New alkanesulfonate-based quinazolinone-acetohydrazide scaffolds: Rational design, synthesis, molecular docking, anticancer properties and potential EGFR and its T790M/L858R mutants inhibitors

Leveraging their potential anticancer properties, two novel series of quinazolinone-based scaffolds, 3a-i and 7a-i, have been designed, synthesized, and scanned for their anticancer efficacy across three diverse human cancer cell lines, HepG-2, MCF-7, and HCT-116, alongside a normal cell line (BJ-1). Erlotinib and Doxorubicin served as the reference drugs. Notably, derivatives 3i and 7f exhibited the most potent activity against HepG-2, with IC₅₀ values of 1.66 μM and 1.67 μM, respectively, demonstrating about two-fold greater potency than erlotinib and doxorubicin (IC₅₀ = 2.85 μM and 4.25 μM, respectively). Additionally, compound 7i showed superior efficacy against MCF-7 with an IC₅₀ of 3.25 μM, outperforming erlotinib and doxorubicin (IC₅₀ = 3.56 μM and 5.38 μM, respectively). In the case of colon cancer (HCT-116), compound 7i also displayed the highest cytotoxic activity compared to erlotinib and doxorubicin (IC₅₀ = 1.20 μM versus 3.05 and 5.70 μM, respectively). Notably, most tested compounds exhibited a favorable safety profile against the normal human cell line (BJ-1). Furthermore, the derivatives demonstrated significant inhibitory properties on the Epidermal Growth Factor Receptor (EGFR) besides its mutations, EGFR^L858R and EGFR^T790M, compared with Erlotinib, the reference drug. Compound 7f notably increased Bax and Bcl-2 levels by 1.9 and 1.3 folds, respectively, relative to Erlotinib. Moreover, 7f induced the apoptotic effect, arrested the cell cycle at the G0/G1 phase, and halted the mitotic cycle in HepG-2 cells. To further validate these findings, docking simulations of the promising derivatives 7i and 7f were conducted to assess their anticipated binding affinities with EGFR and its T790M/L858R mutants. Thus, compound 7f has the potential to be developed into a potent anticancer agent.