Kinazolin-4(3H)-on Halkası İçeren Fenollerin Sentezi ve Antioksidan Aktivitelerinin İncelenmesi

Yıl 2025, Cilt: 25 Sayı: 2, 312 - 320

Feyzi Sinan Tokalı , Parham Taslımı

Öz

Bu çalışmada azot içeren altı üyeli heterosiklik bileşiklerin önemli bir bölümünü temsil eden kinazolin-4(3H)-on sınıfına ait dört adet bileşik (1-4) sentezlenmiş ve yapıları NMR (1H ve 13C) ve HRMS spektroskopisi teknikleri kullanılarak karakterize edilmiştir. Uygulama olarak sentezlenen bileşiklerin antioksidan aktiviteleri Fe3+-Fe2+ İndirgeme Kapasitesi, Cu2+-Cu+ İndirgeme Kapasitesi, DPPH (1,1-Difenil 2-pikril hidrazil) Serbest Radikali Süpürme Aktivitesi ve ABTS (2,2-Azino-bis (3-etilbenzo-tiyazolin-6-sülfonik asit) Radikali Süpürme Aktivitesi yöntemleri kullanılarak incelenmiştir. Bileşiklerin antioksidan aktiviteleri standart antioksidanlar olan BHA, BHT, α-Tokoferol ve Trolox’a karşı değerlendirilmiştir. Çalışmadan elde edilen bulgular 2-Metill-3-(2,3,4-trihidroksibenzilidenamino)kinazolin-4(3H)-on (4) bileşiğinin Fe3+-Fe2+ İndirgeme ve Cu2+-Cu+ İndirgeme aktivitesinin sırasıyla 2.163 ve 1.663 absorbans değeriyle bütün standartlardan daha iyi olduğunu göstermiştir. Yine 4 bileşiği IC50: 12.64 µg/mL değeriyle -Tokoferol’den daha güçlü DPPH radikali giderme aktivitesine sahipken IC50: 10.40 µg/mL değeriyle -Tokoferol ile kıyaslanabilir ABTS giderme aktivitesine sahiptir.

Anahtar Kelimeler

Kinazolin-4(3H)-on, Antioksidan, Sentez, NMR, DPPH, Kuprak

Destekleyen Kurum

KAFKAS ÜNİVERSİTESİ

Proje Numarası

2021-FM-69

Synthesis of Phenols Containing Quinazolin-4(3H)-one Ring and Investigation of Their Antioxidant Activities

Öz

In this study, four compounds (1-4) belonging to the quinazolin-4(3H)-one class, which represents a significant part of nitrogen-containing six-membered heterocyclic compounds, were synthesized and their structures were characterized using NMR (1H and 13C) and HRMS spectroscopy techniques. As an application, the antioxidant activities of the synthesized compounds were examined using Fe3+-Fe2+ Reduction Capacity, Cu2+-Cu+ Reduction Capacity, DPPH (1,1-Diphenyl 2-picryl hydrazyl) Free Radical Scavenging Activity and ABTS (2,2-Azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) Radical Scavenging Activity methods. The antioxidant activities of the compounds were evaluated against the standard antioxidants BHA, BHT, α-Tocopherol and Trolox. It has been shown that the Fe3+-Fe2+ Reduction and Cu2+-Cu+ Reduction activities of 2-Methyl-3-(2,3,4-trihydroxybenzylideneamino)quinazolin-4(3H)-one (4) are better than all standards with absorbance values of 2.163 and 1.663, respectively. While it has a stronger DPPH radical scavenging activity than α-Tocopherol with the IC50: 10.40 µg/mL value, it has an ABTS scavenging activity comparable to α-Tocopherol with an IC50: 10.40 µg/mL value.

Anahtar Kelimeler

Quinazolin-4(3H)-one, Antioxidant, Synthesis, NMR, DPPH, Cuprac

Proje Numarası

2021-FM-69

Kaynakça

• Al-Salahi, R., Taie, H.A.A., Bakheit, A.H., Marzouk, M., Almehizia, A.A., Herqash, R., Abuelizz, H.A., 2019. Antioxidant activities and molecular docking of 2-thioxobenzo[g] quinazoline derivatives. Pharmacological Reports, 71, 695-700. http://dx.doi.org/10.1016/j.pharep.2019.04.003
• Alagarsamy, V., Sundar, P.S., Gobinath, M., Nivedhitha, S., Parthiban, P., Shankar, D., Sulthana, M.T., Solomon, V.R., 2013. Synthesis of novel 2-phenyl-3-[2-(substituted amino) ethylamino]quinazolin-4(3H)-ones as a new class of H1-antihistaminic agents. Medicinal Chemistry Research, 22, 2486-2492. https://doi.org/10.1007/s00044-012-0243-3
• Apak, R., Güçlü, K., Ozyürek, M., Karademir, S.E., 2004. Novel total antioxidant capacity index for dietary polyphenols and vitamins C and E, using their cupric ion reducing capability in the presence of neocuproine: CUPRAC method. Journal of Agricultural and Food Chemistry, 52, 7970-7981. https://doi.org/10.1021/jf048741x
• Blois, M.S., 1958. Antioxidant Determinations by the Use of a Stable Free Radical. Nature, 181, 1199-1200. http://dx.doi.org/10.1038/1811199a0
• Farag, D.B., Farag, N.A., Esmat, A., Abuelezz, S.A, Ibrahim, E.A., El-Ella, D.A.A., 2015. Synthesis, 3D pharmacophore, QSAR and docking studies of novel quinazoline derivatives with nitric oxide release moiety as preferential COX-2 inhibitors. Medicinal Chemistry Communications, 6, 283-299. https://doi.org/10.1039/C4MD00392F
• Gao, X., Cai, X., Yan, K., Song, B., Gao, L., Chen, Z., 2007. Synthesis and Antiviral Bioactivities of 2-Aryl- or 2-Methyl-3-(substituted- Benzalamino)-4(3H)-quinazolinone Derivatives. Molecules, 12, 2621-2642. https://doi.org/10.3390/12122621
• Gürsoy-Kol, Ö., Yüksek, H., Manap, S., Tokalı, F.S., 2016. 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. Journal of the Turkish Chemical Society, Section A: Chemistry, 3, 105-120. https://doi.org/10.18596/jotcsa.23635
• He, D., Wang, M., Zhao, S., Shu, Y., Zeng, H., Xiao, C., Lu, C., Liu, Y., 2017. Pharmaceutical prospects of naturally occurring quinazolinone and its derivatives. Fitoterapia, 119, 136-149. http://dx.doi.org/10.1016/j.fitote.2017.05.001
• Kuntikana, S., Bhat, C., Kongot, M., Bhat, S.I., Kumar, A., 2016. An Expeditious Green Cascade Synthesis of 3-Arylideneaminoquinazolin-4(1H)-one Derivatives via ‘Solvent Drop Grinding’ and Their Antioxidant and DNA Protective Studies. ChemistrySelect, 1, 1723-1728. http://dx.doi.org/10.1002/slct.201600362
• Mahdy, H.A., Ibrahim, M.K., Metwaly, A.M., Belal, A., Mehany, A.B.M., El-Gamal, K.M.A., El-Sharkawy, A., Elhendawy, M.A., Radwan, M.M., Elsohly, M.A., Eissa, I.H., 2020. Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers. Bioorganic Chemistry, 94, 103422. https://doi.org/10.1016/j.bioorg.2019.103422
• Mostafavi, H., Islami, M.R., Kahabazzadeh, H., Khaleghi, M., 2019. Synthesis of New Quinazolin-4-(3H)-one Derivatives and Evaluation of Their Biological Activities. ChemistrySelect, 4, 3169-3174. https://doi.org/10.1002/slct.201803039 Mravljak, J., Slavec, L., Hrast, M., Sova, M., 2021. Synthesis and Evaluation of Antioxidant Properties of 2-Substituted Quinazolin-4(3H)-ones. Molecules, 26, 6585. https://doi.org/10.3390/molecules26216585
• Oyaizu, M., 1986. Studies on Products of Browning Reactions: Antioxidative Activities of Product of Browning Reaction Prepared from Glucosamine. Japan Journal of Nutrition, 44, 307-315. http://dx.doi.org/10.5264/eiyogakuzashi.44.307
• Patel, H.M., Noolvi, M.N., Shirkhedkar, A.A., Pardeshi, C.V., Surana, S.J., 2016. Anti-convulsant potential of quinazolinones, RSC Advances, 6, 44435-44455. https://doi.org/10.1039/C6RA01284A
• Pele, R., Marc, G., Stana, A., Ionut, I., Nastasa, C., Tiperciuc, B., Oniga, I., Pîrnau, A., Vlase, L., Oniga, O., 2022. Synthesis of New Phenolic Derivatives of Quinazolin-4(3H)-One as Potential Antioxidant Agents-In Vitro Evaluation and Quantum Studies. Molecules, 27, 2599. https://doi.org/10.3390/molecules27082599
• Pele, R., Marc, G., Ionut, , I., Nastasa, C., Fizeşan, I., Pîrnau, A., Vlase, L., Palage, M., Oniga, S., Oniga, O., 2023. Antioxidant and Cytotoxic Activity of New Polyphenolic Derivatives of Quinazolin-4(3H)-one: Synthesis and In Vitro Activities Evaluation. Pharmaceutics, 15, 136. https://doi.org/10.3390/pharmaceutics15010136
• Peng, J.W., Yin, X.D., Li, H., Ma, K.Y., Zhang, Z.J., Zhou, R., Wang, Y.L., Hu, G.F., Liu, Y.Q, 2021. Design, Synthesis, and Structure- Activity Relationship of Quinazolinone Derivatives as Potential Fungicides. Journal of Agricultural and Food Chemistry, 69, 4604–4614. https://doi.org/10.1021/acs.jafc.0c05475
• Prinsloo, I.F., Zuma, N.H., Aucamp, J., N’Da, D.D., 2021. Synthesis and in vitro antileishmanial efficacy of novel quinazolinone derivatives. Chemical Biology & Drug Design, 97, 383-398. https://doi.org/10.1111/cbdd.13790
• Rahman, M.U., Rathore, A., Siddiqui, A.A., Parveen, G., Yar, M.S., 2014. Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents. Journal of Enzyme Inhibition and Medicinal Chemistry, 29, 733-743. https://doi.org/10.3109/14756366.2013.845820
• Re, R., Pellegrini, N., Proteggentene, A., Pannala, A., Yang, M., Rice-Evans, C., 1999. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Biology & Medicine, 26, 1231-1237. https://doi.org/10.1016/s0891-5849(98)00315-3
• Romero, A.H., Rodriguez, N., Oviedo, H., 2019. 2-Aryl-quinazolin-4(3H)-ones as an inhibitor of leishmania folate pathway: In vitro biological evaluation, mechanism studies and molecular docking. Bioorganic Chemistry, 83, 145-153. https://doi.org/10.1016/j.bioorg.2018.10.028
• Soliman, A.M., Karam, H.M., Mekkawy, M.H., Ghorab, M.M., 2020. Antioxidant activity of novel quinazolinones bearing sulfonamide: Potential radiomodulatory effects on liver tissues via NF-kB/ PON1 pathway. European Journal of Medicinal Chemistry, 197, 112333. https://doi.org/10.1016/j.ejmech.2020.112333
• Tokalı, F.S., 2022. Novel Benzoic Acid Derivatives Bearing Quinazolin-4(3H)-one Ring: Synthesis, Characterization, and Inhibition Effects on α-Glucosidase and α-Amylase. ChemistrySelect, 7, e202204019. https://doi.org/10.1002/slct.202204019
• Tokalı, F.S., Alım, Z., Yırtıcı, Ü., 2023d. Carboxylate- and Sulfonate-Containing Quinazolin-4(3H)-one Rings: Synthesis, Characterization, and Carbonic Anhydrase I–II and Acetylcholinesterase Inhibition Properties. ChemistrySelect, 8, e202204191. https://doi.org/10.1002/slct.202204191
• Tokalı, F.S., Demir, Y., Türkeş, C., Dinçer, B., Beydemir, Ş., 2023c. Novel acetic acid derivatives containing quinazolin-4(3H)-one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors. Drug Development Research, 84, 275-295. https://doi.org/10.1002/ddr.22031
• Tokalı, F.S., Sağlamtaş, R., Öztekin, A., Yırtıcı, Ü., Çomaklı, V., 2023b. New Diacetic Acids Containing Quinazolin-4(3H)-one: Synthesis, Characterization, Anticholinergic Properties, DFT Analysis and Molecular Docking Studies. ChemistrySelect, 8, e202205039. https://doi.org/10.1002/slct.202205039
• Tokalı, F.S., Şenol, H., Ateşoğlu, Ş., Akbaş, F., 2024. A series of quinazolin-4(3H)-one-morpholine hybrids as anti-lung-cancer agents: Synthesis, molecular docking, molecular dynamics, ADME prediction and biological activity studies, Chemical Biology & Drug Design, 104, e14599. https://doi.org/10.1111/cbdd.14599
• Tokalı, F.S., Şenol, H., Bulut, Ş., Hacıosmanoğu-Aldoğan, E., 2023f. Synthesis, characterization and molecular docking studies of highly selective new hydrazone derivatives of anthranilic acid and their ring closure analogue Quinazolin-4(3H)-ones against lung cancer cells A549, Journal of Molecular Structure, 1282, 135176. https://doi.org/10.1016/j.molstruc.2023.135176
• Tokalı, F.S., Şenol, H., Yetke, H.İ., Hacıosmanoğlu-Aldoğan, E., 2023a. Novel quinazoline–chromene hybrids as anticancer agents: Synthesis, biological activity, molecular docking, dynamics and ADME studies. Archiv der Pharmazie, 356, 2300423. https://doi.org/10.1002/ardp.202300423
• Tokalı, F.S., Taslimi, P., Demircioğlu, İ.H., Karaman, M., Gültekin, M.S., Şendil, K., Gülçin, İ., 2021. Design, synthesis, molecular docking, and some metabolic enzyme inhibition properties of novel quinazolinone derivatives. Archiv der Pharmazie, 354, 2000455. https://doi.org/10.1002/ardp.202000455
• Tokalı, F.S., Taslimi, P., Sadeghi, M., Şenol, H., 2023g. Synthesis and Evaluation of Quinazolin-4(3H)-one Derivatives as Multitarget Metabolic Enzyme Inhibitors: A Biochemistry-Oriented Drug Design, ChemistrySelect, 8, e202301158. https://doi.org/10.1002/slct.202301158
• Tokalı, F.S., Taslimi, P., Tuzun, B., Karakuş, A., Sadeghian, N., Gulçin, İ., 2023e. Novel Quinazolinone Derivatives: Potential Synthetic Analogs for the Treatment of Glaucoma, Alzheimer's Disease and Diabetes Mellitus. Chemistry & Biodiversity, 20, e202301134. https://doi.org/10.1002/cbdv.202301134