Acta Pharmaceutica最新文献

This study successfully generated magnetic N-doped carbon dots (CDs-MNPs) that exhibit two distinct functions: pH-responsive targeted drug delivery and powerful antioxidant action. The structural integrity, magnetic characteristics, and thermal stability of the samples were confirmed using comprehensive characterisation techniques, such as scanning electron microscopy, superconducting quantum interference device, Fourier Transform Infrared Spectroscopy, X-ray diffraction, continuous-wave electron para-magnetic resonance, X-ray photoelectron spectroscopy, surface porosity and thermogravimetric analysis. The CDs-MNPs displayed pH-dependent drug release profiles that conformed to zero-order, Higuchi, and Peppas models, demonstrating their ability to provide regulated release. The antioxidant activity of the carbon dots was assessed using the DPPH assay, where the radical scavenging capacity exceeded 80 %. This high level of activity was attributed to the synergistic effects of nitrogen doping and the functional groups present on the carbon dots. The biocompatibility of the specimen (up to 100 mg mL^-1), which is essential for biomedical applications, was confirmed by MTT assays. This study highlights the potential of CDs-MNPs as an effective option for therapeutic interventions, providing customised drug delivery and antioxidant advantages. The antibacterial activity of CDs-MNPs was evaluated against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus bacterial strains, demonstrating significant efficacy. These results highlight the potential of CD-based nanobactericides for applications in biomedical and food monitoring.

The aim of this study was to investigate the potential antidepressant-like effect of combined subthreshold and effective doses of chrysin and fluoxetine in adult male Wistar rats and their potential effects on the serotonergic and noradrenergic systems. Seventy rats were divided into seven experimental groups: vehicle (10 % dimethyl sulfoxide solution, DMSO), chrysin (4 or 20 µmol kg^-1), fluoxetine (1.6 and 3.2 µmol kg^-1), and their combinations. The treatments were administered for 28 consecutive days, and the effects were evaluated in the locomotor activity test (LAT) and forced swim test (FST). The results showed that the treatments did not significantly affect crossings in the LAT. Chrysin, alone or combined, reduced immobility time, increased latency to first immobility and prolonged swimming in the FST, similar to fluoxetine. However, only chrysin (20 µmol kg^-1) and its combination with fluoxetine (1.6 µmol kg^-1) enhanced climbing behaviour in the FST. Chrysin showed an anti-depressant effect, possibly related to enhanced serotonergic and noradrenergic neurotransmission, by increasing climbing and swimming time in the FST. This dual effect suggests a promising antidepressant prototype with different mechanisms of action, allow ing the use of subthreshold doses, which could reduce side effects.

The main protease 3CL^pro of the SARS-CoV-2 virus is a well--established therapeutic target for the treatment of COVID-19. In this study, we screened an in-house compound library and identified a series of α-heteroarylthiomethyl ketones as inhibitors of 3CL^pro. Among these, analogues 31 and 33 emerged as the most interesting candidates with IC ₅₀ values of 95.4 ± 3.1 and 95.0 ± 6.9 µmol L^{- 1}, respectively. Preliminary in vitro studies suggest a potential covalent mode of inhibition, although further studies are required to confirm this mechanism. These findings provide a new chemical scaffold for the development of 3CL^pro-targeting inhibitors.

The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins belong to a family of cytidine deami nases responsible for DNA and RNA sequence editing, playing pivotal roles in a wide range of biological processes, including immune responses, antiviral properties, and genetic mutations. In this work, we investigated the effect of SARS-CoV-2 structural proteins - Envelope (E), Spike (S), Nucleocapsid (N), Membrane (M) and protein ORF6 - on the expression of cytokines Interleukin 8 (IL-8) and Tumor Necrosis Factor-alpha (TNF-α), and APOBEC3s proteins (APOBEC3B and APOBEC3F) genes in Huh-7 and A549 human cell lines. While there is plenty of scientific evidence about the effects of SARS-CoV-2 on the inflammatory cascade, the current literature regarding the impact of SARS-CoV-2 on APOBEC expression is scarce. Our findings reveal a complex relationship between SARS-CoV-2 structural proteins and the host immune response, as certain viral structural proteins (S, M, E) modulate cytokine expression, potentially contributing to the dysregulated immune responses seen in COVID-19 patients. Additionally, our research uncovered interactions between viral proteins and APOBEC genes. This study contributes to a better understanding of the host-virus interactions in the context of SARS-CoV-2 infection and provides some insights into potential therapeutic targets for mitigating the immunopathological consequences of the disease.

A significant amount of data about the different pharmacological activities of the established antimicrobial compound nitroxoline (8-hydroxy-5-nitroquinoline) is available in the scientific literature. On the other hand, its regioisomer 8-hydroxy-6-nitroquinoline was never characterised biochemically and the same also applies to their 1,2,3,4-tetrahydroquinoline analogues. Herein, we determined the influence of pyridine ring saturation and the position of the nitro group on various biochemical characteristics of compounds, such as metal-chelating properties, inhibition of methionine aminopeptidases (MetAPs) from Mycobacterium tuberculosis and human MetAP2, as well as antibacterial activities on Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis. In addition, inhibition of endopeptidase and exopeptidase activities of cathepsin B was determined, together with the ability of new nitroxo-line analogues to reduce intracellular collagen IV degradation. Substantially different biological activities were observed for the 6-nitro regioisomer of nitroxoline, as well as for both of their partially saturated counterparts.

The voltage-gated potassium channel Kv1.3 is a key regulator of T-cell activation and a validated therapeutic target for autoimmune and inflammatory diseases. In this study, a ligand-based design strategy was employed to expand a library of benzamide-derived K_v1.3 inhibitors. Starting from a previously optimised thiophene-based inhibitor, structu ral modifications were introduced to the 2-methoxybenzamide moiety and the central tetrahydropyran or cyclohexane scaffold. A series of ketone, hydroxy, and carbamate derivatives was synthesised and evaluated for K_v1.3 inhibition using whole-cell patch-clamp electrophysiology. Structure-activity relationship analysis revealed that cis-isomers in the hydroxy series exhibited stronger activity than their trans counterparts, with some analogues displaying submicro-molar IC ₅₀ values. In the carbamate series, trans-isomers were generally more potent, with trans-18 and trans-16 achieving IC ₅₀ values of 122 and 166 nmol L-1, respectively. These results provide valuable insights into the design of K_v1.3 inhibitors and support further development of these compounds for immunomodulatory applications.

In the present work, we describe the design, synthesis, and evaluation of a galectin-8-binding fluorescent probe designed for a competitive fluorescence polarization (FP) assay for screening new galectin-8N inhibitors. The probe was characterized for its photophysical properties and its binding affinity for galectin-8N was determined by using FP. We evaluated the probe in a competitive FP assay with three known galectin-8N inhibitors and demonstrated its suitability for high-throughput screening.

Toll-like receptors (TLRs) are essential for the innate immune system as they recognize pathogen-associated molecular patterns and trigger immune responses. Overactivation of TLR8 by endogenous nucleic acids is associated with the development of autoimmune diseases and promotes inflammatory responses. This study presents the design, synthesis, and evaluation of a series of TLR8 antagonists based on the optimization of previously reported 6-(trifluoromethyl)pyrimidin-2-amines, with targeted modifications to further explore structure-activity relationships (SAR) and increase potency. A two-step synthesis involving nucleophilic aromatic substitution and Suzuki coupling was used to prepare two series of new compounds. The biological evaluation revealed that compounds 14 and 26 exhibited promising TLR8 antagonistic activity with IC ₅₀ values of 6.5 and 8.7 μmol L^{- 1}, respectively. Compound 14 showed reduced cell viability at higher concentrations, while compound 26 showed no cytotoxic effects, making it a promising candidate for further investigation.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading global health challenge, exacerbated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. One promising therapeutic target is the enzyme enoyl-acyl carrier protein reductase (InhA), which plays a vital role in the biosynthesis of mycolic acids, essential components of the bacterial cell wall. Direct inhibition of InhA offers a potential strategy for overcoming resistance mechanisms, particularly in cases where the activation of conventional drugs like isoniazid is compromised. This study investigates two novel series of InhA inhibitors based on thiadiazole and tetrahydropyran lead compounds, originally identified through high-throughput screening by GSK. Analogues were synthesised using the copper-catalysed azide-alkyne cycloaddition (CuAAC) click reaction, and their inhibitory activity was tested against InhA. Among the tested compounds, only one exhibited modest inhibitory activity, with an IC ₅₀ of 11 µmol L-1, while others were inactive. Interestingly, during the synthetic efforts, a novel reaction was discovered between aryl methyl ketones and ethynylmagnesium bromide, yielding 1,3-diols, as confirmed by X-ray diffraction analysis. These findings underscore the challenges of optimising InhA inhibitors and highlight the potential of synthetic innovations in exploring new synthetic pathways.

Famotidine, a widely used H₂-receptor antagonist, exhibits sensitivity to oxidative degradation, particularly in the presence of excipients containing peroxide impurities. This study explores the oxidative stability of famotidine under various storage conditions, with a specific focus on excipients with varying peroxide contents. A stability-indicating liquid chromatography-mass spectrometry (LC-MS) method was developed to identify and quantify famotidine degradation products, providing detailed insights into oxidative pathways. In addition, Zeneth software was employed to predict potential degradation products, and its predictive accuracy was evaluated against experimental findings. Antioxidants, including ascorbic acid, propyl gallate, and ethylenediaminetetraacetic acid (EDTA), were incorporated into compressed compatibility mixtures to assess their effects on peroxide-mediated degradation. While propyl gallate and EDTA consistently reduced peroxide levels and enhanced stability, ascorbic acid unexpectedly acted as a pro-oxidant under stress conditions, accelerating peroxide formation in povidone. These findings provide critical insights into mitigating oxidative degradation in famotidine and other solid dosage forms, emphasizing the importance of selecting appropriate excipients, antioxidants, and predictive tools to ensure product stability.