Issue 48, 2023, Issue in Progress

A combined crystallographic and theoretical investigation of noncovalent interactions in 1,3,4-oxadiazole-2-thione-N-Mannich derivatives: in vitro bioactivity and molecular docking

Abstract

Two 1,3,4-oxadiazole-2-thione-N-Mannich derivatives, specifically 5-(4-chlorophenyl)-3-[(2-trifluoromethylphenylamino)methyl]-1,3,4-oxadiazole-2(3H)-thione (1) and 5-(4-chlorophenyl)-3-[(2,5-difluorophenylamino)methyl]-1,3,4-oxadiazole-2(3H)-thione (2), were synthesized and then characterized by elemental analysis and NMR (1H and 13C) spectroscopy and the single crystal X-ray diffraction method. The formed weak intermolecular interactions in the solid-state structures of these derivatives were thoroughly investigated utilizing a variety of theoretical tools such as Hirshfeld surface analysis and quantum theory of atoms in molecules (QTAIM). Furthermore, the CLP-PIXEL and density functional theory calculations were used to study the energetics of molecular dimers. Numerous weak intermolecular interactions such as C–H⋯S/Cl/F/π interactions, a directional C–Cl⋯Cl halogen bond, π-stacking, type C–F⋯F–C contact and a short F⋯O interaction, help to stabilize the crystal structure of 1. Crystal structure 2 also stabilizes with several weak intermolecular contacts, including N–H⋯S, C–H⋯N//Cl/F interactions, a highly directional C1–Cl1⋯C(π) halogen bond and C(π)⋯C(π) interaction. In vitro antimicrobial potency of compounds 1 and 2 was assessed against various Gram-positive and Gram-negative bacterial strains and the pathogenic yeast-like Candida albicans. Both compounds showed marked activity against all tested Gram-positive bacteria and weak activity against Escherichia coli and lacked inhibitory activity against Pseudomonas aeruginosa. In addition, compounds 1 and 2 displayed good in vitro anti-proliferative activity against hepatocellular carcinoma (HepG-2) and mammary gland breast cancer (MCF-7) cancer cell lines. Molecular docking studies revealed the binding modes of title compounds at the active sites of prospective therapeutic targets.

Graphical abstract: A combined crystallographic and theoretical investigation of noncovalent interactions in 1,3,4-oxadiazole-2-thione-N-Mannich derivatives: in vitro bioactivity and molecular docking

Supplementary files

Article information

Article type
Paper
Submitted
21 Oct 2023
Accepted
15 Nov 2023
First published
21 Nov 2023
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2023,13, 34064-34077

A combined crystallographic and theoretical investigation of noncovalent interactions in 1,3,4-oxadiazole-2-thione-N-Mannich derivatives: in vitro bioactivity and molecular docking

L. H. Al-Wahaibi, K. Alagappan, R. M. Gomila, O. Blacque, A. Frontera, M. J. Percino, A. A. El-Emam and S. Thamotharan, RSC Adv., 2023, 13, 34064 DOI: 10.1039/D3RA07169C

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