New Quinazolinone-Thiouracil Derivatives: Design, Synthesis, Anticancer Evaluation, and In Silico Analysis

Quinazolinone and thiouracil derivatives are key scaffolds in anticancer development. This study used a molecular hybridization approach to synthesize new quinazolinone-thiouracil derivatives and evaluated their anticancer activity against three human cancer cell lines, namely breast, lung, and glioblastoma, using SRB assay. Structural elucidation was performed using IR spectroscopy, 1H-NMR, 13C-NMR, mass spectrometry, and elemental analysis. Most compounds show moderate to significant cytotoxic effects, with compound 5d displaying the highest potency (IC50 values of 5.28, 4.02, and 2.88 mu M, respectively). Compound 5d also demonstrated comparable potency to positive controls cisplatin and temozolomide in lung and glioblastoma cancer cell lines and was nearly as effective as mitochondrial division inhibitor-1 (mdivi-1). Furthermore, molecular docking analyses revealed strong binding interactions of the synthesized compounds with dynamin-related protein-1 (drp1). Protein-ligand stability studies and all-atom simulation confirmed the stable binding of compound 5d with drp1. In conclusion, this study identified compound 5d as a potent drp1 inhibitor and promising anticancer drug candidate, deserving further investigation. Quinazolinone and thiouracil derivatives serve as key scaffolds in anticancer research. This study synthesizes quinazolinone-thiouracil derivatives and evaluates their anticancer activity against breast, lung, and glioblastoma cells using the SRB assay. Compound 5d shows the highest potency, with strong binding to drp1 confirmed by molecular docking and simulation, making it a promising anticancer candidate for further investigation. image