Investigation of synthesis, spectroscopic characterization, crystal structure, and computational studies of 3-(4-(dimethylamino)phenyl)-1,5-di(thiophen-2-yl)pentane-1,5-dione as potent against Cathepsin S

The chief purpose of this work was to synthesize and characterize 3-(4-(dimethylamino)phenyl)-1,5-di(thiophen-2-yl)pentane-1,5-dione (4) whose structure was subsequently confirmed by single-crystal X-ray analysis. This molecule adopts a conformation approximating a three-bladed fan. In the crystal, C-H<middle dot><middle dot><middle dot>O and C-H<middle dot><middle dot><middle dot>S hydrogen bonds, together with C-H<middle dot><middle dot><middle dot>pi(ring) interactions form corrugated layers parallel to the bc plane. Electronic structure calculations were performed at the omega B97xd/def2tzvp level to explore the reactivity and topology of the molecule. Quantum theory of atoms in molecule (QTAIM) and NBO studies provide bonding characteristics and the extent of charge transfer with orbital energies computed from FMO theory together with optical and nonlinear optical (NLO) properties. A Hirschfeld surface analysis was performed to explore the nature of interactions in the crystal packing and the dispersion interactions were found to have a significant role in stabilizing the crystal structure. The H<middle dot><middle dot><middle dot>H interactions are the most significant among the intermolecular interactions. Compound 4 was subjected to structural activity relationship analysis and exhibited potency against Cathepsin S. Molecular docking and molecular dynamics analysis were carried out to understand the binding interaction mechanism and stability of 4 in its complex with Cathepsin S. GRAPHICAL ABSTRACT