فهرست نشریات علمی دسترسی آزاد ایران

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.