| Summary: | Here, we described the synthesis of novel pyrazole-<i>s</i>-triazine derivatives via an easy one-pot procedure for the reaction of β-dicarbonyl compounds (ethylacetoacetate, 5,5-dimethyl-1,3-cyclohexadione or 1,3-cyclohexadionone) with <i>N</i>,<i>N</i>-dimethylformamide dimethylacetal, followed by addition of 2-hydrazinyl-4,6-disubstituted-<i>s</i>-triazine either in ethanol-acetic acid or neat acetic acid to afford a novel pyrazole and pyrazole-fused cycloalkanone systems. The synthetic protocol proved to be efficient, with a shorter reaction time and high chemical yield with broad substrates. The new pyrazolyl-<i>s</i>-triazine derivatives were tested against the following cell lines: MCF-7 (breast cancer); MDA-MB-231 (triple-negative breast cancer); U-87 MG (glioblastoma); A549 (non-small cell lung cancer); PANC-1 (pancreatic cancer); and human dermal fibroblasts (HDFs). The cell viability assay revealed that most of the <i>s</i>-triazine compounds induced cytotoxicity in all the cell lines tested. However, compounds <b>7d</b>, <b>7f</b> and <b>7c</b>, which all have a piperidine or morpholine moiety with one aniline ring or two aniline rings in their structures, were the most effective. Compounds <b>7f</b> and <b>7d</b> showed potent EGFR inhibitory activity with IC<sub>50</sub> values of 59.24 and 70.3 nM, respectively, compared to Tamoxifen (IC<sub>50</sub> value of 69.1 nM). Compound <b>7c</b> exhibited moderate activity, with IC<sub>50</sub> values of 81.6 nM. Interestingly, hybrids <b>7d</b> and <b>7f</b> exerted remarkable PI3K/AKT/mTOR inhibitory activity with 0.66/0.82/0.80 and 0.35/0.56/0.66-fold, respectively, by inhibiting their concentrations to 4.39, 37.3, and 69.3 ng/mL in the <b>7d</b>-treatment, and to 2.39, 25.34 and 57.6 ng/mL in the <b>7f</b>-treatment compared to the untreated control.
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