Solvent-free synthesis, anticancer activity and in-silico studies of 7-hydroxy-4-methylquinolin-2(1H)-one analogues

Several analogues (4a–f) of 7-hydroxy-4-methylquinolin-2(1H)-one were synthesized with high efficiency in a solvent-free condition. The new analogues were characterization using infrared (IR), nuclear magnetic resonance (¹H- and ¹³C NMR), and mass spectral data. Subsequently, they were tested for anticancer activity following the protocol established by the National Cancer Institute (NCI US). 7-Hydroxy-4-methyl-N-(naphthalen-1-yl)-2-oxoquinoline-1(2H)-carboxamide (4d) demonstrated significant anticancer activity against a few cancer cell lines including UO-31 (renal cancer) SNB-75 (CNS cancer) and PC-3 (prostate cancer) cell lines with PGI of 50.40, 45.37 and 35.36 respectively. Similarly, 1-((2,4-Dinitrophenyl)amino)-7-hydroxy-4-methylquinolin-2(1H)-one (4b) demonstrated significant anticancer activity against non-small cell lung cancer, HOP-92 with PGI of 43.79 percent. The correlation between the HOMO-LUMO energy gap (∆E) and bioactivity was investigated using density functional theory (DFT). A significant relationship was observed between ∆E and anticancer activity, particularly in compounds 4b and 4d. Furthermore, a molecular docking and dynamics studies against EGFR were carried out to analyze the binding mode of the compounds (4a–f) and dynamic states and binding stability of the most active compound (4d) respectively. The compound 4d had a docking score of −9.962 kcal/mol, indicating H-bond interactions with the residues Thr854 and Met793. In general evaluation of structural parameters over time reveals compound 4d forms a more stable complex with EGFR as compared to gefitinib. All of the compounds adhered to the Lipinski's rule of five, that was a set of parameters used in ADME studies. Additionally, these compounds were predicted to belong to class IV in terms of toxicity, with LD₅₀ values ranging from 1000 to 1200 mg/Kg.