Journal Article

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

Piro, Oscar E., Echeverria, Gustavo A., Lamberti, Yanina A., Gómez Castaño, Jovanny A., Nossa González, Diana L., Erben, Mauricio F., Saeed, Aamer

2025

Overview

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). A series of adamantyl‐based acyl thioureas with trihalophenyl groups is characterized using spectroscopic, computational, and crystallographic methods. Strong intramolecular hydrogen bonds and stable S‐shaped conformations are identified. Crystal packing is influenced by hydrogen bonding and π‐stacking interactions. While antimicrobial activity is limited, the compounds exhibit moderate cytotoxicity against lung and skin cell lines (IC50 = 25–100 μM).

• Subject: acyl thiourea / Adamantane - chemistry / Adamantane - pharmacology / Anti-Bacterial Agents - chemical synthesis / Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - pharmacology / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / conformations / Crystallography, X-Ray / cytotoxicity / Density Functional Theory / Humans / Hydrogen Bonding / Microbial Sensitivity Tests / Molecular Conformation / Molecular Structure / spectroscopy / Structure-Activity Relationship / structures / Thiourea - analogs & derivatives / Thiourea - chemistry / Thiourea - pharmacology