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 IC50 value of 1.89 ± 0.19 µM, markedly superior to that of the reference drug acarbose (IC50: 9.80 ± 0.20 µM). Meanwhile, compound 5h, featuring fluoro and chloro substituents, exhibited significant β-glucosidase inhibition, with an IC50 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.