Synthesis of some new 1,2,4-triazole derivatives, investigation of their fluorescence properties and biological activities

Abstract

In this work, new heterocyclic compounds containing 1,2,4-triazole ring were synthesized starting from iminoester hydrochlorides and benzhydrazide. The fluorescence properties of the novel triazole compounds synthesized were determined in organic solvents such as methanol and DMSO. The diimine derivatives among the new triazoles show high fluorescence intensities in methanol. Reduced diimines (8) have lower fluorescence properties in methanol than diimine compounds (6). The compounds were also tested for their antioxidant and carbonic anhydrase inhibitory (CAI) activities. Low CAI activity was observed. Bis Schiff bases (6) showed better activity with lower IC50 values of 200 and 330 μM. The compounds showed moderate to high antioxidant activity in both DPPH and FRAP antioxidant tests. The SC50 values in DPPH test were as low as 0.01 mg/mL, close to that of standard antioxidants. Similarly, a high TEAC value as 8197 mM was observed showing considerably high FRAP activity. Structural differences were effective on the antioxidant activities of the new compounds. Benzoylhydrazones (2), oxadiazoles (3) and amino-triazoles (4) showed higher activity in both antioxidant tests as compared to compounds 5-8.

Keywords

• 1.2.4-triazoles
• Schiff bases
• antioxidant
• fluorescence
• carbonic anhydrase inhibitory activity

Bazı yeni 1,2,4-triazol türevlerinin sentezi, floresans özellikleri ve biyolojik aktivitelerinin incelenmesi

Öz

Bu çalışmada, iminoester hidroklorürler ve benzhidrazidden başlanarak 1,2,4-triazol halkası içeren yeni heterosiklik bileşikler sentezlendi. Triazol bileşiklerinin floresans özellikleri metanol ve DMSO gibi organik çözücülerde belirlendi. Triazol bileşikleri arasında diimin bileşikleri metanolde yüksek floresans şiddeti gösterdi. İndirgenmiş bileşikler (8) dimin bileşiklerine (6) göre metanolde düşük floresans özelliğine sahiptir. Yeni sentezlenen bileşiklerin antioksidan ve karbonik anhidraz inhibitör (CAI) aktiviteleri incelendi. Bileşiklerde düşük CAI aktivitesi gözlendi. Bis Schiff bazları (6), 200 ve 330 μM'ın altındaki IC50 değerleriyle daha iyi aktiviteye sahipti. Bileşikler DPPH ve FRAP testlerinin her ikisinde de orta ve yüksek seviyede antioksidan aktivite gösterdi. DPPH radikal temizleme testinde bileşiklerin bazılarının SC50 değerleri standart antioksidanlarınkine yakın 0,01 mg/mL seviyesinde olduğu görüldü. Benzer şekilde 8197 mM TEAC değeriyle yüksek FRAP aktivitesi tespit edildi. Yeni bileşiklerin yapısal farklılıkları antioksidan aktivitelerinde etkili oldu. Benzoilhidrazonlar (2), oksadiazoller (3) ve amino-triazoller (4), 5-8 billeşiklerine kıyasla yüksek aktivite gösterdiler.

Anahtar Kelimeler

• 1.2.4-triazol
• Schiff bazı
• antioksidan
• floresans
• karbonik anhidraz inhibitör aktivitesi

References

1. 1. Martins, P., Jesus, J., Santos, S., Raposo, L. R., Roma-Rodrigues, C., Baptista, P. V., Fernandes, A. R., Heterocyclic anticancer compounds: recent advances and the paradigm shift towards the use of nanomedicine’s tool box, Molecules, 2015, 20, 16852-16891.
2. 2. Chen, J., Sun, X. Y., Chai, K. Y., Lee, J. S., Song, M. S., Quan, Z. S., Synthesis and anticonvulsant evaluation of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines, Bioorg. Med. Chem., 2015, 15, 6775-6781.
3. 3. Zhao, Q. J., Song, Y., Hu, H. G., Yu, S. C., Wu, Q. Y., Design, synthesis and antifungal activity of novel triazole derivatives, Chinese Chem. Lett., 2007, 18, 670-672.
4. 4. Gumrukcuoglu, N., Serdar, M., Celik, E., Sevim, A., Demirbas, N., Synthesis and antimicrobial activities of some new 3,5-dialkyl-1,2,4-triazole derivatives, Turk. J. Chem., 2007, 31, 335-348.
5. 5. Emilsson, H., Selander, H., Synthesis and antihypertensive activity of some hydrazones of 3-hydrazino-4H-1,2,4-triazole, Acta Pharm. Suec., 1983, 20, 341-348.
6. 6. Clemence, F., Joliveau-Maushart, C., Meier, J., Cerede, J., Delevallee, F., Benzoni, J., Deraedt, R., Synthèse et activité analgésique dans la série des triazoles-1,2,4 = Synthesis and analgesic activity in 1,2,4-triazole series, Eur. J. Med. Chem., 1985, 20, 257-266.
7. 7. Invidiata, F. P., Furno, G., Simoni, D., Lampronti, I., Musiu, C., Milia, C., Scintu, F., La Colla, P., 3,6-Disubstituted 1,2,4-triazolo[3,4-b][1,3,4] thiadiazoles: Synthesis and evaluation for antimicrobial and antiviral activity, Farmaco, 1997, 52, 259-261.
8. 8. Turan-Zitouni, G., Kaplancikli, Z. A., Ozdemir, A., Chevallet, P., Kandilci, H. B., Gumusel, B., Studies on 1,2,4-triazole derivatives as potential anti-inflammatory agents, Arch. Pharm. (Weinheim), 2007, 340, 586-590.

9. 9. Bekircan, O., Kucuk, M., Kahveci, B., Kolaylı, S., Synthesis of fused heterocyclic 1,3,5-triazines from some n-acyl imidates and heterocyclic amines as anticancer and antioxidant agents, Arch. Pharm. Chem. Life Sci., 2005, 338, 365-372.
10. 10. Bekircan, O., Ozen, T., Gumrukcuoglu, N., Bektas, H., Synthesis and antioxidant properties of some new 3-(4-chlorophenyl)-5-(pyridin-4-yl)-4h-1,2,4-triazole derivatives, Z. Naturforsch., 2008, 63b, 548-554.
11. 11. Holla, B. S., Veerendra, B., Shivananda, M. K., Boja, P., Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles, Eur. J. Med. Chem., 2003, 38, 759-767.
12. 12. Bekircan, O., Kahveci, B., Kucuk, M., Synthesis and anticancer evaluation of some new unsymmetrical 3, 5-diaryl-4h-1, 2, 4-triazole derivatives, Turk. J. Chem., 2006, 30, 29-40.
13. 13. Akhtar, T., Hameed, S., Al-Masoudi, N. A., Khan, K. M., Synthesis and anti-HIV activity of new chiral 1,2,4-triazoles and 1,3,4-thiadiazoles, Heteroatom Chem., 2007, 18, 316-322.
14. 14. Tsukuda, T., Shiratori, Y., Watanabe, M., Ontsuka, H., Hattori, K., Shirai, M., Shimma, N., Modeling, synthesis and biological activity of novel antifungal agents, Bioorg. Med. Chem. Lett., 1998, 8, 1819-1824.
15. 15. Wei, L., Jian-Jun, Q., Zhe, W., Wei, C., Duan-Li, W., Ruo-Yu, L., Antifungal susceptibility testing of clinical isolates of itraconazole-resistant antifungal susceptibility testing of clinical isolates of itraconazole-resistant, Chin. J. Dermatol., 2007, 40, 722-724.
16. 16. Kim, O., Zhang, Y., Wichtowski, J., Huang, S., Fung-Tomc, J., Bronson, J., Ueda, Y., Novel C-acylated triazole derivatives of ravuconazole, an azole antifungal agent, J. Heterocyclic Chem., 2008, 45, 583-588.
17. 17. Lin, R.,C., Sanduja, N., Hariprasad, S.,M., Successful treatment of postoperative fungal endophthalmitis using intravitreal and intracameral voriconazole, J. Ocul. Pharmacol. Th., 2008, 24, 245-248.
18. 18. Nagappan, V., Deresinski, S., Posaconazole: A broad-spectrum triazole antifungal agent, Clin. Infect. Dis., 2007, 45, 1610-1617.
19. 19. Clemons, M., Coleman, R. E., Verma, S., Aromatase inhibitors in the adjuvant setting: bringing the gold to a standard?, Cancer Treat. Rev., 2004, 30, 325-332.
20. 20. 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., 2015, 24, 2815-2824.
21. 21. Ünver, Y., Deniz, S., Çelik, F., Akar, Z., Küçük, M., Sancak, K., Synthesis of new 1,2,4-triazole compounds containing Schiff and Mannich bases (morpholine) with antioxidant and antimicrobial activities, J. Enzyme Inhib. Med. Chem., 2016, 31, 89-95.
22. 22. Bayrak, H., Demirbas, A., Karaoglu, S. A., Demirbas, N., Synthesis of some new 1,2,4-triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial activitie, Eur. J. Med. Chem. 2009, 44, 1057-66.
23. 23. Ye, X. X., Chen, Z. F., Zhang, A. J., Zhang L. X., Synthesis and biological evaluation of some novel Schiff’s bases from 1,2,4-triazole, Molecules, 2007, 12, 1202-1209.
24. 24. Bekircan, O., Kucuk, M., Kahveci, B., Bektas, H., Synthesis and anticancer evaluation of some new 4-amino-3-(p-methoxybenzyl)-4,5-dihydro-1,2,4-triazole-5-one derivatives, Z. Naturforsch., 2008, 63b, 1305-1314.
25. 25. Vanli, E., Misir, M.N., Alp, H., Ak, T., Ozbek, N., Ocak, U., Ocak, M., Ion sensor properties of fluorescent Schiff bases carrying dipicolylamine groups. A simple spectrofluorimetric method to determine cu (II) in water samples, J. Fluorescence, 2017, 27, 1759-1766.
26. 26. Ozbek, N., Alp, H., Celik, G., Ak, T., Cagilci, O. C., Yayli, N., Ocak, U., Ocak, M., A Simple spectrofluorimetric method for iron determination with a chalcone-based Schiff base, J. Fluorescence, 2017, 27, 635-641.
27. 27. Ocak, M., Ak, T., Aktas, A., Ozbek, N., Cagilci, O.C., Gumrukcuoglu, A., Kantekin, H., Ocak, U., Alp, H., Metal complexation properties of Schiff bases containing 1,3,5-triazine derived from 2-hydroxy-1-naphthaldehyde in solution. A simple spectrofluorimetric method to determine mercury (II), J. Fluorescence, 2017, 27, 59-68.
28. 28. Memon, S., Bhatti, A.A., Bhatti, A.A., Ocak, U., Ocak, M., A new calix[4]arene Schiff base sensor for Hg2+ and Au3+, J. Iranian Chem. Soc., 2016, 13, 2275-2282.
29. 29. Bekircan, O., Bektas, H., Synthesis of new bis-1,2,4-triazole derivatives, Molecules, 2006, 11, 469-477.
30. 30. Dabrii, M., Salehi, P., Baghbanzadeh, M., Zolfigol, M. A., Bahramnejad M., Silica sulfuric acid: an efficient and versatile acidic catalyst for the rapid and ecofriendly synthesis of 1,3,4-oxadiazoles at ambient temperature, Synthetic Commun., 2007, 37, 1201-1209.
31. 31. Yang, Y. H., Shi, M., Halogen effects in Robison-Gabriel type reaction of cyclopropanecarboxylic acid N'-substituted-hydrazides with PPh3/CX4, Tetrahedron Letters 2005, 46, 6285-6288.
32. 32. Benzie, I.F.F., Strain, J. J., Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration, Method. Enzymol., 1999, 299, 15-27.
33. 33. Cuendet, M., Hostettmann, P., Potterat, O., Iridoid glucosides with free radical scavenging properties from Fagraea blumei, Helv. Chim. Acta, 1997, 80, 1144-1152.
34. 34. Topal, F., Gulcin, I., Dastan, A., Guney, M., Novel eugenol derivatives: Potent acetylcholinesterase and carbonic anhydrase inhibitors, Int. J. Biol. Macromol., 2017, 94, 845-851.
35. 35. Bekircan, O., Kahveci, B., Kucuk, M., Synthesis and anticancer evaluation of some new unsymmetrical 3,5-diaryl-4H-1,2,4-triazole derivatives, Turk. J. Chem., 2006, 30, 29-41.
36. 36. Bekircan, O., Kucuk, M., Kahveci, B., Bektas, H., Synthesis and anticancer evaluation of some new 4-amino-3-(p-methoxybenzyl)-4,5-dihydro-1,2,4-triazole-5-one derivatives, Z. Naturforsh., 2008, 63b, 1305-14.
37. 37. Serdar, M., Gümrükcüoglu, N., Karaoglu, Ş., Demirbaş, A., Demirbaş, N., Synthesis of some novel 3,5-diaryl-1,2,4-triazole derivatives and investigation of their antimicrobial activities, Turk. J. Chem. 2007, 31, 315-326.
38. 38. Katritzky, A. R., Laurenzo, K. S., Alkylaminonitrobenzenes by vicarious nucleophilic amination with 4-(alkylamino)-1,2,4-triazoles, J. Org. Chem., 1988, 53, 3978-3982.
39. 39. Hollo, G., Bozkurt, B., Irkec, M. Brinzolamide/timolol fixed combination: a new ocular suspension for the treatment of open-angle glaucoma and ocular hypertension, Expert Opinion on Pharmacotherapy, 2009, 10 (12), 2016-2024.
40. 40. Yerlikaya, E., Erdogan, O., Demirdag, R., Senturk, M., Kufrevioglu, O. I., Expression of hCA IX isoenzyme by using sumo fusion partner and examining the effects of antitumor drugs, Turk. J. Biochem., 2015, 40 (4), 334-342.