Synthesis, Electronic Structure, Drug‐Likeness, Spectral Characteristics, And Anticancer Efficacies of Lawsone–Pyrazine Hybrids

Hybridization of pharmacophores is a widely used strategy in anticancer drug design. Although lawsone and pyrazine scaffolds individually possess biological relevance, their combined hybrids remain comparatively less explored. A series of lawsone–pyrazine hybrids were synthesized through a Mannich‐type reaction under sonication and evaluated against MCF‐7 breast cancer cells. ADMET and drug‐likeness properties were predicted using in silico tools. Cytotoxicity was assessed by MTT assay, followed by flow cytometric cell cycle analysis. Molecular docking, molecular dynamics simulations, and density functional theory (DFT) studies were also performed. Most compounds satisfied key drug‐likeness criteria with minor deviations observed for L5. Compounds L7 and L8 showed notable antiproliferative activity with IC 50 values of 6.75 ± 0.75 and 5.22 ± 1.82 µM, respectively, comparable to standard drugs. Docking and MD studies suggested stable interactions of L7 with PR and L8 with HER2. Flow cytometry indicated G0/G1 phase arrest with increased sub‐G0/G1 population, suggesting possible apoptotic involvement. Selected lawsone–pyrazine hybrids, particularly L7 and L8, demonstrated measurable antiproliferative activity supported by computational and cell‐based studies, warranting further mechanistic investigation.