Antioxidant, α-Amylase Inhibition, Computational Analysis Study of Novel Hybrid Pyrazole–Thiazolidine Compounds

Type 2 diabetes mellitus involves both oxidative stress and postprandial hyperglycemia, creating a need for dual-acting therapeutic agents. We designed and synthesized a novel series of thiazolidine–pyrazole carboxamide hybrids (15–20) as dual antioxidant/α-amylase inhibitors. The compounds were assembled from L-cysteine-derived thiazolidine-4-carboxylic acids and 4-aminoantipyrine through a metabolically stable amide linkage, affording trans-rich diastereomeric mixtures (75:25 to 88:12 trans:cis). Structures were confirmed by FT-IR, 1H-NMR, 13C-NMR, and mass spectrometry. All compounds showed concentration-dependent antioxidant and α-amylase inhibitory activities. The 4-methoxyphenyl derivative 19 emerged as the lead dual-acting agent, with IC50 values of 33.7 ± 0.95 μM for DPPH radical scavenging and 19.4 ± 0.96 μg/mL for α-amylase inhibition. Structure–activity relationship analysis revealed that electron-donating groups enhance antioxidant potency by increasing electron density and chemical softness, whereas electron-withdrawing substituents improve enzyme inhibition through complementary polar interactions. Density functional theory (DFT) at the M06-2X/6-31G** level, molecular electrostatic potential (MEP) mapping, non-covalent interaction (NCI) analysis, and molecular docking against catalase (PDB: 1F4J) and α-amylase (PDB: 1B2Y) collectively showed that frontier molecular orbital energies, surface electrostatic balance, and a conserved intramolecular N–H···S hydrogen bond governing conformational pre-organization are key determinants of dual bioactivity. ADMET profiling predicted high gastrointestinal absorption for all compounds, no blood–brain barrier permeation, and favorable drug-likeness with zero Lipinski violations. Compound 19 displayed the cleanest CYP450 inhibition profile and an optimal balance between skin permeation (Log Kp = −5.79 cm/s) and aqueous solubility (Log S = −5.24). These findings establish the thiazolidine–pyrazole carboxamide scaffold as a pharmacologically privileged, synthetically accessible platform for dual-acting antidiabetic drug discovery.