The discovery of antibiotics with novel structures is a crucial strategy to combat antibiotic resistance. This study was motivated by the reported antibacterial activity of local anesthetics. Dyclonine hydrochloride, which shows the highest antibacterial activity among local anesthetics, was selected as the structural scaffold. Based on the structural characteristics of quaternary ammonium salt antibiotics, a series of dyclonine quaternary ammonium salt derivatives were designed and synthesized, and their analgesic and antibacterial activities were evaluated. The target compounds exhibited almost no analgesic effect but generally showed varying degrees of antibacterial effects against Gram-positive bacteria. Compound 17, the most potent derivative, had a minimum inhibitory concentration (MIC) of 0.5 μg/mL against S. aureus (MIC of amoxicillin against S. aureus: 2 μg/mL; MIC of dyclonine hydrochloride against S. aureus: 64 μg/mL). Further animal experiments demonstrated that compound 17 displayed excellent in vivo antibacterial activity. In addition, the preliminary action mechanism of compound 17 was studied using membrane depolarization assays, confirming that compound 17 exerted antibacterial effects by acting on bacterial cell membranes. In summary, this study identifies the β-aminoketone quaternary ammonium salt as a promising core structure for further antibiotic development.

The overuse of antibiotics has led to widespread bacterial resistance, and developing antibiotics with novel structural scaffolds is a crucial strategy to address this challenge. Based on the antibacterial potential of local anesthetics, this study selected dyclonine - the one with the highest antibacterial activity - as the parent scaffold, and designed and synthesized two series of β-aminoketone-based twin-drugs using a symmetrical twin-drug design. Their analgesic and antibacterial activities were evaluated. Structure-activity relationship (SAR) analysis revealed that the linker chain length is a critical determinant of antibacterial activity. In vitro assays showed that compound I-9 exhibited potent antibacterial activity (MIC = 2 μg/mL against S. aureus), low hemolytic activity (HC50 > 1280 μg/mL), and a rapid bactericidal effect, which was associated with membrane depolarization. Furthermore, in vivo evaluation in a mouse abscess model demonstrated that compound I-9 had stronger antibacterial activity than vancomycin. In conclusion, compound I-9 is a promising novel antibiotic candidate worthy of further research, and this study provides a new structural scaffold for the design of new antibiotics.

For more than sixty years, the piperidinopropiophenone derivative dyclonine is used as a local anesthetic in human and veterinary medicines. Dyclonine-containing drugs (Dyclone, DycloPro) have been developed as anti-itching medications and pain relievers in dermatology and dentistry. The product is used also as a protectant of mucosal surfaces to facilitate endoscopic examination. In the present review, the history of dyclonine is retraced and its multiple pharmaceutical usages are discussed. Synthetic strategies to obtain dyclonine are summarized. The goal of this study was also to analyze all pharmacological activities of the drug and its molecular targets. Dyclonine is considered a potent and selective antagonist of TRPV3 channels but it inhibits also histone methyltransferase G9a, aldehyde dehydrogenase 2 (ALDH2) and a few other proteins. The contribution of these targets to the drug activities is discussed. The better knowledge of the pharmacology of dyclonine has raised novel opportunities to use the drug for the treatment of neurodegenerative diseases, notably Parkinson disease and Friedreich's ataxia, and to combat drug-resistant cancers, such as chemo-resistant head and neck squamous cell carcinoma and glioblastoma. Preliminary evidence for the activity of dyclonine-containing drug combinations to treat multiple myeloma and solid tumors are discussed. An overview of dyclonine pharmacology is offered. This unsung drug has not finished talked about it.

Oligodendrocytes are critical for CNS myelin formation and are involved in preterm-birth brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatments. We present a pharmacogenomic approach that identifies compounds with potent pro-oligodendrogenic activity, selected through a scoring strategy (OligoScore) based on their modulation of oligodendrogenic and (re)myelination-related transcriptional programs. Through in vitro neural and oligodendrocyte progenitor cell (OPC) cultures, ex vivo cerebellar explants, and in vivo mouse models of PBI and MS, we identify FDA-approved leucovorin and dyclonine as promising candidates. In a neonatal chronic hypoxia mouse model mimicking PBI, both compounds promote neural progenitor cell proliferation and oligodendroglial fate acquisition, with leucovorin further enhancing differentiation. In an adult MS model of focal de/remyelination, they improve lesion repair by promoting OPC differentiation while preserving the OPC pool. Additionally, they shift microglia from a pro-inflammatory to a pro-regenerative profile and enhance myelin debris clearance. These findings support the repurposing of leucovorin and dyclonine for clinical trials targeting myelin disorders, offering potential therapeutic avenues for PBI and MS.

Recurrent oral ulcers are common oral mucosal lesions that severely reduce patients' quality of life. Commercial mucoadhesive films are easily disrupted due to oral movement and complex wet environments, thus reducing drug utilization and even causing toxic side effects. Herein, we report a mucoadhesive film composed of Ca[2+]-crosslinked carboxymethylated cellulose nanofibers and alginate, in which two drugs of dexamethasone (DXM) and dyclonine hydrochloride (DYC) are loaded for the treatment of oral ulcers. The wet films have a high Young's modulus of 7.1 ± 2.6 MPa and a large strain of 53.6 ± 9.8 % and adhere to tissue strongly, which allows them to resist the deformation caused by frequent oral movement. The films also have nice durability against water and excellent biocompatibility. Moreover, the drug release was controlled at different rates. The fast release of DYC facilitates the quick relief of pain, while the slow release of DXM benefits the long-term treatment of wounds. Finally, the animal experiment demonstrates the films displayed excellent therapeutic efficacy in healing oral ulcers.

Background: Cod liver oil has anti-inflammatory properties and could help regulate recurrent aphthous stomatitis (RAS). An orthogonal experiment was used to evaluate and improve the dosage form of compound cod liver oil, which has replaced the previously used liniment preparation based on film method. Methods: An orthogonal experiment was adopted, and the appearance and film-forming time of the film coating agents were used as indicators. The optimal ratio in the preparation process for the compound cod liver oil film agent was then optimized. A method for determination of compound cod liver oil film was established using High-Performance Liquid Chromatography (HPLC). Results: The results indicate that the blank films prepared using 55 mg polyvinyl alcohol (PVA) (PVA low), 45 mg of PVA (PVA medium), and 10 mg glycerol had the optimal performance, which was defined as PVAa. The drug-carrying film prepared from 3 mL PVAa (i.e., film-forming material with the optimal proportion), 30 mg dexamethasone acetate, and 30 mg metronidazole had the optimal performance. The verified sample has a complete and smooth appearance, uniform thickness and color, and no evident bubbles, which meets the requirements for a film agent defined in the Chinese Pharmacopoeia, 2020 edition. HPLC was used to determine the major components: dexamethasone acetate, metronidazole, and dyclonine hydrochloride, and the optimal separation effect was obtained. The method has advantages of good specificity, good linear results, high recovery rate, and good repeatability. Conclusion: This study proposes an optimized compound cod liver oil film former agent and preparation method. The results indicate that the compound cod liver oil film former agent had good performance, reflecting the high feasibility of this research method. The detection method of compound cod liver oil film was established by HPLC. The method was feasible, and the validity and stability of the formulation and preparation technology were guaranteed. The role of the newly developed agent in patients with RAS should be investigated further.

NAC transcription factors (TFs) are one of the largest TF families in plants, and TaNACs have been known to participate in the regulation of the transcription of many yield-regulating genes in bread wheat. The TaCKX gene family members (GFMs) have already been shown to regulate yield-related traits, including grain mass and number, leaf senescence, and root growth. The genes encode cytokinin (CK) degrading enzymes (CKXs) and are specifically expressed in different parts of developing wheat plants. The aim of the study was to identify and characterize TaNACs involved in the cis-regulation of TaCKX GFMs. After analysis of the initial transcription factor data in 1.5 Kb cis-regulatory sequences of a total of 35 homologues of TaCKX GFMs, we selected five of them, namely TaCKX1-3A, TaCKX22.1-3B, TaCKX5-3D, TaCKX9-1B, and TaCKX10, and identified five TaNAC genes: TaNACJ-1, TaNAC13a, TaNAC94, TaNACBr-1, and TaNAC6D, which are potentially involved in the cis-regulation of selected TaCKX genes, respectively. Protein feature analysis revealed that all of the selected TaNACs have a conserved NAC domain and showed a stable tertiary structure model. The expression profile of the selected TaNACs was studied in 5 day-old seedling roots, 5-6 cm inflorescences, 0, 4, 7, and 14 days-after-pollination (DAP) spikes, and the accompanying flag leaves. The expression pattern showed that all of the selected TaNACs were preferentially expressed in seedling roots, 7 and 14 DAP spikes, and flag leaves compared to 5-6 cm inflorescence and 0 and 4 DAP spikes and flag leaves in Kontesa and Ostka spring wheat cultivars (cvs.). In conclusion, the results of this study highlight the potential role of the selected TaNACs in the regulation of grain productivity, leaf senescence, root growth, and response to various stresses.