Antityrosinase Activities and in silico ADME Properties of Fluorine-containing 1,2,4-triazole-5-on Derivatives

Yıl 2022, Cilt: 50 Sayı: 4, 319 - 324, 09.10.2022

Ümmühan Çakmak , Fulya Öz Tuncay

https://doi.org/10.15671/hjbc.1053348

Cited By: 1

Öz

Bu çalışmada, flor içeren 1,2,4-triazol-5-on türevlerinin (2a-b, 3a-b, 4a-d, 5a-b, 6a-b, 7a-b, 8a-b ve 9a-b) klinik öneme sahip tirosinaz enziminin aktivitesi üzerine inhibisyon potansiyelleri incelenmiştir. Moleküllerin IC50 değerleri belirlenmiştir. Moleküller arasında en iyi inhibisyon özelliği gösteren molekülün inhibisyon türü ve Ki değeri hesaplanmıştır. Ticari olarak temin edilen mantar tirosinaz için optimum reaksiyon şartları belirlendikten sonra, kinetik çalışmalar yapılarak en düşük IC50 değerine sahip molekülün 8b olduğu tespit edilmiştir. Referans inhibitör molekül olarak kullanılan kojik aside (IC50=45,7±0,9 µM) göre 8a-b, 9a-b (IC50 değerleri sırasıyla 32,2±0,7 µM; 22,9±0,6 µM; 22,8±0,5 µM; 23,8±0,6 µM) moleküllerinin tirosinaz aktivitesi üzerinde oldukça etkili inbitör özelliğine sahip olduğu tespit edilmiştir. 8b molekülü için inhibisyon türü nonkompetetif olarak belirlenmiş ve Ki değeri 6,09±0,12 µM olarak hesaplanmıştır. Ayrıca tüm moleküllerin ADME özellikleri de incelenmiş olup, her bir molekülün ilaç aday molekülü olarak yüksek bir potansiyele sahip olduğu tespit edilmiştir. Bu sonuçlar neticesinde 8a-b ve 9a-b molekülleri, tirosinaz aktivitesine karşı oldukça etkili ve umut verici inhibitör bileşikler olarak kabul edilebilir.

Anahtar Kelimeler

ADME özellikleri, antitirosinaz aktivite, triazoller

Teşekkür

As the authors, we thank Olcay BEKIRCAN for the synthesis and supply of the materials used in this study.

Kaynakça

• 1. J.Li, L.Feng, L.Liu, F.Wang, L.Ouyang, L.Zhang, X.Hu, and G. Wang, Recent advances in the design and discovery of synthetic tyrosinase inhibitors, Eur. J. Med. Chem., 224 (2021) 113744.
• 2. H.Yang, Z.Wang, W.Song, Z.Zhao and Y.Zhao, Isolation of proanthocyanidins from Pinus thunbergii needles and tyrosinase inhibition activity, Process Biochem., 100 (2021) 245-251.
• 3. Y.Wang, T.Duan, M.Hong, Y.Zhou, H.Huang, X.Xiao, J.Zheng, H.Zhou and Z.Lu, Quantitative proteomic analysis uncovers inhibition of melanin synthesis by silk fibroin via MITF/tyrosinase axis in B16 melanoma cells, Life Sci., 284 (2021) 119930.
• 4. K.Tang, Y.Jiang, H.Zhang, W.Huang, Y.Xie, C.Deng, H.Xu, X.Song and H.Xu, Design, synthesis of Cinnamyl-paeonol derivatives with 1, 3-Dioxypropyl as link arm and screening of tyrosinase inhibition activity in vitro, Bioorg. Chem., 106 (2021) 104512.
• 5. A.Bari, U.Ghani, S.A.Syed and Riazullah, Thiosemicarbazide binds with the dicopper center in the competitive inhibition of mushroom tyrosinase enzyme: Synthesis and molecular modeling of theophylline analogues, Bioorganic Med. Chem. Lett., 36 (2021) 127826.
• 6. M.Asanuma, I.Miyazaki and N.Ogawa, Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease, Neurotox. Res., 5 (2003) 165-176.
• 7. N.Jucevičiūtė, I.Banaitytė, A.Vaitkus and R.Balnytė, Preclinical signs of Parkinson's disease: A possible association of Parkinson's disease with skin and hair features, Med. Hypotheses, 127 (2019) 100-104.
• 8. Y.Feng, Z.Wang, J.Chen, H.Li, Y.Wang, D.Ren and J.Lu, Separation, identification and molecular docking of tyrosinase inhibitory peptides from the hydrolysates of defatted walnut (Juglans regia L.) meal, Food Chem., 353 (2021) 129471.
• 9. Y.Li, B.Deng, S.Yang, H. Tian and B.Sun, A colorimetric fluorescent probe for the detection of tyrosinase and its application for the food industry, J. Photochem. Photobiol, 419 (2021) 113458.
• 10. M.He, M.Fan, W.Liu, Y. Li and G.Wang, Design, synthesis, molecular modeling and biological evaluation of novel kojic acid derivatives containing bioactive heterocycle moiety as inhibitors of tyrosinase and antibrowning agents, Food Chem., 362 (2021) 130241.
• 11. A.Ekennia, D.Uduagwu, O.Olowu, O.Nwanji, O.Oje, B.Daniel, S.Mgbii and C. Emma-Uba, Biosynthesis of zinc oxide nanoparticles using leaf extracts of Alchornea laxiflora and its tyrosinase inhibition and catalytic studies, Micron, 141 (2021) 102964.
• 12. O.Bekircan, N.Baltaş, E.Menteşe and E.Gültekin, Synthesis of new fluorine-containing 1,2,4-triazole-5-on derivatives with their anti-urease, anti-xanthine oxidase and antioxidant activities, Rev. Roum. Chim., 61(10) (2016) 733-746.
• 13. Molinspiration Chemoinformatics, http://www.molinspiration.com/cgi-bin/properties, 2021.
• 14. Molsoft, https://www. molsoft.com/mprop/, 2021.
• 15. J.C.Espin, M.Mercedes, R.Varon, J.Tudela and F.Garcia Canovas, A continuous spectrophotometric method for determining the monophenolase and diphenolase activities of apple polyphenol oxidase, Anal. Biochem., 231 (1995) 237-246.
• 16. I.Değirmencioğlu, F.Oz Tuncay, U.Cakmak, and Y.Kolcuoglu, The synthesis of novel piperazine-benzodioxole substituted phthalocyanines and investigation of their α-amylase and tyrosinase inhibition properties, J. Organomet. Chem., 951 (2021) 122012.
• 17. H.Lineweaver and D.Burk, The determination of enzyme dissociation constants, J. Am. Chem. Soc, 56 (1934) 658-666.
• 18. A.Mermer, N.Demirbas, U.Cakmak, A.Colak, A.Demirbas, M.Alagumuthu and S. Arumugam, Discovery of novel sulfonamide-based 5-arylidenerhodanines as effective carbonic anhydrase (II) ınhibitors: microwave-assisted and ultrasound-assisted one-pot four-component synthesis, molecular docking and anti-ca II screening studies, J. Heterocycl. Chem., 56 (2019) 2460-2468.
• 19. S.Akin, H.Ayaloglu, E.Gultekin, A.Colak, O.Bekircan, and M.Yildirim Akatin, Synthesis of 1,2,4-triazole-5-on derivatives and determination of carbonic anhydrase II isoenzyme inhibition effects, Bioorg. Chem., 83 (2019) 170-179.
• 20. U.Cakmak, , F.Oz-Tuncay, S.Basoglu-Ozdemir, E.Ayazoglu-Demir, I.Demir, A.Colak, S.Celik-Uzuner, S.Sag Erdem and N.Yildirim, Synthesis of hydrazine containing piperazine or benzimidazole derivatives and their potential as α-amylase inhibitors by molecular docking, inhibition kinetics and in vitro cytotoxicity activity studies, Med. Chem. Res., 30 (2021) 1886-1904.
• 21. C.A.Lipinski, F.Lombardo, B.W.Dominy and P.J.Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Deliv. Rev., 64 (2012) 4-17.