Design, synthesis, and biological evaluation of novel 1,5-diarylpyrazole carboxamides with dual inhibition of EGFR and COX-2 for the treatment of cancer and inflammatory diseases.

This study presents a series of dual-target epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) inhibitors developed as anticancer and anti-inflammatory agents. These novel inhibitors were designed based on key pharmacophoric features of known selective EGFR/COX-2 inhibitors with distinct chemical structures, and various substituents were selected according to rational criteria. Many of the novel compounds exhibited excellent antiproliferative activities and EGFR/COX-2 inhibitory activity. Among them, 10a exhibited the highest potency against cancer cell lines, with IC50 values of 6.7, 9.0, and 13.0 μM against leukemia, cervical cancer, and pancreatic cancer cell lines, respectively. Moreover, the optimal compound 10a was tested in a cell viability assay using human PC12 normal cell line and exhibited low cytotoxicity (IC50 = 77.4 μM, SI = 8.6, 11.5, 5.9) and it might be used as a potent, selective and safe antitumor agent. It also exhibited high inhibitory activity against EGFR (IC50 = 6.0 μM) and COX-2 (IC50 = 50 μM, SI = 3.8). Mechanistic studies revealed that 10a increased the cell population in the S phase and induced cell cycle arrest mainly in this phase. Moreover, an increase in apoptotic HeLa cells was observed following treatment with 10a. In addition, 8d was identified as the most potent and selective COX-2 inhibitor, with an IC50 value of 12.5 μM and SI of 16. Molecular docking studies demonstrated that 10a and 8d adopted orientations in the EGFR and COX-2 binding sites are oriented and fit in a similar manner to those of ligand inhibitors, supporting the experimental results.