Exploring the effect of substituents on the supramolecular assemblies built by non-covalent interactions in three closely related 1,3,4-oxadiazole-2 (3H)-thione derivatives: An evaluation of antimicrobial and anti-proliferative activities

Three closely related 1,3,4-oxadiazole-2(3H)-thione N-Mannich bases were synthesized and characterized by spectroscopic and single crystal X-ray diffraction methods. X-ray analysis reveals that the title molecules adopt Lshaped conformation, and a slight structural deviation around substituent groups is noted. The Hirshfeld surface and 2D fingerprint plots demonstrate the effect of substituents (piperidine, morpholine, and thiomorpholine) on the intermolecular interactions. The CLP-PIXEL energy analysis identified the most significant interactions in the molecular dimers (that characterize the crystal packing) with respect to the total intermolecular interaction energies. These dimers are held together by various non-covalent interactions including C-H & sdot;& sdot;& sdot;S/N/O/Cl/pi interactions in addition to unconventional lone pair & sdot;& sdot;& sdot;pi interactions. A molecule with thiomorpholine substituent is favoured by two sigma-hole interactions (Cl & sdot;& sdot;& sdot;Cl halogen bond and S & sdot;& sdot;& sdot;N chalcogen bond) in the solid state. Furthermore, the molecular electrostatic potential (MEP) surfaces and deformation electron density help to describe the existence of sigma-hole on the Cl and thione S atoms. Noncovalent interaction index (NCI) and quantum theory of atoms in molecules (QTAIM) methods are used to delineate the nature of observed noncovalent interactions in the molecular dimers. In vitro data of antibacterial and anti-proliferative activities indicate that compound with morpholine substituent showed a moderate antibacterial activity against all tested Gram-positive bacterial strains. However, molecules with piperidine and thiomorpholine showed notable effectiveness against the HepG-2 cell line. Molecular docking analysis was performed with two liver cancer targets, VEGFR2 and RET, in order to understand the interactions between the ligand and the active site residues of these targets.