Antiproliferative properties of new pyrazine-pyrazole hybrid compounds: synthesis, characterization and molecular modeling studies

New pyrazole-based analogues coupled with a pyrazine core were successfully synthesized, using 2-(4-acetylphenyl)aminopyrazine (1) as starting material, and their structures were established from the NMR, IR, and mass spectroscopic analyses. The DFT computations showed that these hybrids adopted nonplanar geometries and comparable HOMO-LUMO features. Moreover, the frontier orbital energies have been exploited in the evaluation of principal reactivity descriptors, which designated the hybrid 3b to have the lowest electronegativity and hardness values. In addition, the cytotoxic activity was investigated against HepG2, HT-29, and MCF-7 cancer cell lines, as well as the normal WI-38 cells, using Dasatinib as the reference drug. Analogue 3c revealed the strongest anticancer performance, with IC₅₀ values ranging from 7.48 ± 0.18 to 11.20 ± 0.01 µM. Antiviral activity against H5N1 was also examined using a plaque reduction assay, where compounds 3c and 7c achieved remarkable inhibition levels of 100% and 88%, respectively, at non-toxic concentrations. Moreover, the molecular docking studies supported their potential by revealing favorable interactions with the 3Q3X protein target. The SwissADME pharmacokinetic predictions indicated that all compounds exhibit drug-like properties, including high gastrointestinal absorption and full compliance with Lipinski’s rule of five. Accordingly, the synthesized pyrazine-pyrazole hybrids represent promising scaffolds for future multi-functional anticancer and antiviral drug development.