Syntheses of new pyridazine-based scaffolds,<i> in</i><i> vitro</i> antidiabetic studies against <i>α</i>-glucosidase and <i>α</i>-amylase enzymes supported by kinetic and molecular docking studies
JOURNAL OF MOLECULAR STRUCTURE, cilt.1376, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1376
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.molstruc.2026.146985
- Dergi Adı: JOURNAL OF MOLECULAR STRUCTURE
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Recep Tayyip Erdoğan Üniversitesi Adresli: Evet
Özet
The synthesis and spectral characterization of twenty-one (21) pyridazine-derived molecules (1-21) were accomplished to investigate their potential antidiabetic and antioxidant activities. Enzymatic assays against alpha-glucosidase and alpha-amylase, together with antioxidant evaluations using CUPRAC, FRAP, and DPPH methods, demonstrated that most compounds exhibited potent inhibitory activity. Notably, compounds 9 and 2 exhibited remarkable enzyme-inhibitory activity. Compound 9 showed superior inhibitory potential compared to acarbose, displaying IC50 values of 1.18 f 0.01 & micro;M against alpha-glucosidase and 3.86 f 0.01 & micro;M against alpha-amylase, while compound 2 exhibited IC50 values of 4.99 f 0.01 & micro;M and 7.56 f 0.01 & micro;M, respectively. Enzyme kinetic studies revealed both competitive and uncompetitive modes of inhibition, indicating distinct interaction profiles with the target enzymes. Molecular docking analyses supported the experimental findings by confirming strong interactions between the most active compounds and key catalytic residues of alpha-glucosidase (ARG-200, HIS-332, ASP-333, ARG-400) and alpha-amylase (TRP-59, TYR-62, GLU-233). The synthesized compounds also exhibited notable antioxidant activity, with compound 2 displaying the highest ferric and cupric reducing capacities. In silico ADME profiling indicated favorable oral bioavailability, acceptable absorption, and low predicted cardiotoxicity risk for the leading derivatives, particularly compound 9. Collectively, these results highlight the pyridazine scaffold as a promising chemotype for the development of multifunctional agents targeting hyperglycemia and oxidative stress in diabetes management.