Novel Isoxazole‐Sulfonylurea Hybrids: Synthesis, Molecular Docking, ADMET Analysis, and Antidiabetic Evaluation via α‐Amylase Inhibition

Abstract A novel series of isoxazole‐sulfonylurea hybrids ( 9a–j and 10a–j ) was synthesized via the reaction of isoxazole‐sulfonamides ( 5 and 7 ) with carbamates ( 8a–j ) under mild conditions. The synthetic strategy employed avoids the use of hazardous reagents such as phosgene and isocyanates, leading to high yields (84%–97%). The structures of synthesized compounds were confirmed by spectroscopic techniques, including 1 H NMR, 13 C NMR, IR, mass spectrometry, and elemental analysis. The α‐amylase inhibition of these hybrids was evaluated in vitro, revealing potent inhibition with IC 50 values ranging from 0.61 to 6.74 µM. Notably, compounds 9j and 10j exhibited the most potent inhibition IC 50 = 0.88 ± 0.09 µM and 0.61 ± 0.03 µM, respectively, surpassing the standard inhibitor Acarbose (IC 50 = 1.11 ± 0.03 µM). Molecular docking studies against porcine pancreatic α‐amylase (PDB ID: 1OSE) revealed strong binding affinities for several synthesized compounds, with binding energies ranging from −9.9 to −6.4 kcal/mol. The most potent inhibitors ( 9c , 9a , 9j , and 10j ) exhibited superior interactions with key active site residues compared to acarbose, highlighting their promising role as potential antidiabetic agents. Moreover, ADMET predictions indicated that 9j demonstrated high gastrointestinal absorption, better solubility, and lower TPSA, making them promising candidates for further pharmacological evaluation.