Synthesis, DFT study, and molecular docking of novel quinoline-4-carboxamide derivatives as potential oxireductase inhibitors

A series of novel quinoline-4-carboxamide derivatives was designed, synthesised, and assessed for their potential to inhibit key oxidoreductase proteins implicated in advancement of cancer progression. To understand the electronic properties and reactivity of the synthesised molecules, density functional theory (DFT) calculations were performed at the B3LYP/631G(d,p) level. Key global reactivity descriptors, including the energy of the highest occupied molecular orbital (HOMO), the energy of the lowest unoccupied molecular orbital (LUMO), energy gap(ΔE), ionisation potential (I), electronic affinity (A), electronegativity (χ), chemical potential (μ), hardness (H), softness (S), electrophilicity (ω) were calculated. Subsequently, molecular docking studies were conducted to determine the binding affinities and interaction modes of the synthesised quinoline-4-carboxamides within the active sites of target oxidoreductase proteins, namely dihydroorotate dehydrogenase (PDB ID. 3U2O ), cyclooxygenase-2 (PDB ID. 5IKT ), and peroxiredoxin-2 (PDB ID. 5IJT ). The combined DFT and docking data provide a strong rationale for further biological evaluation and optimization of these compound as potential anticancer agents. • A series of novel quinoline-4-carboxamides was synthesised, explored their potential as anticancer agents. • DFT studies to evaluate FMO, MEP, and global reactivity descriptors. • Molecular docking conducted against key targets: peroxiredoxin-2 (5IJT), cyclooxygenase-2 (5IKT), and Dihydroorotate Dehydrogenase (3U2O). • Studies revealed strong hydrogen bonding and hydrophobic interactions, particularly for derivatives bearing electron-withdrawing substituents, indicating enhanced target specificity. • The combined DFT and docking analyses revealed that quinoline-4-carboxamide scaffolds possess promising pharmacological profiles.