Crystal structure, Hirshfeld surface analysis and DFT studies of 5-(adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole, a potential 11\u03b2-HSD1 inhibitor

Lamya H Al-Wahaibi,Ali A El-Emam,Jacques Joubert,Nora H Al-Shaalan,Olivier Blacque

doi:10.1038/s41598-019-56331-z

Abstract

5-(Adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole (4) was identified as a potential 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor and this paper describes the in-depth structural analysis thereof. Compound 4 was synthesized in a 92% yield and its 3D-structure confirmed by single-crystal X-ray diffraction. Hirshfeld surface analysis indicated that H…H, C-H…C, C-H…Cl and especially C-H…N hydrogen bond interactions are the primary contributors to the intermolecular stabilisation in the crystal. In order to explore the properties of 4, free from the influence of the crystal field, density functional theory (DFT) calculations were conducted. Results indicated that the DFT optimized geometry of 4 produced a conformer (4a) that is significantly different from the crystal structure. Further experiments confirmed that the crystal structure is not the absolute minimum conformation. This indicated that the crystal packing forces has significantly influenced the conformation thereof. Frontier molecular orbital energies and net atomic charges were also calculated to elucidate the electronic properties of 4a. These results provided insight into areas of the molecule that may present with the ability to form binding interactions at the 11β-HSD1 active site. Molecular docking experiments revealed important intermolecular interactions between 4a and 11β-HSD1. These results indicate that 4 may be considered for further drug design endeavors.

Highlights

The insertion of an adamantyl moiety into various bioactive molecules leads to compounds with relatively higher lipophilicity, which in turn results in modification of their bioavailability and modulates their therapeutic indices[1,2,3]
In continuation of our on-going interest in the structural studies and biological application of adamantane derivatives[23,24,25,26,27], we report the crystal structure, Hirshfeld surface analysis, density functional theoretical studies and electronic properties of the title adamantane-triazole hybrid derivative 4
Molecular docking experiments at the 11β-HSD1 active site were conducted in order to predict the potential 11β-HSD1 binding affinity and binding interactions of 4

Summary

Introduction

The insertion of an adamantyl moiety into various bioactive molecules leads to compounds with relatively higher lipophilicity, which in turn results in modification of their bioavailability and modulates their therapeutic indices[1,2,3]. These hydrogen bonds add to the potential stability of the molecules within the crystal field and enables the formation, in addition to other short range contacts (Fig. 4b), of the three-dimensional network structure. The Hirshfeld surface and subsequent fingerprint plots were calculated to quantify the intermolecular contacts present within the crystal structure of compound 429,30.

Results

Conclusion