In Silico, in vitro, and in vivo studies of a 2-substituted quinazolin-4(3H)-one in T-cell acute lymphoblastic leukemia.

This study reports the synthesis, physicochemical characterization, and preliminary pharmacological evaluation of a novel 2-substituted quinazolin-4(3H)-one, Qona11. The compound was synthesized from 2-aminobenzamide and 1H-benzo[d]imidazole-2-carbaldehyde in dimethyl sulfoxide with a 55 % yield, in a catalyst-free, atom-efficient process that adheres to Green Chemistry principles. Structural confirmation was achieved through IR (1667 cm-1, carbonyl), 1H NMR (13.50 and 12.50 ppm, NH protons), and 13C NMR (161.17 ppm, carbonyl carbon). In silico analysis suggested Qona11 possesses favorable oral bioavailability, high intestinal absorption, limited CYP450 inhibition, and predicted blood-brain barrier permeability. Toxicity predictions highlighted potential hepatotoxicity, neurotoxicity, and respiratory toxicity, while no significant risks for cardiotoxicity, carcinogenicity, immunotoxicity, or cytotoxicity were found. Comparative analysis with idelalisib revealed similar toxicity profiles to Qona11, distinct from vincristine. Biological evaluation in acute leukemia models demonstrated concentration- and time-dependent cytotoxicity, with Jurkat T-ALL cells being more sensitive (IC50 2.3 μM) than NB4 APL cells (IC50 12.7 μM). Flow cytometry confirmed apoptosis induction in Jurkat cells via mitochondrial permeabilization and caspase 3 activation. In vivo studies in NOD/SCID mice bearing Jurkat xenografts showed that Qona11 (100 mg.kg-1) was well tolerated with no systemic toxicity, although it did not inhibit leukemia cell proliferation in immune-independent models. Overall, Qona11 exhibits promising anticancer activity and low systemic toxicity, warranting further preclinical investigation in solid tumor models and combination therapies.