PRECLINICAL EVALUATION OF QONA11, A NOVEL QUINAZOLINONE, IN T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA

This work describes the evaluation of the novel derivative Qona11 (2-substituted quinazolin-4(3H) -one), synthesised via the condensation of 2-aminobenzamide and 1H-benzo[d]imidazole-2-carbaldehyde, with its structure confirmed by IR and ¹H/¹³C NMR spectroscopy. In silico characterisation predicted a favourable pharmacokinetic profile with high intestinal absorption, low CYP450 inhibition potential, and blood-brain barrier permeability. Regarding in silico toxicity, potential hepatotoxic, neurotoxic, and respiratory risks were indicated, although no significant alerts for cardiotoxicity, carcinogenicity, or immunotoxicity were found. In vitro assays in acute leukaemia models revealed dose- and time-dependent cytotoxicity, with selectivity for the T-cell line (Jurkat, IC50 = 2.3 µM) over the promyelocytic line (NB4, IC50 = 12.7 µM). The mechanism of action in the sensitive lineage was attributed to apoptosis induction via mitochondrial membrane permeabilisation and caspase-3 activation, as confirmed by flow cytometry. In an in vivo xenograft model of Jurkat cells in NOD/SCID mice, Qona11 (100 mg.kg-1) was well tolerated, showing no signs of systemic toxicity; however, it did not inhibit leukaemia progression in this specific model. In conclusion, Qona11 exhibits promising in vitro activity and an adequate initial safety profile, justifying further pre-clinical investigations, including solid tumour models and combination therapy studies.