Discovery of 1H-indazole-6-amine Derivatives as Anticancer Agents: Simple But Effective

Background: Indazole is a promising structure present in various biological activity compounds; in particular, many 6-aminoindazole-containing compounds demonstrated anticancer activity. In our previous research, we discovered some of the 6-aminoindazole derivatives with excellent cytotoxicity in the human colorectal cancer cell line (HCT116). Objective: In this study, a series of 6-substituted amino-1H-indazole derivatives were designed and synthesized through simple and well-known chemical reactions, which were evaluated for anti-proliferative activity in four human cancer cell lines. Methods: The title compounds were designed based on the structures of potential anticancer candidates in our previous report. The synthesis of 6-aminoindazole derivatives through acetylation and reductive amination with 6-amininoindazole as the starting material. Sulforhodamin B (SRB) assay was used for in vitro biological evaluation of synthesized compounds. Various physicochemical properties of them were predicted by online site Molinspiration. Results: Seven out of eight synthesized compounds showed growth inhibitory activity with IC50 values from 2.9 to 59.0 μM range in all four tested cancer cell lines. Of them, the compound N-(4-fluorobenzyl)- 1H-indazol-6-amine (9f) exhibited a potent anti-proliferative activity, with an IC50 value of 14.3±4.4 μM in the human colorectal cancer cell (HCT116) and non-cytotoxicity in the normal cell (lung fibroblast cells, MRC5, IC50 >100 μM). Conclusion: The bioactivity result and conformance of the physicochemical properties of the synthesized compounds to the "rule of three" for hit-like compounds suggested that 9f was effective and could be used as a hit for the development of novel anticancer agents.