Synthesis, in-silico and in-vitro evaluation of quinoline-chromene hybrids as dual topoisomerase inhibitors.

Quinoline and chromene scaffold are recognized to possess anticancer activities but their synergistic potential has never been studied extensively. Our present work investigated a selectively designed series of quinoline-chromene hybrids using an integrative approach combining computational and experimental evaluations. Molecular docking experiments performed on topoisomerase I (3QX3) and II (4FM9) showed high binding affinities with lead molecules 6c, 6l, and 6j having greater efficacy in comparison to standard agents camptothecin and amsacrine. Moreover, molecular dynamics simulations confirmed the stability of the complexes of the ligand and the protein with low RMSD values and positive MM-GBSA binding free energies. ADMET profiling predicted high oral bioavailability, metabolic stability, and tolerable levels of toxicity with encouraging drug-like behavior. Seven of these hybrids were experimentally assessed for cytotoxicity in several cancer cell lines (HepG2, Hep3B, HCT-116, and MCF-7) and showed selective behavior in relation to normal cells (HEK-293 cells). Notably, the compounds 6c and 6l showed sub-micromolar IC₅₀ values and strong dual topoisomerase I/II inhibition and verified their mode of action. Structure-activity relationship (SAR) analysis showed that substituents with an electron-donating effect increased π-π stacking and hydrogen bonding and associated well with enhanced potency and selectivity. Collectively, these results position quinoline-chromene hybrids as important leads in anticancer treatment and emphasize the advantages of scaffold hybridization in attaining efficient, selective, and mechanistically established inhibition of the topoisomerase.