Weak halogen and hydrogen bonds in three closely related acridine-1,8 (2H,5H)-dione derivatives: Experimental and computational exploration

Three potential anticancer agents, acridine-1,8(2H,5H)-dione derivatives (unsubstituted: 2a, 4-NO2: 2b , and 3Cl: 2c ), have been structurally characterized using single-crystal X-ray diffraction analysis. In their crystalline forms, these structures exhibit various intermolecular interactions, resulting in distinct self-assemblies. All three structures feature intramolecular C=O & sdot;& sdot;& sdot;C(pi) (lp & sdot;& sdot;& sdot;pi) contacts, characterized by NCI plot and QTAIM analyses. The energetics of molecular dimers were fully characterized for all three compounds using CLP-PIXEL and DFT methods. Compound 2a is stabilized by intermolecular C-H & sdot;& sdot;& sdot;O/pi interactions, short Csp3-H & sdot;& sdot;& sdot;H-Csp3 and C & sdot;& sdot;& sdot; C contacts. The crystal structure of 2b displays numerous C - H & sdot;& sdot;& sdot; O interactions, as well as C-H & sdot;& sdot;& sdot;N/pi interactions. The crystal structure 2c exhibits C-H & sdot;& sdot;& sdot;O/pi/Cl interactions, along with a Cl & sdot;& sdot;& sdot;O halogen bond that stabilizes one of the molecular dimers. Hirshfeld surfaces and the corresponding 2D fingerprint plots reveal the effect of substitutions on intermolecular interactions, particularly on H & sdot;& sdot;& sdot; H and H & sdot;& sdot;& sdot; O interactions. Lattice energy calculations were carried out to study the packing stability of these compounds, with the NO2 derivative showing a higher packing stability than the 3-Cl and unsubstituted compounds. Furthermore, the Cl & sdot;& sdot;& sdot;O halogen bond was characterized by molecular electrostatic potential surface and deformation electron density maps. The topological properties of the intermolecular interactions observed in various molecular dimers indicate their closed- shell nature. Molecular docking simulations demonstrated that all three title compounds exhibit anticancer activity, particularly against two lung cancer targets (EGFR and ALK).