Universidade Regional do Cariri

Hydrazones are pharmacologically versatile compounds with emerging therapeutic potential. Here, we report the synthesis, structural characterization, and the anxiolytic potential of the hydrazone derived from hydralazine, (E)-1-(2-(pyridin-4-ylmethylene)hydrazineyl)phthalazine (HDZH4PIR). The molecular structure of the polycrystalline form of HDZH4PIR was confirmed by ¹H and ¹³C NMR, and structural confirmation of its crystalline form was carried out by single-crystal X-ray diffraction. The anxiolytic potential in the adult zebrafish model of HDZH4PIR in its crystal and polycrystal forms was evaluated by vivo and in silico studies. Both forms were well-tolerated up to 40 mg kg^-1 (LD₅₀ > 40 mg kg^-1), supporting safety for behavioral assays. In open-field tests, both forms reduced locomotion slightly without causing sedation. In the light/dark task, both forms showed diazepam-like anxiolytic activity, with distinct profiles: crystalline HDZH4PIR was most potent at 20-40 mg kg^-1 and acted via serotonergic (5-HT₁A) pathways. In contrast, polycrystalline HDZH4PIR showed a hormetic response and acted via GABA_A receptors. This mechanistic divergence was confirmed through antagonist profiling and molecular docking studies that showed that polycrystals bound strongly to the benzodiazepine site of GABA_A receptors (ΔG = -9.0 kcal mol^-1), while crystals preferred the 5-HT_1A orthosteric site (ΔG = -8.7 kcal mol^-1). ADMET predictions suggest that crystallization enhances safety but reduces oral bioavailability and blood-brain barrier permeability. In conclusion, HDZH4PIR is a promising dual-pathway anxiolytic candidate, with its crystalline form enhancing serotonergic modulation and its polycrystalline form targeting GABA_A receptors.

Understanding how metal-organic complexes behave under extreme conditions is crucial for designing advanced materials. Here, we present a comprehensive investigation of the [Cu(Bip)₂(Cl)]⁺ complex. Its structural properties were characterized by powder X-ray diffraction with Rietveld refinement. Additionally, the study incorporated High-pressure Raman spectroscopy (up to 7.5 GPa), which was complemented by density functional theory (DFT) calculations for accurate vibrational mode assignment, alongside Hirshfeld surface analysis. Our results reveal a gradual conformational phase transition in the [Cu(Bip)₂(Cl)]⁺ complex occurring between 1.0 and 4.0 GPa. This transition is primarily driven by changes in intermolecular interactions, including the emergence of a new CH stretching mode and subtle variations in the CuCl stretching mode. Notably, the molecular framework of the complex remains remarkably rigid, with only minimal pressure-induced shifts observed in its internal vibrational modes up to 7.5 GPa. This contrasts with pure pyridine, which undergoes significant structural changes under pressure. The enhanced rigidity of [Cu(Bip)₂(Cl)]⁺ stems from the distinct nature of its intermolecular forces: while hydrogen bonds in pyridine contribute to great mechanical strength, the van der Waals forces in [Cu(Bip)₂(Cl)]⁺ promote compressibility, enabling a progressive conformational transition rather than abrupt structural collapse. The structural reversibility and stability of the complex under pressure highlight its potential for applications in variable-pressure environments, such as sensors and optoelectronic devices.

The escalating antimicrobial resistance of Klebsiella pneumoniae poses a critical public health challenge, demanding innovative therapeutic strategies. This study investigated the antibacterial activity of eugenol (EOL) and its potential as a resistance-modulating agent when combined with conventional antibiotics-amoxicillin (AXL), azithromycin (AZT), cephalexin (CEF), and ciprofloxacin (CIP)-against clinical multidrug-resistant isolates. EOL exhibited intrinsic antibacterial activity with MIC values ranging from 1024 to 2048 μg/mL. Checkerboard assays revealed synergistic interactions between EOL and AXL or AZT (FICI ≤0.5), while combinations with CEF and CIP were indifferent. These synergistic effects were corroborated by growth inhibition curves, time-kill kinetics, and biofilm suppression assays, all of which demonstrated a marked reduction in bacterial viability and biofilm formation. Molecular docking and quantum mechanical calculations further elucidated the enhanced binding affinities and intermolecular interactions between AXL-EOL complexes and key resistance-related targets (KPC, LpxC, and particularly the quorum-sensing regulator SdiA), with interaction energies reaching up to -52.06 kcal/mol. Altogether, the findings underscore the potential of EOL as a potent adjuvant that augments the efficacy of conventional antibiotics, offering a promising pathway toward the development of targeted therapies against multidrug-resistant K. pneumoniae.