Novel Pyrrolidine-Based Pyrazolines as α‑Glucosidase Inhibitors: Microwave-Assisted Synthesis, Antidiabetic Activity,...

Due to their unique properties, small multitargeted drugs containing a fluorinated aromatic moiety and nitrogenous heterocycles are widely available on the market. Considering the pharmacological significance of organofluorine and heterocyclic compounds, in this study, we synthesized a series of pyrazoline derivatives (14-27) containing a pyrrolidine moiety and substituted them with a fluorine atom or a fluorine-containing (-CF₃ or -OCF₃) group at different positions. Also, the antidiabetic activities of new pyrazolines were screened by in vitro α-glucosidase and α-amylase activity assays in order to investigate their potential use in the treatment of Diabetes Mellitus, one of the most common and rapidly spreading diseases of today. The findings of this research indicated that compound 21, having a trifluoromethoxy group at the ortho position of the pyrrolidine-based pyrazolines at the phenyl ring, was determined to be the most effective α-glucosidase inhibitor with IC₅₀ values of 52.79 ± 6.00 μM, compared to acarbose (IC₅₀: 121.65 ± 0.50 μM). Molecular modeling studies demonstrated the high specificity of the most active pyrazoline-pyrrolidine hybrid molecules to the active site of α-glucosidase and their potential to exert inhibitory effects through various interactions with basic residues. Furthermore, molecular dynamics simulations provided comprehensive information about the structural properties and binding mechanisms of the complexes.