Unusual short intramolecular N–H⋅⋅⋅H–C contact and weak intermolecular interactions in two N-(adamantan-1-yl)piperazine carbothioamides: Crystallography, quantum chemical study and in vitro urease inhibitory activity

Abstract

Crystal structures of two closely related N-(adamantan-1-yl)piperazine carbothioamides have been examined in detail using the Hirshfeld surface, fingerprint analysis, PIXEL energy for molecular dimers and noncovalent interaction (NCI) plots for intermolecular interactions. Both compounds namely, ethyl 4-[(adamantan-1-yl)carbamothioyl]piperazine-1-carboxylate (1) and N-(adamantan-1-yl)-4-(2-methoxyphenyl)piperazine-1-carbothioamide (2) crystallized in the triclinic system with two crystallographically independent molecules in each case. X-ray analysis indicates that the piperazine ring in one of the molecules of 1 exhibits a boat and chair conformation in the other crystallographically independent molecule, while the corresponding ring in 2 adopts a chair conformation. An analysis of the fingerprint plots of the Hirshfeld surface provides a qualitative picture of how carboxylate and methoxyphenyl substituents contribute to stabilizing the crystal packing. Both structures show unusually short intramolecular N–H⋅⋅⋅H–C contact with some geometrical constraints in addition to intramolecular C–H⋅⋅⋅S interactions. The role of intramolecular N–H⋅⋅⋅H–C contact was established with potential energy surface scan and structural optimization. The CLP-PIXEL calculation gives the intermolecular interaction energies for the molecular dimers in these structures. Many dimers in 1 are stabilized by C–H⋅⋅⋅O/S/π interactions, while others are stabilized by short H⋅⋅⋅H contacts. Intermolecular C–H⋅⋅⋅O interactions do not occur in 2. There are, however, intermolecular C–H⋅⋅⋅S/π interactions and short H⋅⋅⋅H contacts in some dimers. We used NCI plots to identify the nature of the observed noncovalent interactions. Compared to the control inhibitor (thiourea), the title compounds have good inhibitory activity against urease in vitro. Molecular docking analysis identifies the key active site residues involved in intermolecular interactions between a small molecule and an enzyme.