YENİ PİRAZOL-BARBİTÜRAT HİBRİTLERİNİN α-GLUKOZİDAZ İNHİBİTÖRLERİ OLARAK SENTEZİ VE BİYOLOJİK DEĞERLENDİRİLMESİ

Öz

Amaç: Tip 2 diyabet, kronik hiperglisemi ile karakterize edilen ve dünya genelinde önemli bir sağlık sorunu olan metabolik bir hastalıktır. α-Glukozidaz inhibitörleri postprandiyal kan şekeri düzeylerinin kontrolünde önemli rol oynasa da, mevcut ilaçlar çeşitli yan etkiler ve sınırlı etkinlik göstermektedir. Bu çalışmada, daha etkili α-glukozidaz inhibitörleri geliştirmek amacıyla yeni pirazol-barbitürat hibrit bileşikleri tasarlanmıştır.

Gereç ve Yöntem: Hedef moleküller rasyonel tasarımla sentezlenmiş ve NMR ile HRMS analizleri kullanılarak karakterize edilmiştir. α-Glukozidaz enzimine karşı inhibitör etkileri p-NPG substratı kullanılarak in vitro ortamda değerlendirilmiştir. Enzim aktivitesi spektrofotometrik olarak ölçülmüş ve IC₅₀ değerleri hesaplanmıştır.

Sonuç ve Tartışma: Sentetik türevlerden yalnızca 4-bifenil grubu taşıyan 17f bileşiği güçlü α-glukozidaz inhibitör aktivitesi göstermiştir (IC₅₀=35.28±1.14 µM) ve referans ilaç akarbozdan daha etkili bulunmuştur. Diğer türevler (IC₅₀>200 µM) etkisizdir. Aromatik hacim ve hidrofobikliğin enzim bağlanmasında önemli rol oynadığı gözlemlenmiştir. Moleküler kenetlenme çalışmaları, 17f’in enzim aktif bölgesindeki π–π etkileşimleri ve hidrofobik bağlanma ile uyumlu olduğunu desteklemiştir. Bulgular, 17f bileşiğini antidiabetik ajan geliştirme süreci için potansiyel bir aday olarak ortaya koymaktadır.

Anahtar Kelimeler

• α-Glukozidaz
• barbitürat
• doking
• pirazol

SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL PYRAZOLE-BARBITURATE HYBRIDS AS ALPHA-GLUCOSIDASE INHIBITORS

Öz

Objective: Type 2 diabetes is a global health problem marked by chronic hyperglycemia. α-Glucosidase inhibitors help regulate postprandial glucose levels, but current drugs have side effects and limited efficacy. This study aimed to develop novel pyrazole–barbiturate hybrids as more effective α-glucosidase inhibitors.

Material and Method: Type 2 diabetes is a global health problem marked by chronic hyperglycemia. α-Glucosidase inhibitors help regulate postprandial glucose levels, but current drugs have side effects and limited efficacy. This study aimed to develop novel pyrazole–barbiturate hybrids as more effective α-glucosidase inhibitors.

Result and Discussion: Only compound 17f, featuring a 4-biphenyl group, showed strong α-glucosidase inhibition (IC₅₀=35.28±1.14 µM), outperforming the reference drug acarbose. The other compounds were inactive (IC₅₀>200 µM). The findings highlight the importance of aromatic bulk and hydrophobicity in enzyme binding. Molecular docking supported the observed activity of 17f, indicating favorable π–π stacking and hydrophobic interactions. These results suggest 17f as a promising candidate for further development as an antidiabetic agent.

Anahtar Kelimeler

• α-Glucosidase
• barbiturate
• docking
• pyrazole

Etik Beyan

The authors declare that the ethics committee approval is not required for this study.

Teşekkür

The authors would like to thank the Faculty of Pharmacy, Van Yüzüncü Yıl University, for its support and contributions to this study

Kaynakça

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