synthesis, characterization, tyrosine kinase inhibitory studies and molecular docking analysis of pyrazine-2-carboxamide derivatives

Three derivatives of pyrazine-2-carboxamide have been synthesized: 3-amino-n-butylpyrazine-2-carboxamide (1), 3-amino-n-isobutylpyrazine-2-carboxamide (2), and 3-amino-n-(4-methylbenzyl) pyrazine-2-carboxamide (3). the structures of these compounds were elucidated using nmr (1h, 13c, hmbc, and hsqc) and mass spectrometry data. the three compounds, along with the three previously reported pyrazine-2-carboxamide derivatives—3-amino-n-phenylpyrazine-2-carboxamide (4), 3-hydroxy-6-nitropyrazine-2-carboxamide (5), and 6-fluoro-3-hydroxypyrazine-2-carboxamide (6)—were assessed as inhibitors of eight tyrosine kinases (tks) at a concentration of 10 µm, using the bioluminescence method and a single-dose profile protocol. the results showed that the six compounds exhibited diverse inhibitory activities (1-41%) against different tks. compounds 4 and 3 showed the highest action as tyrosine kinase inhibitors (tkis) among the other compounds. compound 4 inhibited 41% of axl receptor tyrosine kinase 1 (axl1) activity and 34% of tyrosine kinase receptor a (trka) activity, while compound 3 inhibited 21% of axl1 activity. molecular docking analysis revealed that these compounds interact with tks through hydrogen bonds and hydrophobic interactions. the binding energies of 3-axl1, 4-axl1, and 4-trka are -7.0, -6.3, and -6.8 kcal/mol, respectively. hydrogen bonds between compound 4 and axl1 are established at pro672 (3.6 å) and met674 (3.1 å), while those between compound 4 and trka are found at met592 (3.8 å and 4.2 å). the inhibitory activity of compound 4 against axl1 and trka and compound 3 against axl1 are highlighted in this work. the two compounds present potential for their development as anticancer targets for axl1 and trka. the result represents a promising starting point for developing potent tkis from pyrazine-2-carboxamide derivatives.