Background/Objectives: This study investigates the use of natural deep eutectic solvents (NADESs) in enhancing the solubility and skin permeation of a lidocaine base, a lipophilic form, in hydrogel systems. The aim was to develop an environmentally sustainable and biocompatible alternative to conventional lidocaine formulations, improving the dermal permeation and therapeutic efficacy. Methods: The lidocaine base was dissolved in a hydrophilic NADES system composed of choline chloride and citric acid, facilitating enhanced solubility, likely through new molecular interactions. Then, pH-adjusted hydrogels were formulated and optimized by employing a 3² full factorial design. Raman and nuclear magnetic resonance (NMR) spectroscopy were applied to evaluate the stability of lidocaine in the optimal formulation. The biopharmaceutical properties were investigated using in vitro drug release and skin permeation studies. In vivo tests assessed physiological skin parameters such as the hydration and transepidermal water loss. Results: The developed NADES-containing hydrogel significantly improved the solubility and stability of lidocaine. Skin permeation studies demonstrated enhanced dermal permeation compared with conventional hydrogel and ointment. These improvements, namely the enhanced solubility of lidocaine in the formulation and its increased permeation, were attributed to the dual effect of the NADES. Conclusions: NADES-containing hydrogels represent a promising green technology for formulating lidocaine-containing dermal preparations. This approach offers a biocompatible, natural-based alternative that can enhance the bioavailability and efficacy of topical anesthetics.

Background/Objectives: Research on cyclodextrin-based metal-organic frameworks (CD-MOFs) is still in its infancy, but their potential for use in drug delivery—expressly in the lung—seems promising. We aimed to use the freeze-drying method to create a novel approach for preparing CD-MOFs. MOFs consisting of γ-cyclodextrin (γCD) and potassium cations (K⁺) were employed to encapsulate the poorly water-soluble model drug Ibuprofen (IBU) for the treatment of cystic fibrosis (CF). Methods: Using the LeanQbD^® software (v2022), we designed the experiments based on the Quality by Design (QbD) concept. According to QbD, we identified the three most critical factors, which were the molar ratio of the IBU to the γCD, incubation time, and the percentage of the organic solvent. light-, scanning electron microscope (SEM) and laser diffraction were utilized to observe the morphology and particle size of the samples. In addition, the products were characterized by Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR). Results: Based on characterizations, we concluded that a γCD-MOF/IBU complex was also formed using the freeze-drying method. Using formulations with optimal aerodynamic properties, we achieved 38.10 ± 5.06 and 47.18 ± 4.18 Fine Particle Fraction% (FPF%) based on the Andersen Cascade Impactor measurement. With these formulations, we achieved a fast dissolution profile and increased IBU solubility. Conclusions: This research successfully demonstrates the innovative use of freeze-drying to produce γCD-MOFs for inhalable IBU delivery. The method enabled to modify the particle size, which was crucial for successful pulmonary intake, emphasizing the need for further investigation of these formulations as effective delivery systems.

Chronic kidney disease (CKD) is associated with anxiety; however, its exact mechanism is not well understood. Therefore, the aim of the present study was to assess the effect of moderate CKD on anxiety in rats. 5/6 nephrectomy was performed in male Wistar rats. 7 weeks after, anxiety-like behavior was assessed by elevated plus maze (EPM), open field (OF), and marble burying (MB) tests. At weeks 8 and 9, urinalysis was performed, and blood and amygdala samples were collected, respectively. In the amygdala, the gene expression ofAvpand the gene and protein expression ofCrh,Crhr1, andCrhr2were analyzed. Furthermore, the plasma concentration of corticosterone, uremic toxins, and tryptophan metabolites was measured by UHPLC-MS/MS. Laboratory tests confirmed the development of CKD. In the CKD group, the closed arm time increased; the central time and the total number of entries decreased in the EPM. There was a reduction in rearing, central distance and time in the OF, and fewer interactions with marbles were detected during MB. CKD evoked an upregulation of gene expression ofCrh,Crhr1, andCrhr2, but notAvp, in the amygdala. However, there was no alteration in protein expression. In the CKD group, plasma concentrations of p-cresyl-sulfate, indoxyl-sulfate, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, xanthurenic acid, 5-hydroxyindoleacetic acid, picolinic acid, and quinolinic acid increased. However, the levels of tryptophan, tryptamine, 5-hydroxytryptophan, serotonin, and tyrosine decreased. In conclusion, moderate CKD evoked anxiety-like behavior that might be mediated by the accumulation of uremic toxins and metabolites of the kynurenine pathway, but the contribution of the amygdalar CRH system to the development of anxiety seems to be negligible at this stage.

KYNAs, a compound with endogenous neuroprotective functions and an indole that is a building block of many biologically active compounds, such as a variety of neurotransmitters, are reacted in a transformation building upon Mannich bases. The reaction yields triarylmethane derivatives containing two biologically potent skeletons, and it may contribute to the synthesis of new, specialised neuroprotective compounds. The synthesis has been investigated via two procedures and the results were compared to those of previous studies. A possible alternative reaction route through acid catalysis has been established.

Alkoxyalkylation and hydroxyalkylation methods utilizing oxo-compound derivatives such as aldehydes, acetals or acetylenes and various alcohols or water are widely used tools in preparative organic chemistry to synthesize bioactive compounds, biosensors, supramolecular compounds and petrochemicals. The syntheses of such molecules of broad relevance are facilitated by acid, base or heterogenous catalysis. However, degradation of the N-analogous Mannich bases are reported to yield alkoxyalkyl derivatives via the retro-Mannich reaction. The mutual derivative of all mentioned species are quinone methides, which are reported to form under both alkoxy- and aminoalkylative conditions and via the degradation of the Mannich-products. The aim of this review is to summarize the alkoxyalkylation (most commonly alkoxymethylation) of electron-rich arenes sorted by the methods of alkoxyalkylation (direct or via retro-Mannich reaction) and the substrate arenes, such as phenolic and derived carbocycles, heterocycles and the widely examined indole derivatives.

Background: 8-Hydroxyquinoline and phthalimide are two significant heterocyclic scaffolds in medicinal chemistry due to their pharmacological profiles. Hybridizing these pharmacophores and further modifying them via modified Mannich reactions provides a strategy to improve their physicochemical parameters and selectivity toward multidrug-resistant (MDR) cancer cells. Objectives: To synthesize a series of 8-hydroxyquinoline–phthalimide hybrids and their Mannich base derivatives and evaluate their cytotoxic activity and resistance-selective properties against sensitive Colo205 and resistant Colo320 cancer cell lines. Methods: Four hybrid compounds were synthesized by reacting 5-amino-8-hydroxyquinoline with different phthalic anhydride derivatives. Twelve fine-tuned derivatives were prepared by using the modified Mannich reaction. Cytotoxic activity was measured using the MTT assay, and relative resistance (RR) was calculated to determine selectivity toward the resistant cell line. P-glycoprotein (Pgp) ATPase activity was evaluated for the most active compounds. Results: All derivatives displayed cytotoxic activity, with higher potency toward the resistant Colo320 cell line. Compounds 2 and 4 showed the strongest activity against both cell lines (IC₅₀ down to 4.88 µM). Compounds 5, 8a, 9a, and 9c retained potent activity against Colo320 (IC₅₀ = 9.89–22.79 µM). Incorporating a CH₂–N group at position C7 substantially enhanced the selectivity for MDR cells. Compounds 9c, 9a, and 8a exhibited the highest selectivity, with RR values of 0.29, 0.33, and 0.35, respectively. Compounds 2, 4, 5, 8a, and 9a showed inhibitory effects on Pgp ATPase activity. Conclusions: The newly synthesized HQ–phthalimide hybrids represent promising candidates for targeting MDR in colorectal cancer, with Mannich modification enhancing the selectivity toward resistant cells.