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

Abstract

Here, we synthesized a newseries of mono - and bis (dimethylpyrazolyl)- s -triazine derivatives. The synthetic methodology involved the reaction of different mono- and 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 - and 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-1 H -pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine 4f , N -(4-chlorophenyl)-4,6-bis(3,5-dimethyl-1 H -pyrazol-1-yl)-1,3,5-triazin-2-amine 5c , and 4,6- bis (3,5-dimethyl-1 H -pyrazol-1-yl)- N -(4-methoxyphenyl)-1,3,5-triazin-2-amine 5d showed promising activity against these cancer cells: 4f [(IC 50 = 4.53 ± 0.30 μM (MCF-7); 0.50 ± 0.080 μM (HCT-116); and 3.01 ± 0.49 μM (HepG2)]; 5d [(IC 50 = 3.66 ± 0.96 μM (HCT-116); and 5.42 ± 0.82 μM (HepG2)]; and 5c [(IC 50 = 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 IC 50 value of 61 nM compared to that of Tamoxifen (IC 50 value 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.

Bis(dimethylpyrazolyl)-aniline- s -triazine derivatives as efficient corrosion inhibitors for C-steel and computational studies

“…To explore further the application of the s-triazine-based molecules as corrosion inhibitors, three compounds having different electronic effects with either electron donating or withdrawing effects were selected, resynthesized and characterized by the El-Faham group [45]. The target compounds were prepared according to scheme 1 [45,66]. The structures of the three derivatives PTA-1-PTA-3 were confirmed by NMR and agreed with the reported data [45] (electronic supplementary material, synthetic method).…”

“…However, advanced progress in the topic adopted Monte Carlo (MC) simulations to provide more insight into the interactions between the corrosion inhibitors and the metal surface [51,52]. products in high yield by following the reported method in the literature [45] (electronic supplementary material, synthetic method).…”

Pyrazolyl-s-triazine with indole motif as a novel of epidermal growth factor receptor/cyclin-dependent kinase 2 dual inhibitors

“…2H,7.49 (d,1H,8.13 (d,1H,8.36 (s,1H,12.18 (s,1H,NH); 13 C-NMR (DMSOd 6 ): δ 182. 9, 136.7, 135.5, 125.2, 123.4, 123.2, 121.2, 116.5, 114.5, 112.4, 29.4. 2.1.1.2 Synthesis of mono-hydrazinyl-s-triazine derivatives 2a-k 2a-k were synthesized following the method reported in (Farooq et al, 2019;Shawish et al, 2022a;Shawish et al, 2022b).…”

“…A new series of pyrazolyl-indole-s-triazine derivatives were prepared via two synthetic approaches. Mono-hydrazinyls-triazine derivatives were used as a common starting material in both synthetic pathways and were prepared following the method reported in (Farooq et al, 2019;Shawish et al, 2022a;Shawish et al, 2022b). In addition, the first synthetic approach involved another starting material, namely cyanoacetyl indole 1, which was prepared following the method described by Bergman and coworkers (Bergman et al, 2004).…”

“…Based on this finding, our research group recently developed a new hybrid of the 1,3,5-triazine core structure, XIX (Shawish et al, 2022b) and XX (Shawish et al, 2022a) (Figure 2) targeting the EGFR/PI3K/AKT/ mTOR cascades. Here we report a novel series of compounds bearing three distinct pharmacophores, namely pyrazole, 1,3,5-triazine, and indole motifs.…”