Synthesis and biological evaluation of novel 4-(2-fluorophenoxy)-2-(1h- tetrazol-1-yl)pyridines bearing semicarbazone moieties as potent antitumor agents

Article abstract of DOI:10.1002/ardp.201300188

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 μM) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC₅₀ = 3.61, 2.19, 2.32 μM), and 17, 3.2, and 2.9 times better than PAC-1 (IC₅₀ = 1.36, 1.17, 2.83 μM) 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. A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their cytotoxic activities in vitro. The most promising compound 10p was further examined for enzymatic activity, with the goal to investigate the molecular mechanisms of action.