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 4a-c, 5c, 5g, and 5m 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-alpha, B-Raf and VEGFR-2, was tested for the most active candidates. The tested compounds exhibited notable activity as PI3K-alpha inhibitors where compound 5g was found to have the highest inhibitory effect, compounds 4c and 5c showed good activities and compounds 4b and 5m had moderate activities. In B-Raf (V600E) kinase assay, compound 4b was showed the highest inhibitory activity comparable to sorafenib, while compounds 4a and 5g showed weak inhibitory effect. Regarding VEGFR-2 kinase assay, compound 4c had the best inhibitory activity compared to sorafenib, while compound 5g showed weak inhibitory effect. Molecular docking study was performed to understand the mode of binding between compounds 4b,c and 5c,m and PI3K-alpha, 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.