An Exploration of the Antidiabetic Potential of 2‐Thio‐4‐quinazolinone Scaffolds Using In Vitro and In Silico Approaches

Diabetes, a complicated metabolic disease, upsets glucose regulation and disturbs multiple organs, often resulting in problems like neuropathy and cardiovascular diseases. There is a pressing need to develop effective antidiabetic agents capable of managing glucose metabolism without compromising vital physiological functions. This study highlights the synthesis of 2‐thio‐4‐quinazolinones ( 5a – j ), the base‐catalyzed intramolecular cyclization of corresponding 2‐fluorobenzoyl‐3‐aryl thioureas ( 4a – j ), and their exploration for α‐ and β‐glucosidase inhibition. All the synthesized compounds exhibited strong α‐ and β‐glucosidase inhibition, with compound 5a , containing chloro and nitro substituents, showing the most potent α‐glucosidase inhibition with an IC 50 value of 1.89 ± 0.19 µM, markedly superior to that of the reference drug acarbose (IC 50 : 9.80 ± 0.20 µM). Meanwhile, compound 5h , featuring fluoro and chloro substituents, exhibited significant β‐glucosidase inhibition, with an IC 50 value of 0.95 ± 0.32 µM. Molecular docking validated the strong binding affinities of compounds 5a and 5h with α‐ and β‐glucosidase, exhibiting binding energies of −37.00 and −40.00 kJ/mol, respectively, and DFT calculations elucidated their mode of action, electronic properties, and stability. In addition, the drug‐likeness analysis carried out through SwissADME established its pharmacologic feasibility. These results underline the amazing inhibitory potential of 2‐thio‐4‐quinazolinones as promising lead candidates for the treatment of diabetes.