Ngo Xuan Hoang, Van-Hai Hoang, T. Ngo
May 12, 2022
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Letters in Drug Design & Discovery
Abstract
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 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. 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. 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). 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.