Solvent-free synthesis, anticancer activity and in-silico studies of 7-hydroxy-4-methylquinolin-2(1 H )-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)-2oxoquinoline-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 (Delta E) and bioactivity was investigated using density functional theory (DFT). A significant relationship was observed between Delta 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.