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

Abstract:

Here, we synthesized a newseries of mono- A nd bis(dimethylpyrazolyl)-s-triazine derivatives. The synthetic methodology involved the reaction of different mono- A nd dihydrazinyl-s-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 mono- A nd bis(dimethylpyrazolyl)-s-triazine derivatives was studied against three cancer cell lines, namely, MCF-7, HCT-116, and HepG2. N-(4-Bromophenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine 4f, N-(4-chlorophenyl)-4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2-amine 5c, and 4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(4-methoxyphenyl)-1,3,5-triazin-2-amine 5d showed promising activity against these cancer cells: 4f [(IC50= 4.53 ± 0.30 μM (MCF-7); 0.50 ± 0.080 μM (HCT-116); and 3.01 ± 0.49 μM (HepG2)]; 5d [(IC50= 3.66 ± 0.96 μM (HCT-116); and 5.42 ± 0.82 μM (HepG2)]; and 5c [(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 4f exhibited potent EGFR inhibitory activity with an IC50value of 61 nM compared to that of Tamoxifen (IC50value of 69 nM), with EGFR inhibition of 83 and 84%, respectively, at a concentration of 10 μM. Interestingly, 4f 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 4f exhibited promising antiproliferative activity in HCT-116 cells through apoptosis induction by targeting the EGFR and its downstream pathway.