Structural and Conformational Analysis and Biological Activity of Adamantyl-Based Acyl-Thioureas Bearing Trihalophenyl Substituents

Abstract

A series of six closely related acyl thiourea derivatives featuring adamantyl/noradamantyl groups at the 1-acyl position and 3-trihalophenyl substituents at the thiourea moiety are comprehensively characterized through spectroscopic, computational, and X-ray crystallographic methods. Vibrational spectroscopy (IR and Raman) reveals significant redshifts in the NH and CO stretching bands, confirming the presence of strong intramolecular NH···OC hydrogen bonds. Conformational analysis using molecular mechanics and DFT calculations identifies several conformers, with the most stable adopting an S-shaped geometry where the CO and CS bonds are oppositely oriented—a configuration that was experimentally validated by single-crystal X-ray diffraction. In the solid state, crystal packing is governed by hydrogen-bonding interactions (H···OC and H···SC) facilitated by the acyl-thiourea core. The bulky adamantyl/noradamantyl groups impose steric constraints, whereas the halogenated phenyl rings promote stabilizing π-stacking and halogen interactions. Biological evaluation demonstrates limited antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Burkholderia cenocepacia, and Staphylococcus aureus, but moderate cytotoxicity against A549, 16HBE14o-, and HaCaT cell lines (IC₅₀ = 25–100 μM).