Synthesis, Cytotoxic Evaluation, Molecular Docking, and In Silico ADME Studies of Novel Quinazolinone-Based Aldazine Derivatives Using Chitosan Sulfonic Acid as a Recyclable Catalyst

A series of novel quinazolinone-based aldazine and ketazine derivatives (4a–l and 6) was synthesized through the condensation of hydrazine intermediate 2 with substituted aldehydes and isatin using chitosan sulfonic acid (CS–SO3H) as a recyclable heterogeneous catalyst. The reactions were performed under conventional reflux and solvent-free grinding conditions. The grinding method afforded the target compounds in higher yields (84–90%) within shorter reaction times (21–33 min) using 10 mol% CS–SO3H at 25 °C. The synthesized compounds were characterized using spectroscopic and elemental analyses. Cytotoxic evaluation against HepG-2 liver carcinoma cells identified compound 4k as the most potent derivative, with an IC50 value of 4.47 ± 0.25 µM. Compounds 4b, 4f, 4h, and 4k exhibited low cytotoxicity toward the non-tumor LLC-MK2 cell line, with IC50 values above 100 µM and selectivity indices of >20.28, >16.00, >16.61, and >22.37, respectively. SAR analysis indicated that heterocyclic substitution, electron-donating groups, and hydrogen-bonding functionalities enhanced cytotoxic activity, whereas bulky aromatic systems and strong electron-withdrawing groups reduced potency. Molecular docking and in silico ADME studies supported the experimental findings and identified compound 4k as a promising candidate for further investigation.