Synthesis and Biological Evaluation of Novel 4-(2-Fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines Bearing Semicarbazone Moieties as Potent Antitumor Agents

A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their in vitro antitumor potency. Some of the compounds (10b, 10c, 10e-10h, 10m-10p, 10r, and 11b) exhibited moderate to excellent antitumor activity as compared to sorafenib and PAC-1, as well as low levels of toxicity toward the human fetal lung fibroblast cell line WI-38. The most promising compound 10p (IC50=0.08, 0.36, 0.97 mu M) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC50=3.61, 2.19, 2.32 mu M), and 17, 3.2, and 2.9 times better than PAC-1 (IC50=1.36, 1.17, 2.83 mu M) against three cancer cell lines (HT-29, H460, and MKN-45), respectively. In addition, further studies examining enzymatic activity suggested that the marked pharmacological activity observed might be ascribed to an inhibitory action against CRAf kinase.