X-ray characterization, Hirshfeld surface analysis, DFT calculations, in vitro and in silico lipoxygenase inhibition (LOX) studies of dichlorophenyl substituted 3-hydroxy-chromenones

This work reports the synthesis and X-ray characterization of three dichlorophenyl substituted 3-hydroxy-chromen-4-one derivatives, i.e., 2-(2,4-dichlorophenyl)-3-hydroxy-4H-chromen-4-one (1), 2-(2,3-dichlorophenyl)-3-hydroxy-4H-chromen-4-one (2), and 2-(2,6-dichlorophenyl)-3-hydroxy-4H-chromen-4-one (3). The solid-state architecture of these three isomers is quite different due to the large influence of the Cl-substituents on the dihedral angle between the phenyl and chromenone rings. The different assemblies and synthons have been studied using Hirshfeld surface analysis and by computing their interaction energies and different contributions (electrostatic, polarization, dispersion and repulsion). Furthermore, only one isomer forms directional halogen bonding interactions (C-ClMIDLINE HORIZONTAL ELLIPSISO) that have been analyzed using MEP surface calculations and characterized using a combination of QTAIM and NCIplot index computational methods. The ability to form halogen bonds depending on the substitution has also been analyzed. The docking results showed that compound 1 forms strong binding interactions with soybean lipoxygenase followed by compounds 2 and 3. The molecular docking results are in good agreement with the bioactivity data of 1-3 (IC50 values) against lipoxygenase.