Synthesis and Biological Evaluation of Novel Isoxazole‐Amide Analogues as Anticancer and Antioxidant Agents

Abstract

Cancer now is one of the leading causes of mortality in the world. There has been a lot of effort to discover new anticarcinogenic agents that allow treatment with fewer side effects. A series of isoxazole-carboxamide derivatives (<b>2a</b>-<b>2g</b>) were synthesised and evaluated for their cytotoxic activity against breast (MCF-7), cervical (HeLa), and liver (Hep3B) cancer cell lines and their antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The results showed that <b>2d</b> and <b>2e</b> were the most active compounds against Hep3B cells, with a half-maximal inhibitory concentration (IC₅₀) of around 23 <i>μ</i>g/ml; <b>2d</b> showed the highest activity against HeLa cells, with an IC₅₀ 15.48 <i>μ</i>g/ml. However, <b>2a</b> had the lowest IC₅₀ (39.80 <i>μ</i>g/ml) against MCF-7 cells. By contrast, compound <b>2</b>g was inactive against all cancer cell lines, with IC₅₀ values >400 <i>μ</i>g/ml. Both <b>2d</b> and <b>2e</b> reduced Hep3B secretion of alpha-fetoprotein (to 1829.33 ± 65.91 ng/ml and 1758.66 ± 54.04 ng/ml, respectively). Furthermore, in cell cycle analysis, <b>2d</b> and <b>2e</b> induced a delay in the G2/M phase of 18.07%, which is similar to the doxorubicin positive control. Moreover, <b>2d</b> and <b>2e</b> reduced the necrosis rate of Hep3B threefold and instead shifted the cells to apoptosis. Our results indicate that <b>2d</b> and <b>2e</b> have potent and promising anticancer activity. However, compound <b>2a</b> was the most active as antioxidant agent (IC₅₀ = 7.8 ± 1.21 <i>μ</i>g/ml) compared with Trolox as a positive control (IC₅₀ 2.75 <i>μ</i>g/ml).