemistry Letters 2008, 18, 1308-1311.
- (a) Brzozowski, Z.; Saczewski, F. and Gdaniec, M. Synthesis, structural characterization and anti-tumor activity of novel 2,4-diamino-1,3,5-triazine derivatives. European Journal Medicinal Chemistry 2000, 35(12), 1053-1064. (b) Rita, M.; Simona, S.; Giovanni, S.; Francesca, V. and Lisa, D. V. In vitro cytotoxic activities of 2-alkyl-4,6-diheteroalkyl-1,3,5-triazines: New molecules in anti-cancer research. Journal Medicinal Chemistry 2004, 47, 4649-4652.
- Kukla, M. J.; Ludovici, D.W.; Janssen, P. A. J.; Heeres, J. and Moereels, E. L. Preparation and anti-HIV activity of diamino-1,3,5-triazine derivatives. Pat. Appl. 1998, 4, 223-226.
- Kosary, J.; Kasztreiner, E.; Rabloczky, G. and Kurthy, M. Synthesis and cardiotonic activity of 2,4-diamino-1,3,5-triazines. European Journal Medicinal Chemistry 1989, 24, 97-99.
- Brzozowski, Z.; Saczewski, F. and Gdaniec, M. Synthesis, structural characterization and anti-tumor activity of novel 2,4-diamino-1,3,5-triazine derivatives. European Journal Medicinal Chemistry 2000, 35(12), 1053-1064.
- Alfonso, C. A. M.; Lourenco, N. T. and Rosatella, A. A. Synthesis of 2,4,6-tri-substituted-1,3,5-triazine. Molecules 2006, 11, 81-102.
- (a) Ames, M. M. Hexamethylmelamine: Pharmacology and mechanism of action. Cancer Treatment Review 1991, 13, 3105 (b) Newkome, G. R.; Yao, Z.; Baker, G. and Gupta, R. Cascade molecules: A new approach to micelles. Journal of Organic Chemistry 1985, 50, 2003-2004.
- Zollinger, H. Colour Chemistry: Synthesis, properties, and applications of organic dyes and pigments. John Wiley and Sons Inc. New York, 2001, pp56.
- Lee, J.; Broughton, R. M.; Akdag, A.; Worley, S. D. and Huang, T. S. Preparation and application of an s-triazine based novel N-melamine biocide for antimicrobial fibres. Chemistry and Material Science 2009, 8(2), 148-154.
- Blotny, G. Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis. Tetrahedron 2008, 62(41), 9507-9522.
- Venkataraman and Wagle, D. R. Cyanuric chloride: a useful reagent for converting carboxylic acids into chlorides, esters, amides and peptides. Tetrahedron Letters 1979, 20(32), 3037-3040.
- Chaudhary, A. S. and Bishop, C. T. Coupling of amino acids and amino sugars with cyanuric chloride. Canadian Journal of Chemistry 1972, 50(13), 1987-1991.
- (a) Tavanai, H.; Hamadani, A. Z. and Askani, M. Modelling of colour yield for selective reactive dyes in dyeing cotton cloth by two phase Pad-steam method. Iranian Polymer Journal 2006, 15(3), 207-217. (b) Singh, M. Structural interaction of novel dendrimer and subunits with water estimated with excess molar volumes, viscosities and free energies. Bulletin Chemical Society Ethiop 2011, 25(1), 119-126.
- Lukashov, O. I.; Sokolova, N. A. ; Morozov, A. V.; Kazakov, P. V. , Mirzabekova, N. S. and Kuz’mina, N. E. Synthesis of the myorelaxant 1,3,5-tris-(2΄-diethylbenzylammonioethyl)- 1,3,5-triazine-2,4,6-trione tribromide. Pharm. Chem.J., 2012, 46, (4), 46 – 49.
- Raval, J.P. et al. In vitro antimycobacterial activity of novel N-(4- (substituted phenyl amino)-6-(pyridin-2-ylamino)-1, 3, 5-triazin-2- yl) isonicotinohydrazide. Chem. Res. 2010, 9324.
- Singh, M. Structural interaction of novel dendrimer and subunits with water estimated with excess molar volumes,viscosities and free energies. Bulletin Chemical Society Ethiop 2011, 25(1), 119-126.
- Salimon J., Saih N., Yousif E., Hameed A., and Ibraheem H., “Synthesis, characterization and biological activity of Schiff bases of 2, 5- dimercapto-1,3,4-thiadiazole”, Australian Journal of Basic and Applied Sciences, 2010, 4(7), 2016-2021.
- Nalage S. V., Kalyankar M. B., Patil V. S., Bhosale S. V., Deshmukh S. U. and Pawar R. P., “An efficient noncatalytic protocol for the synthesis of trisubstituted imidazole in polyethylene glycol using microwaves”, The Open Catalysis Journal, 2010, 3, 58-61.
- Praveen, C., Kalyanasunram, A., and Perumal, P. T. Gold (III)-catalyzed synthesis of isoxazoles by cycloisomerization of α, β-acetylenic oximes. Synlett 2010, 777-781.
- Crossley J. A., and Browne D. L., An alkynyliodide cycloaddition strategy for the construction of iodoisoxazoles. J. Org. Chem 2010, 75(15), 5414-5416.
- Dubrovskiy A. V., and Larock R. C., Synthesis of benzisoxazoles by the [3+2] cycloaddition of in situ generated nitrile oxides and arynes. Org. Lett. 2010, 12(6), 1180-1183.
- Upadhyay, A.; Gopal, M.; Srivastava, C. and Pandey, N. D. Isoxazole derivatives as a potential insecticide for managing Callosobruchus chinensis. Journal of Pesticide Science 2010, 35(4), 464-469.
- Zuo X., Mi N., Fan Z.J., Zheng Q.X., Zhang H.K., Wang H., and Yang Z. K., “Synthesis of 4-methyl -1,2,3-thiadiazole derivatives via tUgi reaction and their biological activities” , J. Agric. Food. Chem., 2010, 58, 2755-2762.
- Wang Z. H., Guo Y. Z., Zhang J., Ma L., Song H. B., and Fan Z. J., “Synthesis and biological activity of organotin 4-methyl-1,2,3-thiadiazole-5-carboxylates and benzo [1,2,3]thiadiazole-7-carboxylates”, J. Agric. Food Chem., 2010 March 10, 58(5), 2715-2719
How to cite this article:
Anupama, Khan I and Singh B: Synthesis of Biologically Important s-Triazine Based Chalcones. Int J Pharm Sci Res 2015; 6(8): 3209-14.doi: 10.13040/IJPSR.0975-8232.6(8).3209-14.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.