Synthesis and Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as TGF-β Type I Receptor Kinase Inhibitors
oleh: Li-Min Zhao, Zhen Guo, Yi-Jie Xue, Jun Zhe Min, Wen-Jing Zhu, Xiang-Yu Li, Hu-Ri Piao, Cheng Hua Jin
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2018-12-01 |
Deskripsi
The transforming growth factor-β (TGF-β), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles <b>14a</b>⁻<b>d</b>, <b>15a</b>⁻<b>d</b>, <b>16a</b>⁻<b>d</b>, <b>17a</b>⁻<b>d</b>, <b>18a</b>⁻<b>d</b>, <b>19a</b>⁻<b>d</b>, <b>25a</b>, <b>25b</b>, <b>25d</b>, <b>26a</b>, <b>26b</b>, <b>26d</b>, <b>27b</b>, and <b>27d</b> were synthesized and evaluated for their activin TGF-β type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound <b>19b</b> inhibited TGF-β type I receptor kinase phosphorylation with an IC<sub>50</sub> value of 0.28 µM, with 98% inhibition at 10 µM. Compound <b>19b</b> also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound <b>3</b> (LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.