In the present study, a series of 6-substituted aminoindazole derivatives were designed, synthesized, and evaluated for bio-activities.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme participating in tryptophan metabolism that has been implicated in numerous cancers. In the present study, a series of novel 5/6-amino indazole derivatives having amide linker were designed, synthesized, and evaluated for IDO1 inhibitory activity. The compounds were initially designed based on the known structural feature of IDO1 active site, and the important role of the indazole scaffold in interaction with IDO1 active site. Thirteen compounds exibited the moderate to excellent inhibitory activity (49% to 100% at the concentration of 1.0 mM). One of them, compound, 2-(6-amino-1H-indazol-1-yl)-N-(4-chlorophenyl) acetamide (19d), with chloro substituents group at para-position increased the activity upto 100%, equal to that value of the positive control, IDO5L. This research suggests that 5/6-amino indazole moiety combined with amide template is a potential scaffold for IDO1 inhibition as anti-cancer agents.

Background: Indazole is a promising structure, which presents in various biological activity compounds; in particular, many 6-aminoindazole-containing compounds demonstrated anticancer activity. In our previous research, we discovered some of 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 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 antiproliferative activity in four human cancer cell lines. Method: 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 value 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 antiproliferative 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.