Supramolecular Networks of Picrate Derivatives with Tunable Hydrogen-bonding Densities for Selective Bacterial Killing
To address the broad challenge of antimicrobial resistance by bacterial pathogens, a series of substituted anilines/acid hydrazide co-crystallized with picric acid (HPA) was synthesized, structurally characterized and its biological activity examined: [An<sup>+</sup>---PA...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:dnet:ubarcelona__::ea1863038866ff024c95e40056e42e13 |
| Acceso en línea: | https://hdl.handle.net/2445/229440 |
| Access Level: | acceso embargado |
| Palabra clave: | Enllaços d&apos hidrogen Química supramolecular Bacteris Hydrogen bonding Supramolecular chemistry Bacteria |
| Sumario: | To address the broad challenge of antimicrobial resistance by bacterial pathogens, a series of substituted anilines/acid hydrazide co-crystallized with picric acid (HPA) was synthesized, structurally characterized and its biological activity examined: [An<sup>+</sup>---PA<sup>-</sup>] (<strong>1</strong>), [OAP<sup>+</sup>---PA<sup>-</sup>] (<strong>2</strong>), [OMe<sup>+</sup>---PA<sup>-</sup>] (<strong>3</strong>) and [CBH<sup>+</sup>---PA<sup>-</sup>] (<strong>5</strong>) (where An: Aniline, OAP: <em>o</em>-aminophenol, OMe: 4-methoxyaniline, CBH: 4-chlorobenzhydrazide). X-ray crystallographic analysis shows supramolecular 1/2-dimensional networks for <strong>1</strong>−<strong>3</strong> and a 3-dimensional architecture for <strong>5 </strong>(D…A of 2.6−2.8 Å for <strong>5</strong>) with the asymmetric unit comprising a 1:1 aminium-picrate pair, stabilized by hydrogen bonding and charge transfer. On the other hand, association of picric acid with 4-nitroaniline (NA) in 2:1 stoichiometry, [(HPA)<sub>2</sub>---NA] (<strong>4</strong>), does not show deprotonation of picric acid giving rise to a herringbone arrangement in soli state ruled by π-π stacking (~3.8 Å). Hirshfeld Surface Analysis shows that hydrogen bonding is the strongest intermolecular interaction between the species forming the cocrystals, suggesting as the driving force in their formation and stabilization. Systematic evaluation of broad-spectrum antibacterial activity against <em>Staphylococcus aureus</em> and <em>Escherichia coli</em> have established a significant structure-function correlation in their minimum inhibitory concentration dependences (1−1000 µg/mL), zone of inhibitions (5.9−28.1 mm), crystal violet staining and morphological analysis. Comparative FE-SEM profiles show a prominent damage of the naked peptidoglycan layer in the Gram-positive cell walls while moderate blebbing in the Gram-negative outermost membranes on 24h treatment with <strong>5</strong>. In conclusion, [CBH<sup>+</sup>---PA<sup>-</sup>] emerges out as the best bactericidal agent in this 5-membered family owing to its predominant hydrogen-bonding density in the supramolecular network aided by additional participation of the acyl oxygen. Hemolytic assay of <strong>5</strong> and <strong>3</strong> confirms their safety profile in humans on erythrocytes at MIC doses. Molecular docking simulations on AutoDock tool prove a DNA gyrase B-inhibiting pathway for killing bacterial cells, active site being the ATP binding pocket (PDB: <em>5D7R, Chain A</em>). Docking scores indicate the most favorable protein-ligand interaction for <strong>5</strong> (-10.02 kcal/mol) that largely comprises salt-bridges and conventional hydrogen bonding type non-covalent interactions and involving Arg144, Glu58 as key residues (1.86−2.1 Å). <em>In silico</em> DFT calculations on <strong>5</strong> and <strong>3</strong> gives the minimum HOMO−LUMO gap (0.398−0.822 eV) and the maximum electrophilicity (w)/chemical potential (µ) values for <strong>5 </strong>(94.18 eV / 6.12 eV) and <strong>3 </strong>(67.53 eV / 7.45 eV). ADMET analysis using the SwissADME web tool confirms its hydrophilic nature and inability to cross the blood-brain barrier, thus establishing its drug-likeliness. All results converge to 4-chlorobenzhydrazinium picrate as a lead compound for antibacterial drug development (MIC = 1 µg/mL) with a 200-fold selectivity index to <em>S. aureus</em>-mediated infections. Additionally, <strong>5</strong> is a promising co-drug as it enhances the antibiotic efficiency of ampicillin for Gram-positive pathogens. |
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