Isoquinolinedione-urea hybrids: Synthesis, antibacterial evaluation, drug-likeness, molecular docking and DFT studies

Abstract In the present study, we applied the molecular hybridization approach to combine isoquinolinedione and urea pharmacophores in the same molecules. The hybrid compounds (IU1-IU14) were obtained by the reaction of 2-aminohomophthalimide and an equivalent amount of various isocyanate derivatives. After confirming the chemical structures and evaluating drug-likeness properties, the synthesized compounds were examined for their antibacterial activities against a wide range of bacteria. The compounds possessing lipophilic halogen substituents showed better activities against Gram-positive bacteria, particularly Staphylococcus aureus strains. This activity trend was further supported by molecular docking studies in the ATP pocket of S. aureus DNA gyrase. Several important parameters such as, ionization potential (IP), electron affinity (EA), global chemical hardness (η), global softness (σ), and electronegativity (χ) were carried out to gain insights into the structural properties and stabilities of selected active compounds by means of density functional theory (DFT) at the B3LYP functional using basis set B3LYP/6-311G(d,p). Electrostatic potential maps (ESPs) and frontier orbital visualizations were further used to comment on molecular polarity and stability.