Synthesis, Single‐Crystal X‐Ray Investigation, Computational Evaluation, Molecular Docking, and Dynamics Simulation of New Tetrahydroisoquinoline Derivatives

ABSTRACT The title compounds, 7‐acetyl‐3‐(ethylthio)‐6‐hydroxy‐1,6‐dimethyl‐8‐phenyl‐5,6,7,8‐tetrahydroisoquinoline‐4‐carbonitrile ( 4 ) and 2‐((7‐acetyl‐4‐cyano‐6‐hydroxy‐1,6‐dimethyl‐8‐phenyl‐5,6,7,8‐tetrahydroisoquinolin‐3‐yl)thio)‐ N ‐(4‐chlorophenyl)acetamide ( 5 ) were synthesized by reaction of 7‐acetyl‐8‐phenyl‐4‐cyano‐1,6‐dimethyl‐6‐hydroxy‐5,6,7,8‐tetrahydroisoquinoline‐3(2 H )‐thione ( 2 ) with ethyl iodide or N ‐(4‐chlorophenyl)‐2‐chloroacetamide ( 3 ), respectively, in the presence of sodium acetate. Structures of these compounds were characterized based on their elemental analyses and spectroscopic data. The crystal structures of 5,6,7,8‐tetrahydroisoquinolines 4 and 5 were determined by x‐ray diffraction. The intermolecular H⋯H interactions make a significant contribution to stabilizing the supramolecular assemblies of 4 and 5 . The Hirshfeld surface analysis also reveals the presence of hydrogen bond interactions in the crystal packing. Electronic structure calculations were performed at the M062X/DEF2TZVP method. The reactivity and charge transfer properties were predicted by NBO and FMO analysis. The quantum theory of atoms in molecules (QTAIM) study has been exploited for the determination of the nature of bonding and the role of noncovalent interaction in the present compound. In addition, the nonlinear optical properties of the crystal were calculated using the same DFT method. Structural activity relationship analysis of 4 and 5 showed that Maltose‐binding protein fusion to a C‐terminal fragment of the V1a vasopressin receptor (MBPV1R) is a good target and further molecular docking, molecular dynamics, and ADMET analysis were carried out to understand future drug candidacy.