Antidiabetic and Cytotoxicity Studies of Novel Quinazolinone-1,3,4-Thiadiazole Molecular Hybrids

In the treatment of diabetes mellitus (DM), inhibition of carbohydrate-hydrolysing enzymes, such as α-amylase, has emerged as a promising therapeutic strategy. In the present study, a series of quinazolinone-1,3,4-thiadiazole molecular hybrids were designed, synthesized and biologically evaluated for their antidiabetic potential. The full structural elucidation of each molecular hybrid was carried out using 1D/2D NMR spectroscopy, FT-IR and high-resolution mass spectrometry (HRMS). All the synthesized compounds, including intermediates (2a-c, 3a-g) and final hybrids (5a-u), were tested for α-amylase inhibition. Compounds 3b and 5t exhibited approximately twofold higher potency than the standard drug acarbose. Cytotoxicity evaluation against hepatocellular carcinoma (HepG2) cells revealed no significant cytotoxicity, with IC₅₀ values exceeding 100 µM. Furthermore, molecular docking and simulation studies were conducted to analyse the ligand-receptor interactions, while ADME/T predictions suggested that the most potent compounds possess favourable drug-like properties and could serve as promising lead candidates for further development.