Synthesis, characterization and biological activities of N-Mannich bases and amide compounds developed from heterocyclic triazol-5-one derivatives: 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones

Abstract

Among heterocyclic compounds, 1,2,4-triazoles are valuable chemical structures known for their broad spectrum of biological activities and unique roles in medicinal chemistry applications, especially in drug development processes. In this study, eight 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives were synthesized and reacted with 3-nitrobenzoyl chloride to obtain N-[3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-one-4-yl]-3-nitrobenzamide derivatives. Subsequently, the amide derivatives underwent Mannich reactions with formaldehyde and morpholine, resulting in four N-Mannich bases. The structures of a total of 12 synthesized compounds were elucidated using IR, 1H-NMR and 13C-NMR spectroscopic techniques. The biological activities of the compounds were evaluated in vitro. Antioxidant properties were assessed using reducing power, free radical scavenging, and metal chelating activity assays. Additionally, antimicrobial activities were tested against five microorganisms (Bacillus cereus, Klebsiella pneumoniae, Staphylococcus aureus, Serratia marcescens, and Candida albicans) using the agar well diffusion method. The results indicated that the compounds exhibited weak antioxidant activity, while some demonstrated notable antimicrobial effects.

Keywords

• 4,5-Dihydro-1H-1,2,4-triazol-5-one,
• Amide
• Mannich Base
• Antioxidant Activity
• Antimicrobial Activity

Heterohalkalı triazol-5-on türevlerinden geliştirilen N-Mannich bazı ve amid bileşiklerinin sentezi, karakterizasyonu ve biyolojik aktivitelerinin araştırılması: 3-alkil(aril)-4-amino-4,5-dihidro-1H-1,2,4-triazol-5-on

Abstract

Heterosiklik bileşiklerden biri olan 1,2,4-triazoller, ilaç geliştirme sürecinde ve tıbbi kimyada sahip oldukları geniş biyolojik aktivite yelpazesi sayesinde önemli bir kimyasal sınıf oluşturmaktadır. Bu çalışmada, 8 adet 3-alkil(aril)-4-amino-4,5-dihidro-1H-1,2,4-triazol-5-on türevi bileşik, 3-nitrobenzoil klorür ile reaksiyona sokularak N-[3-alkil(aril)-4,5-dihidro-1H-1,2,4-triazol-5-on-4-il]-3-nitrobenzamid türevleri elde edilmiştir. Sonrasında, bu amid türevleri, Mannich reaksiyonuna tabi tutularak formaldehit ve morfolin varlığında dört adet N-Mannich türevi bileşik sentezlenmiştir. Toplamda 12 farklı bileşiğin yapısal özellikleri IR, 1H-NMR ve 13C-NMR spektroskopik yöntemlerle detaylı şekilde incelenmiştir. Elde edilen bileşiklerin biyolojik aktiviteleri in vitro yöntemlerle değerlendirilmiştir. Antioksidan aktiviteleri indirgeme gücü ve serbest radikal temizleme kapasiteleri üzerinden ölçülmüş, ayrıca metal şelatlama testleriyle desteklenmiştir. Antimikrobiyal aktiviteler ise Bacillus cereus, Klebsiella pneumoniae, Staphylococcus aureus, Serratia marcescens ve Candida albicans gibi mikroorganizmalara karşı agar kuyucuk yöntemi kullanılarak test edilmiştir. Sonuçlar, bileşiklerin antioksidan özelliklerinin zayıf olduğunu, ancak belirli bileşiklerin antimikrobiyal etkiler sergilediğini ortaya koymuştur.

Keywords

• 4,5-Dihidro-1H-1,2,4-triazol-5-on,
• Amid
• Mannich Bazı
• Antioksidan Aktivite
• Antimikrobiyal Aktivite

References

1. [1] Klusaitė, A., Vičkačkaitė, V., Vaitkevičienė, B., Karnickaitė, R., Bukelskis, D., Kieraitė-Aleksandrova, I., & Kuisienė, N. (2016). Characterization of antimicrobial activity of culturable bacteria isolated from Krubera-Voronja Cave. International journal of speleology, 45(3), 275-287.
2. [2] Davies, J., & Davies, D. (2010). Origins and evolution of antibiotic resistance. Microbiology and Molecular Biology Reviews, 74(3), 417-433.
3. [3] Ventola, C. L. (2015). The antibiotic resistance crisis: Part 1: Causes and threats. Pharmacy and Therapeutics, 40(4), 277.
4. [4] Monaghan, R. L., & Barrett, J. F. (2006). Antibacterial drug discovery-Then, now and the genomics future. Biochemical Pharmacology, 71(7), 901-909.
5. [5] Yu, D., & Huiyuan, G. (2002). Synthesis and antibacterial activity of linezolid analogues. Bioorganic & medicinal chemistry letters, 12(6), 857-859.
6. [6] Birben, E., Sahiner, U. M., Sackesen, C., Erzurum, S., & Kalayci, O. (2012). Oxidative stress and antioxidant defense. World allergy organization journal, 5, 9-19.
7. [7] McClements, D. J., & Decker, E. A. (2000). Lipid oxidation in oil-in-water emulsions: Impact of molecular environment on chemical reactions in heterogeneous food systems. Journal of food science, 65(8), 1270-1282.
8. [8] Oğuz, E. F., & Erel, Ö. (2023). İnsan organizmasında, reaktif oksijen türlerinin ve serbest radikallerin oluşumu; Moleküler çeşitliliği ve biyokimyasal özellikleri. Turkiye Klinikleri Pulmonary Medicine-Special Topics, 16(3), 1-8.

9. [9] Hussain, H. H., Babic, G., Durst, T., Wright, J. S., Flueraru, M., Chichirau, A., & Chepelev, L. L. (2003). Development of novel antioxidants: Design, synthesis, and reactivity. The Journal of Organic Chemistry, 68(18), 7023-7032.
10. [10] Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M., & Telser, J. (2007). Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology, 39(1), 44-84.
11. [11] Singh, R. J., & Singh, D. K. (2010). Reaction of 4-amino-4, 5-dihydro-1H-1, 2, 4-triazol-5-one with some carboxylic acid anhydrides and their antiinflammatory activity. Asian Journal of Chemistry, 22(4), 2664.
12. [12] Yüksek, H., Koca, E., Beytur, M., Gürsoy-Kol, Ö., Aytemiz, F., & Alkan, M. (2016). Synthesis, antioxidant and antimicrobial activities of some 1-acetyl-3-alkyl (aryl)-4-[4-(4-methylbenzoxy) benzylidenamino]-4,5-dihydro-1H-1, 2, 4-triazol-5-ones. Journal of Chemical and Pharmaceutical Research, 8(7), 905-911.
13. [13] Zhang, B. (2019). Comprehensive review on the anti-bacterial activity of 1, 2, 3-triazole hybrids. European Journal of Medicinal Chemistry, 168, 357-372.
14. [14] Rusu, A., Moga, I. M., Uncu, L., & Hancu, G. (2023). The role of five-membered heterocycles in the molecular structure of antibacterial drugs used in therapy. Pharmaceutics, 15(11), 2554.
15. [15] Hassan, F. A., & Younus, K. W. (2012). Biological evaluation of some azole derivatives in cooling fluids (lubricant oils). Res. J. Bio. Sci, 7(1), 48-51.
16. [16] Roman, G. (2015). Mannich bases in medicinal chemistry and drug design. European journal of medicinal chemistry, 89, 743-816.
17. [17] Tramontini, M., & Angiolini, L. (1994). Mannich bases-chemistry and uses (Vol. 5). Florida: CRC Press.
18. [18] Demirbas, N., Ug̵urluog̵lu, R., & Demirbas, A. (2002). Synthesis of 3-alkyl (Aryl)-4-alkylidenamino-4, 5-dihydro-1H-1, 2, 4-triazol-5-ones and 3-alkyl-4-alkylamino-4, 5-dihydro-1H-1, 2, 4-triazol-5-ones as antitumor agents. Bioorganic & medicinal chemistry, 10(12), 3717-3723.
19. [19] Güzeldemirci, N. U., & Küçükbasmacı, Ö. (2010). Synthesis and antimicrobial activity evaluation of new 1, 2, 4-triazoles and 1, 3, 4-thiadiazoles bearing imidazo [2, 1-b] thiazole moiety. European journal of medicinal chemistry, 45(1), 63-68.
20. [20] Kahveci, B., Özil, M., Menteşe, E., Bekircan, O., & Buruk, K. (2008). Microwave-assisted synthesis and antifungal activity of some new 1H-1, 2, 4-triazole derivatives. Russian Journal of Organic Chemistry, 44, 1816-1820.
21. [21] Irak, Z. T., & Beytur, M. (2019). 4-Benzilidenamino-4, 5-dihidro-1H-1, 2, 4-triazol-5-on türevlerinin antioksidan aktivitelerinin teorik olarak incelenmesi. Journal of the Institute of Science and Technology, 9(1), 512-521.
22. [22] Thakkar, S. S., Thakor, P., Doshi, H., & Ray, A. (2017). 1, 2, 4-Triazole and 1, 3, 4-oxadiazole analogues: Synthesis, MO studies, in silico molecular docking studies, antimalarial as DHFR inhibitor and antimicrobial activities. Bioorganic & Medicinal Chemistry, 25(15), 4064-4075.
23. [23] Chohan, Z. H., Sumrra, S. H., Youssoufi, M. H., & Hadda, T. B. (2010). Metal based biologically active compounds: Design, synthesis, and antibacterial/antifungal/cytotoxic properties of triazole-derived Schiff bases and their oxovanadium (IV) complexes. European journal of medicinal chemistry, 45(7), 2739-2747.
24. [24] Aktaş-Yokuş, Ö., Yüksek, H., Manap, S., Aytemiz, F., Alkan, M., Beytur, M., & Gürsoy-Kol, Ö. (2017). In-vitro biological activity of some new 1, 2, 4-triazole derivatives with their potentiometric titrations. Bulgarian Chemical Communications, 49(1), 98-106.
25. [25] Gürsoy-Kol, Ö., Aytemiz, F., Manap, S., & Yüksek, H. (2024). Synthesis and biological evaluation of 3-Alkyl (Aryl)-4-(4-methylthio-benzylideneamino)-4, 5-dihydro-1H-1, 2, 4-triazol-5-one derivatives. Caucasian Journal of Science, 11(1), 50-57.
26. [26] Oyaizu, M. (1986). Studies on products of browning reaction. Antioxidative activities of products of browning reaction prepared from glucosamine. The Japanese Journal of Nutrition and Dietetics, 44(6), 307-315.
27. [27] Blois, M. S. (1958). Antioxidant determinations by the use of a stable free radical. Nature, 181(4617), 1199-1200.
28. [28] Dinis, T. C. P., Madeira, V. M. C., & Almeida, M. L. M. (1994). Action of phenolic derivates (acetoaminophen, salycilate and 5-amino salycilate) as inhibitors of membrane lipid peroxidation and as peroxyl radical scavengers. Arch Biochem Biophy, 315(1), 161-169.
29. [29] Ahmad, I., Mehmood, Z., & Mohammad, F. (1998). Screening of some Indian medicinal plants for their antimicrobial properties. Journal of Ethnopharmacology, 62(2), 183-193.
30. [30] Perez, C., Pauli, M., & Bazerque, P. (1990). An antibiotic assay by agar-well diffusion method. Acta Biologiae et Medecine Experimentaalis, 15, 113-115.
31. [31] Demirbas, N., Karaoglu, S. A., Demirbas, A., & Sancak, K. (2004). Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1, 3, 4] thiadiazol-2-yl) methyl-5-oxo-[1, 2, 4] triazole and 1-(4-phenyl-5-thioxo-[1, 2, 4] triazol-3-yl) methyl-5-oxo-[1, 2, 4] triazole derivatives. European journal of medicinal chemistry, 39(9), 793-804.