X-ray and theoretical investigation of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak non-covalent interactions, chemotherapeutic activities and QM/MM binding energy

Abstract

A detailed exploration of crystal packing of two adamantane-isothiourea hybrid derivatives along with a known closely related structure has been performed to delineate the effect of halogen substituents and the role of weak intermolecular interactions in their supramolecular architectures. The adamantane-isothiourea hybrid derivatives used in the present study are (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-phenylisothiourea (1), C 24 H 27 BrN 2 S and (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-(3chlorophenyl)isothiourea (2), C 24 H 26 BrClN 2 S, characterized by X-ray crystallography. The X-ray structures revealed that the molecular conformation of 1 and 2 are different and stabilized by intramolecular C-HÁÁÁN interactions. In addition, a short intramolecular HÁÁÁH contact is formed in 2. The Hirshfeld surface analysis was used to delineate the nature of different intermolecular interactions and their contributions toward crystal packing. The quantitative analysis of strengths of molecular dimers existed in 1 and 2 has been performed using the PIXEL method. The electrostatic potential map clearly revealed nature and strength of r-holes at Br and Cl atoms. The topological analysis was used to characterize the nature and the strength of various intermolecular interactions including the type I BrÁÁÁBr contact. Interestingly, all the H-H bonding observed in 1 and 2 show closed-shell in nature. Further, an in-vitro antimicrobial activity studies suggest that the title compounds exhibited potent antibacterial activity against all the tested Gram-positive bacterial strains and Gram-negative Escherichia coli. Compound 2 showed marked anti-proliferative activity against MCF-7 and HeLa cell lines.

Crystallographic and Theoretical Exploration of Weak Hydrogen Bonds in Arylmethyl N′-(adamantan-1-yl)piperidine-1-carbothioimidates and Molecular Docking Analysis

“…Figure 5 illustrates the structure of the energy framework as ladder-like, with horizontal and diagonal tubes connecting adjacent ladders. A similar topology has also been observed in the crystal structure of (Z)-3-(adamantan-1-yl)-S-(4-bromobenzyl)-1-(3-chlorophenyl)isothiourea 30 and in the closely related structure REMHID, as expected. In the ladder, the large vertical tubes correspond to intermolecular C−H•••S In the crystal structure of compound 1, the diameter of the cylindrical tubes for dispersion and the total interaction energies are comparable, which suggests that the dispersion energy component is predominant in the interaction energies of the molecular pairs.…”

“…The 3D structure of human sphingosine kinase 1 (SPHK1) was used as a target protein (PDB ID: 4V24) and prepared for docking as described earlier. 30 The location of the inhibitor PF-543 (PDB ligand ID: GYR) molecule was used to generate the receptor grid box. The compounds (1 and 2) were prepared for molecular docking using the LIGPREP module with an OPLS3e force field.…”

“…The structure and energetics of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-(4bromobenzyl)isothioureas have recently been described. 30 Further, an intramolecular C−H•••N interaction stabilizes the molecular conformation of these compounds. Different kinds of weak noncovalent interactions, such as C−H 37,38 C−H•••Br, 39 and lp•••π 40,41 interactions, play essential roles in the self-assembly of molecules in the solid state.…”

“…On the other hand, thiourea and isothiourea derivatives were proved to possess diverse chemotherapeutic activities, including anticancer, , antiviral, , antituberculosis, and antimalarial activities. Following an interest in the chemotherapeutic, − structural, and energetic properties of the weak noncovalent interactions − of adamantane-based derivatives, the title adamantane-isothiourea hybrid derivatives 1 and 2 were synthesized and proved to possess potent broad-spectrum antibacterial and antiproliferative activities …”

“…Further, a weak intermolecular C–H···S interaction generates a centrosymmetric dimer with the R 2 2 (14) ring. The structure and energetics of ( Z )-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)- S -(4-bromobenzyl)­isothioureas have recently been described . Further, an intramolecular C–H···N interaction stabilizes the molecular conformation of these compounds.…”