Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-<i>s</i>-triazine Derivatives Targeting EGFR/PI3K/AKT/mTOR Signaling Cascades

Abstract

Here, we synthesized a newseries of <i>mono</i>- and <i>bis</i>(dimethylpyrazolyl)-<i>s</i>-triazine derivatives. The synthetic methodology involved the reaction of different mono- and dihydrazinyl-<i>s</i>-triazine derivatives with acetylacetone in the presence of triethylamine to produce the corresponding target products in high yield and purity. The antiproliferative activity of the novel <i>mono</i>- and <i>bis</i>(dimethylpyrazolyl)-<i>s</i>-triazine derivatives was studied against three cancer cell lines, namely, MCF-7, HCT-116, and HepG2. <i>N</i>-(4-Bromophenyl)-4-(3,5-dimethyl-1<i>H</i>-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine <b>4f</b>, <i>N</i>-(4-chlorophenyl)-4,6-bis(3,5-dimethyl-1<i>H</i>-pyrazol-1-yl)-1,3,5-triazin-2-amine <b>5c</b>, and 4,6-<i>bis</i>(3,5-dimethyl-1<i>H</i>-pyrazol-1-yl)-<i>N</i>-(4-methoxyphenyl)-1,3,5-triazin-2-amine <b>5d</b> showed promising activity against these cancer cells: <b>4f</b> [(IC₅₀ = 4.53 ± 0.30 μM (MCF-7); 0.50 ± 0.080 μM (HCT-116); and 3.01 ± 0.49 μM (HepG2)]; <b>5d</b> [(IC₅₀ = 3.66 ± 0.96 μM (HCT-116); and 5.42 ± 0.82 μM (HepG2)]; and <b>5c</b> [(IC₅₀ = 2.29 ± 0.92 μM (MCF-7)]. Molecular docking studies revealed good binding affinity with the receptor targeting EGFR/PI3K/AKT/mTOR signaling cascades. Compound <b>4f</b> exhibited potent EGFR inhibitory activity with an IC₅₀ value of 61 nM compared to that of Tamoxifen (IC₅₀ value of 69 nM), with EGFR inhibition of 83 and 84%, respectively, at a concentration of 10 μM. Interestingly, <b>4f</b> showed remarkable PI3K/AKT/mTOR inhibitory activity with 0.18-, 0.27-, and 0.39-fold decrease in their concentration (reduction in controls from 6.64, 45.39, and 86.39 ng/mL to 1.24, 12.35, and 34.36 ng/mL, respectively). Hence, the synthetic 1,3,5-triazine derivative <b>4f</b> exhibited promising antiproliferative activity in HCT-116 cells through apoptosis induction by targeting the EGFR and its downstream pathway.