Optimization of pyrazole/1,2,4-triazole as dual EGFR/COX-2 inhibitors: Design, synthesis, anticancer potential,...

A novel series of pyrazol-4-yl-1,2,4-triazole-3-thiol derivatives 14a-l was designed, prepared and characterized by many spectroscopic techniques. All the novel compounds were screened for their anti-proliferative activity towards breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and lung cancer cell line (A-549) utilizing celecoxib, erlotinib and osimertinib as standards. Compounds 14b, 14g and 14k were the most active towards HT-29, MCF-7 and A-549 cell lines, sequentially with IC₅₀ = 1.20-2.93 μM compared with celecoxib (IC₅₀ = 16.47-41.45 μM), erlotinib (IC₅₀ = 1.95-33.57 μM) and osimertinib (IC₅₀ = 0.75-3.45 μM). These most active derivatives 14b, 14g and 14k were further investigated for their inhibitory potential against COX and EGFR enzymes. These compounds 14b, 14g and 14k suppressed COX-2 (IC₅₀ = 0.560-4.692 μM), EGFR^WT (IC₅₀ = 0.121-0.423 μM) and EGFR^T790M (IC₅₀ = 0.076-0.764 μM) enzymes. Compounds 14b, 14g and 14k displayed apoptosis induction by up-regulating Bax and down-regulating Bcl-2 protein levels. Cell cycle analysis recorded that exposure of MFC-7 cells to compound 14g resulted in a significant increase in the percentage of cells at the G2/M to 39.15 % compared to the standard erlotinib (9.87 %). Docking study of the most potent candidates 14b, 14g and 14k within COX-2, EGFR^WT and EGFR^T790M active regions was conducted to suggest the binding mode of these compounds inside these target enzymes.