Determination of Inhibitory Effects of Thiazole Derivatives on Glutathione Reductase

Year 2021, Volume: 21 Issue: 6, 1315 - 1323, 31.12.2021

Arzu Öztürk Kesebir

https://doi.org/10.35414/akufemubid.1019128

Cited By: 1

Abstract

Glutathione reductase enzyme (GR) is an important enzyme that catalyzes the formation of reduced glutathione (GSH) from oxidized glutathione (GSSG) and undertakes the task of maintaining the GSH/GSSG ratio in the body. This important task has made the inhibition of GR an important target in the treatment of many diseases. Therefore, it is very important to identify new GR inhibitors that can be used in drug design. In vitro anticancer studies of different 2-aminothiazole analogs have been shown to have potent inhibitory activities against a wide variety of human cancer cell lines, including lung, leukemia, breast, ovarian, kidney, melanoma, colon, CNS, and prostate. We investigated the inhibition effect of six thiazole derivatives, which contain an amino group at the C-2 position and used as a core structure in therapeutic applications, on GR isolated from fresh human erythrocytes. We determined the IC50 values of compounds 2-amino-4-(2,4-difluorophenyl) thiazole, 2-amino-4-(4-bromophenyl)thiazole, 2-amino-5-methyl-4-phenylthiazole, 2-amino-4-(5,6,7,8-tetrahydro-2-naphthyl)thiazole, 2-amino-4-(4-chlorophenyl)thiazole, 4-(3,4-difluorophenyl)-1,3-thiazole-2-amino 0,64 µM, 3,69 µM, 42,8 µM, 0,91 µM, 0,63 µM ve 21 µM respectively. Ki values were calculated as 0,006±0,00048 µM, 0,33±0,11 µM, 63,61±0,33 µM, 0,905±0,073 µM, 0,89±0,47 µM, 97,44 µM respectively. It was observed that 2-amino-4-(2,4-difluorophenyl) thiazole had the highest inhibition effect and 4-(3,4-difluorophenyl)-1,3-thiazol-2-amino had the lowest inhibition effect. It was observed that only 2-amino-4-(2,4-difluorophenyl)thiazole exhibited competitive inhibition, while other compounds exhibited non-competitive inhibition. Our study shows that these thiazole derivatives are potent GR inhibitors and can be used as a guide for the identification of new drug candidates.

Keywords

Thiazole, Glutathione Reductase, Inhibition, Enzyme, Drug Design, Antioxidant

Tiyazol Türevlerinin Glutatyon Redüktaz Üzerindeki İnhibitör Etkilerinin Belirlenmesi

Abstract

Glutatyon redüktaz (GR), oksitlenmiş glutatyondan (GSSG) indirgenmiş glutatyonun (GSH) geri kazanımını katalize ederek GSH/GSSG oranını korumak için gerekli olan önemli bir antioksidan enzimdir. Bu hayati görev nedeniyle, GR'nin inhibisyonu birçok hastalığın tedavisinde önemli bir hedeftir, bu nedenle ilaç tasarımında yol gösterici olacak yeni GR inhibitörlerini belirlemeyi amaçladık. Daha önce, farklı 2-aminotiyazol analoglarının in vitro antikanser değerlendirme çalışmaları, meme, lösemi, akciğer, kolon, CNS, melanom, yumurtalık, böbrek ve prostat gibi çok çeşitli insan kanserli hücre hatlarına karşı güçlü ve seçici nanomolar inhibitör aktiviteleri sergiledikleri çalışmalarla doğrulandı. Çalışmamızda taze insan eritrositlerinden izole edilen GR üzerine, C-2 pozisyonunda amino grubu içeren ve terapötik uygulamalarda çekirdek yapı olarak kullanılan tiyazol türevi altı maddenin inhibisyon etkisini araştırdık. 2-amino-4-(2,4-diflorofenil)tiyazol, 2-amino-4-(4-bromofenil)tiyazol, 2-amino-5-metil-4-feniltiyazol, 2-amino-4-(5,6) ,7,8-tetrahidro-2-naftil)tiyazol, 2-amino-4-(4-klorofenil)tiyazol, 4-(3,4-diflorofenil)-1,3-tiyazol-2-amino bileşiklerinin sırasıyla IC50 değerleri 0,64 µM, 3,69 µM, 42,8 µM, 0,91 µM, 0,63 µM ve 21 µM olarak belirledik. Ki değerleri ise sırasıyla 0,006±0,00048 µM, 0,33±0,11 µM, 63,61±0,33 µM, 0,905±0,073 µM, 0,89±0,47 µM, 97,44 µM olarak hesaplandı. En yüksek inhibisyon etkisini 2-amino-4-(2,4-diflorofenil) tiyazol, en düşük inhibisyon etkisini ise 4-(3,4-diflorofenil)-1,3-tiyazol-2-aminonun gösterdiği görüldü. Sadece 2-Amino-4-(2,4-diflorofenil) tiyazolün yarışmalı inhibisyon sergilediği, diğer bileşiklerin yarışmasız inhibisyon sergilediği görüldü. Çalışmamız,bu tiyazol türevlerinin güçlü GR inhibitörleri olduğunu, yeni ilaç adayların belirlenmesi için yol gösterici olarak kullanılabileceğini göstermektedir.

Keywords

Tiyazol, glutatyon redüktaz, inhibisyon, enzim, ilaç tasarımı, antioksidan.

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