SYNTHESIS, CHARACTERIZATION AND ANTIOXIDANT ACTIVITIES OF NOVEL 1-(MORPHOLINE-4-YL-METHYL)-3-ALKYL(ARYL)-4-[4-(DIMETHYLAMINO)-BENZYLIDENAMINO]-4,5-DIHYDRO-1H-1,2,4-TRIAZOL-5-ONES

Abstract

In this paper, eight novel 1-(morpholine-4-yl-methyl)-3-alkyl(aryl)-4-[4-(dimethylamino)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-ones (2) were obtained by the reactions of 3-alkyl(aryl)-4-[4-(dimethylamino)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-ones (1) with formaldehyde and morpholine. The novel synthesized compounds were identified by IR, ¹H NMR and ¹³C NMR spectral data. Besides, the newly synthesized compounds were analysed for their in vitro potential antioxidant capacities in three different assays. All of the compounds demonstrated significant activity for metal chelating effect.

Keywords

• 4
• 5-Dihydro-1H-1
• 2
• 4-triazol-5-one
• Syntheses; Mannich base; Antioxidant capacity.

References

1. Tramontini M, Angiolini L. Mannich Bases: Chemistry and Uses. CRC Press; 1994. 289 p.
2. Savariz FC, Formagio ASN, Barbosa VA, Foglio MA, Carvalho JE de, Duarte MCT, et al. Synthesis, antitumor and antimicrobial activity of novel 1-substituted phenyl-3-[3-alkylamino(methyl)-2-thioxo-1,3,4-oxadiazol-5-yl] β-carboline derivatives. J Braz Chem Soc. Sociedade Brasileira de Quimica; 2010;21(2):288–98.
3. CHEN Y, WANG G, DUAN N, CAO T, WEN X, YIN J, et al. Synthesis and Antitumor Activity of Fluoroquinolone C3-Isostere Derivatives: Oxadiazole Mannich Base Derivatives. Chinese J Appl Chem. 2012;29(11):1246–50. DOI: 10.3724/SP.J.1095.2012.00537.
4. El-Emam AA, Al-Tamimi A-MS, Al-Omar MA, Alrashood KA, Habib EE. Synthesis and antimicrobial activity of novel 5-(1-adamantyl)-2-aminomethyl-4-substituted-1,2,4-triazoline-3-thiones. Eur J Med Chem. 2013 Oct;68:96–102.
5. Maddila S, Jonnalagadda SB. New Class of Triazole Derivatives and Their Antimicrobial Activity. Lett Drug Des Discov. 2012;9(7):687-93.
6. Das S, Das U, Bandy B, Gorecki DKJ, Dimmock JR. 2-[4-(4-Methoxyphenylcarbonyloxy)benzylidene]-6-dimethylaminomethyl cyclohexanone hydrochloride: a Mannich base which inhibits the growth of some drug-resistant strains of Mycobacterium tuberculosis. Pharmazie. PMC Canada manuscript submission; 2010 Nov;65(11):849–50.
7. Sriram D, Yogeeswari P, Gopal G. Synthesis, anti-HIV and antitubercular activities of lamivudine prodrugs. Vol. 40, European Journal of Medicinal Chemistry. 2005.
8. Liu D, Yu W, Li J, Pang C, Zhao L. Novel 2-(E)-substituted benzylidene-6-(N-substituted aminomethyl)cyclohexanones and cyclohexanols as analgesic and anti-inflammatory agents. Med Chem Res. Springer-Verlag; 2013 Aug;22(8):3779–86. DOI: 10.1007/s00044-012-0362-x.

9. Köksal M, Gökhan N, Küpeli E, Yesilada E, Erdoğan H. Synthesis, analgesic and antiinflammatory properties of certain 5-/6-acyl-3-(4-substituted-1-piperazinylmethyl)-2-benzoxazolinones derivatives. Arch Pharm (Weinheim). 2005 Mar;338(2-3):117–25.
10. Nithinchandra, Kalluraya B, Aamir S, Shabaraya AR. Regioselective reaction: Synthesis, characterization and pharmacological activity of some new Mannich and Schiff bases containing sydnone. Eur J Med Chem. 2012;54:597–604.
11. Manjunatha K, Poojary B, Lobo PL, Fernandes J, Kumari NS. Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives. Eur J Med Chem. 2010;45(11):5225–33.
12. Ozkan-Daguyan I, Sahin F, Koksal M. Synthesis, Characterization and Antimicrobial Activity of Novel 3,5-Disubstituted-1,3,4-oxadiazole-2-ones. Rev Chim -Bucharest- Orig Ed. 2013;64(5):534–9.
13. Frank P V, Manjunatha Poojary M, Damodara N, Chikkanna C. Synthesis and antimicrobial studies of some Mannich bases carrying imidazole moiety. Acta Pharm. 2013 Jun;63(2):231–9.
14. Pati HN, Das U, Kawase M, Sakagami H, Balzarini J, De Clercq E, et al. 1-Aryl-2-dimethylaminomethyl-2-propen-1-one hydrochlorides and related adducts: A quest for selective cytotoxicity for malignant cells. Bioorg Med Chem. 2008 May;16(10):5747–53.
15. Pau A, Murineddu G, Asproni B, Murruzzu C, Grella GE, Pinna G a, et al. Synthesis and cytotoxicity of novel hexahydrothienocycloheptapyridazinone derivatives. Molecules. 2009;14(9):3494–508.
16. Chen D, Zhai X, Yuan QH, Luo J, Xie SC, Gong P. Synthesis and in vitro anti-hepatitis B virus activity of 1H-benzimidazol-5-ol derivatives. Vol. 21, Chinese Chemical Letters. 2010.
17. Köksal M, Bilge SS. Synthesis and Antidepressant-Like Profile of Novel 1-Aryl-3-[(4-benzyl)piperidine-1-yl]propane Derivatives. Arch Pharm (Weinheim]. 2007 Jun;340(6):299–303. DOI: 10.1002/ardp.200700028.
18. Kodhati V, Vanga MR, Yellu NR. Synthesis and Anti Bacterial and Anti-ulcer Evaluation of New S-mannich Bases of 4,6-diaryl-3,4-dihydropyrimidin-2(1H)-thiones. J Korean Chem Soc. 2013 Apr;57(2):234–40.
19. Rajasekaran A, Rajamanickam V, Darlinquine S. Synthesis of some new thioxoquinazolinone derivatives and a study on their anticonvulsant and antimicrobial activities. Eur Rev Med Pharmacol Sci. 2013 Jan;17(1):95–104.
20. Görlitzer K, Meyer H, Walter RD, Jomaa H, Wiesner J. [1]Benzothieno[3,2-b]pyridin-4-yl-amine – Synthese und Pru ¨fung auf Wirk-samkeit gegen Malaria. Pharmazie. 2004;59:506–12.
21. Hamama WS, Zoorob HH, Gouda MA, Afsah EM. Synthesis and antimicrobial and antioxidant activities of simple saccharin derivatives with N-basic side chains. Pharm Chem J. Springer US; 2011 May;45(2):118–24. DOI: 10.1007/s11094-011-0573-3.
22. McClements D, Decker E. Lipid oxidation in oil-in-water emulsions: Impact of molecular environment on chemical reactions in heterogeneous food systems. J Food Sci. 2000;65(8):1270–82. DOI: 10.1111/j.1365-2621.2000.tb10596.x.
23. Yüksek H, Akyıldırım O, Yola ML, Gürsoy-Kol Ö, Çelebier M, Kart D. Synthesis, In Vitro Antimicrobial and Antioxidant Activities of Some New 4,5-Dihydro-1 H -1,2,4-triazol-5-one Derivatives. Arch Pharm (Weinheim). 2013;346(6):470–80. DOI: 10.1002/ardp.201300048.
24. Aktas-Yokus O, Yuksek H, Gursoy-Kol O, Alpay-Karaoglu S. Synthesis and biological evaluation of new 1,2,4-triazole derivatives with their potentiometric titrations. Med Chem Res. Springer US; 2015;24(7):2813–24. DOI: 10.1007/s00044-015-1334-8.
25. Chidananda N, Poojary B, Sumangala V, Kumari NS, Shetty P, Arulmoli T. Facile synthesis, characterization and pharmacological activities of 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 5,6-dihydro-3,6-disubstituted-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles. Eur J Med Chem. 2012;51:124–36. DOI: 10.1016/j.ejmech.2012.02.030.
26. Saadeh HA, Mosleh IM, Al-Bakri AG, Mubarak MS. Synthesis and antimicrobial activity of new 1,2,4-triazole-3-thiol metronidazole derivatives. Monatshefte fur Chemie. 2010;141(4):471–8. DOI: 10.1007/s00706-010-0281-9.
27. Bahçeci Ş, Yüksek H, Ocak Z, Azakli I, Alkan M, Özdemir M. Synthesis and Potentiometric Titrations of Some New 4-(Benzylideneamino)-4,5-dihydro-1H-1,2,4-triazol-5-one Derivatives in Non-Aqueous Media. Collect Czechoslov Chem Commun. Institute of Organic Chemistry and Biochemistry AS CR, v.v.i.; 2002;67(8):1215–22.
28. Oyaizu M. Studies on products of browning reaction. Antioxidative activities of products of browning reaction prepared from glucosamine. JapaneseJ Nutr Diet. 1986;44(17):307–15. DOI: 10.5264/eiyogakuzashi.44.307.
29. Blois M. Antioxidant Determinations by the Use of a Stable Free Radical. Nature. Nature Publishing Group; 1958 Apr;181(4617):1199–200. DOI: 10.1038/1811199a0.
30. Dinis TCP, Madeira VMC, Almeida LM. Action of Phenolic Derivatives (Acetaminophen, Salicylate, and 5-Aminosalicylate) as Inhibitors of Membrane Lipid Peroxidation and as Peroxyl Radical Scavengers. Arch Biochem Biophys. 1994;315(1):161–9. DOI: 10.1006/abbi.1994.1485
31. Chung YC, Chang CT, Chao WW, Lin CF, Chou ST. Antioxidative activity and safety of the 50% ethanolic extract from red bean fermented by Bacillus subtilis IMR-NK1. J Agric Food Chem. 2002 Apr;50(8):2454–8. DOI: 10.1021/jf011369q
32. Yildirim A, Mavi A, Kara AA. Determination of antioxidant and antimicrobial activities of Rumex crispus L. extracts. J Agric Food Chem. 2001;49(8):4083–9. DOI: 10.1021/jf0103572
33. Baumann J, Wurn G, Bruchlausen V. Prostaglandin synthetase inhibiting O2 – radical scavenging properties of some flavonoids and related phenolic compounds. Naunyn-Schmiedebergs Arch Pharmacol. 1979;308:R27.
34. Soares JR, Dinis TCP, Cunha AP, Almeida LM. Antioxidant activities of some extracts of Thymus zygis. Free Radic Res. 1997;26(5):469–78. DOI: 10.3109/10715769709084484
35. Yamaguchi F, Ariga T, Yoshimura Y, Nakazawa H. Antioxidative and anti-glycation activity of garcinol from Garcinia indica fruit rind. J Agric Food Chem. 2000;48(2):180–5. DOI: 10.1021/jf990845y.
36. Halliwell B. Antioxidants: The Basics-what they are and how to Evaluate them. Adv Pharmacol. 1996;38(C):3–20.
37. Finefrock AE, Bush AI, Doraiswamy PM. Current status of metals as therapeutic targets in Alzheimer’s disease. Vol. 51, Journal of the American Geriatrics Society. 2003. p. 1143–8. DOI: 10.1046/j.1532-5415.2003.51368.x