Novel hydrazone-derived pyrazole-benzofuran compounds inhibit cancer cell growth by targeting MMPs, caspases, and PI3K/AKT/mTOR signaling pathway

In this research, a series of novel pyrazole-benzofuran hydrazone hybrids (3a-h) were designed, synthesis and evaluated for their anticancer potential. All hybrid pyrazole-benzofuran derivatives were purified and characterized by using 1H NMR, 13C NMR, and ESI-HRMS analyses. Their cytotoxic potentials were evaluated against human lung carcinoma (A-549) and colorectal adenocarcinoma (HT-29) cell lines, and mouse fibroblast (3T3-L1) cells using XTT assay. The findings demonstrated that all compounds exhibited a dose-dependent anti-proliferative effect against the cancer cell lines under investigation. Compound 3d was particularly distinguished by its noteworthy IC50 value of 0.28 μM and a selectivity index of 103.85 on A549 cells. Advanced mechanistic anticancer investigations employing flow cytometry revealed that compound 3d triggered apoptosis in A549 cells by inducing mitochondrial membrane disruption and activating multiple caspases. Furthermore, both flow cytometry and Western blot analysis showed that the 3d molecule significantly suppressed the PI3K/AKT/mTOR signaling pathway, which is vital for cellular proliferation. In summary, the findings suggest that compound 3d has the potential to be evaluated as a therapeutic agent for the treatment of lung cancer. © 2026 Elsevier Inc.