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

Here, we synthesized a newseries of - and (dimethylpyrazolyl)--triazine derivatives. The synthetic methodology involved the reaction of different mono- and dihydrazinyl--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 - and (dimethylpyrazolyl)--triazine derivatives was studied against three cancer cell lines, namely, MCF-7, HCT-116, and HepG2. -(4-Bromophenyl)-4-(3,5-dimethyl-1-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine , -(4-chlorophenyl)-4,6-bis(3,5-dimethyl-1-pyrazol-1-yl)-1,3,5-triazin-2-amine , and 4,6-(3,5-dimethyl-1-pyrazol-1-yl)--(4-methoxyphenyl)-1,3,5-triazin-2-amine showed promising activity against these cancer cells: [(IC = 4.53 ± 0.30 μM (MCF-7); 0.50 ± 0.080 μM (HCT-116); and 3.01 ± 0.49 μM (HepG2)]; [(IC = 3.66 ± 0.96 μM (HCT-116); and 5.42 ± 0.82 μM (HepG2)]; and [(IC = 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 exhibited potent EGFR inhibitory activity with an IC value of 61 nM compared to that of Tamoxifen (IC value of 69 nM), with EGFR inhibition of 83 and 84%, respectively, at a concentration of 10 μM. Interestingly, 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 exhibited promising antiproliferative activity in HCT-116 cells through apoptosis induction by targeting the EGFR and its downstream pathway.