Abstract
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 14a–d, 15a–d, 16a–d, 17a–d, 18a–d, 19a–d, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d 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 19b inhibited TGF-β type I receptor kinase phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 19b also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (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.
Highlights
Transforming growth factor-β (TGF-β) superfamily members have a wide range of cellular functions, including cell proliferation, differentiation, adhesion, migration, and apoptosis [1]
We reported the effect of quinoxaline groups and
We reported the effect of length of side chainsand attached ring, and positional isomers activity of compounds quinoxaline groups lengthtoofpyrazole side chains attached to pyrazole ring, on andthe positional isomers on the containing pyrazole rings, but the effect of the pyridine portion attached to pyrazole ring on the activity activity of compounds containing pyrazole rings, but the effect of the pyridine portion attached to of the compounds was not discussed
Summary
Transforming growth factor-β (TGF-β) superfamily members have a wide range of cellular functions, including cell proliferation, differentiation, adhesion, migration, and apoptosis [1]. ALK5 autophosphorylation and TGF-β-induced of extracellular matrix genes at sub-micromolar concentrations in reporter assays, as shown. 4, high which showedtohigh selectivity to 320 body [13] These series of compounds were selective for ALK5, compared with p38α kinase. Kinases in human body [13] These series of compounds were selective for ALK5, compared with. Pyrazole ring on the activity of the compounds was not discussed. Previous studies, we found that the introduction electron-donating electron-donating groups quinoxaline or quinoline failed to increase inhibition groups into quinoxaline or into quinoline rings failed to increaserings. This is due to the steric hindrance of their rigid structures.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
