Design, Synthesis and Molecular Docking Study of Novel 1,3,5-Triazine and 2-Phenylquinazoline Derivatives as Promising Anticancer Agents

We report the synthesis of new series of 1,3,5-triazines and 2-phenylquinazolines as anti-cancer agents. Compounds <b>4a-c, 5c, 5g</b>, and <b>5m</b> showed the highest cytotoxic effect against, most notably, leukemia, non-small cell lung cancer, colon carcinoma, CNS cancer, melanoma and renal cancer. The inhibitory activity against three different kinases; PI3K-α, B-Raf and VEGFR-2, was tested for the most active candidates. The tested compounds exhibited notable activity as PI3K-α inhibitors where compound <b>5g</b> was found to have the highest inhibitory effect, compounds <b>4c</b> and <b>5c</b> showed good activities and compounds <b>4b</b> and <b>5m</b> had moderate activities. In B-Raf (V600E) kinase assay, compound <b>4b</b> was showed the highest inhibitory activity comparable to sorafenib, while compounds <b>4a</b> and <b>5g</b> showed weak inhibitory effect. Regarding VEGFR-2 kinase assay, compound <b>4c</b> had the best inhibitory activity compared to sorafenib, while compound <b>5g</b> showed weak inhibitory effect. Molecular docking study was performed to understand the mode of binding between compounds <b>4b,c</b> and <b>5c,m</b> and PI3K-α, B-Raf and VEGFR-2 as target kinase enzymes. Generally, the synthesized 1,3,5-triazine derivatives were more promising anticancer agents than phenylquinazoline derivatives. The results support the fact that these compounds are worth optimizing for some new drugs in the future. A series of novel 1,3,5-triazine and 2-phenylquinazoline derivatives were designed, synthesized and evaluated in this study. Six 1,3,5-triazine compounds showed high activity as anticancer agents.