| Using the EGFR allosteric inhibitor EAI045 as the lead compound, through a scaffold-hopping strategy, the benzisoindol-1-one core was replaced with a quinazolinone, and a methylpiperazinyl pyridine group was introduced. Rational modifications were made to the para-hydroxyfluorophenyl fragment and the 2-aminothiazole structure. Two novel quinazolinone inhibitors were designed, synthesized, and evaluated. In vitro evaluation of tumor cell proliferation inhibition showed that compound 1h had IC50 values of 3.33 μM and 2.24 μM for non-small cell lung cancer A549 and H1975 cell lines, respectively, while 2h had IC50 values of 1.90 μM and 4.44 μM, which are superior to the IC50 values of EAI045 (＞10 μM and 27.65 μM), both showing good antiproliferative activity. In vitro cell functional experiments indicated that 1h significantly inhibited the colony formation, migration, and invasion abilities of H1975 cells in a concentration-dependent manner. Preliminary in vitro metabolic stability evaluation showed that compound 1h has moderate stability in rat plasma, with 60.54% remaining after 3 hours of incubation, and exhibited good stability in liver microsomal metabolism, with a half-life (T1/2) of 187 minutes. In summary, this study successfully obtained a novel quinazolinone compound 1h with significant inhibitory activity against non-small cell lung cancer H1975 cells. It exhibited marked antiproliferative, migration, and invasion inhibitory effects in vitro and had good metabolic stability, making it a promising lead compound for further development. |
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