Design, synthesis, in silico studies, molecular docking, ADMET and anticancer activity of novel...

New pyrazole and 1,3-thiazolyl-pyrazole derivatives were prepared in high yields.

The structures of the desired compounds were determined and characterized using ¹H NMR, ¹³C NMR, FT-IR, and ESI-MS spectroscopy. The compounds were screened for anticancer activity against human epithelial colorectal adenocarcinoma (Caco-2). The anticancer mechanisms were investigated with apoptosis studies and molecular docking. Using Auto Dock vina, the effective chemicals were docked into the human epidermal growth factor receptor (BAX, caspase-3, and TNF-α) to investigate anticancer activity.

Among the tested compounds, pyrazole compounds 13 and 8 exhibited the highest result effect against the tested Caco-2 cell line (IC₅₀ = 2.12 ± 55.17 μM) and (IC₅₀ = 2.44 ± 59.92 μM), respectively. While compounds 5b and 15c displayed the moderate result effect against the tested Caco2cell line (IC₅₀ = 2.33 ± 20.4 μM) and (IC₅₀ = 1.54 ± 9.65 μM) respectively. Molecular docking analysis revealed that compounds 8, 5b, 13, and 15c exhibit strong binding affinities to BAX, with binding energies of -8.20, -7.90, -7.50, and -7.70 kcal/mol and show significant binding affinities to caspase-3, with binding energies of -6.80, -7.00, -7.30, and -7.60 kcal/mol, respectively. Also, compounds 8, 5b, 13, and 15c display strong binding affinities to TNF-α, with binding energies of -7.60, -7.10, -6.50, and -6.80 kcal/mol, respectively.

The activity of synthesized 1 H-substituted carbothioamide pyrazole derivatives was increased when added to thiazole with different electron-withdrawing groups.