Archiv der Pharmazie最新文献

The current research investigates a new therapeutic strategy for the management of knee osteoarthritis (KOA). For this purpose, we developed mixed polymeric micelles (MPM) encapsulating a natural phytotherapeutic drug, vanillic acid (VA), for intra-articular (IA) delivery. The developed systems were characterized by their particle size profile, zeta potential, morphology, physical stability, and in vitro drug release. Cremophor was found to be an essential component for the production of MPM with optimum particle size profile, as well as maintaining an F127/Cremophor/TPGS weight ratio of 3:2:1. Coating the optimized formulation with hyaluronic acid (HA) provided a dual benefit of sustaining VA release and providing synergistic anti-osteoarthritic activity in an monosodiumiodoacetate-induced KOA model in rats. The proposed HA-coated MPM system encapsulating VA provides a promising strategy for the inhibition of KOA progression.

Carbazoles are an important class of aromatic compounds having numerous applications in pharmaceuticals, including anticancer, anti-inflammatory, and antibacterial activity. Traditional synthesis methods, while successful, frequently use toxic chemicals, hazardous solvents, and energy-intensive procedures, raising serious environmental problems. This study discusses current advances in green carbazole synthetic approaches, with a focus on environmentally friendly strategies such as microwave-assisted reactions, photoredox catalysis, and the use of recyclable metal catalysts such as gold and palladium. Sustainable techniques, such as solvent-free processes, aqueous systems, and renewable resources, are explored alongside mechanistic insights into improving atom economy and reducing waste. These changes, which incorporate green chemistry concepts, not only increase the sustainability of carbazole synthesis but also expand its therapeutic potential, paving the way for environmentally friendly advances in medicinal chemistry.

Pulmonary fibrosis (PF) is a progressive and fatal disease, and recent studies have revealed its key role in the autotaxin (ATX)-lysophosphatidic acid (LPA) signaling pathway, revealing the therapeutic potential of targeting ATX. Herein, starting from PAT-409, a series of novel ATX inhibitors containing the 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one core were designed to improve the pharmacological activity and physicochemical properties. The most promising compound 19 exhibited potent ATX inhibition (IC₅₀ = 4.2 nM) and significantly reduced lipophilicity (cLogP = 2.992) compared with PAT-409 (IC₅₀ = 4.9 nM, cLogP = 7.647). Molecular dynamics simulations indicated that 19 bound to the ATX protein in a highly stable manner. Furthermore, predictive analyses of drug-like properties and toxicity uncovered that 19 demonstrated comparable safety to PAT-409 while exhibiting significantly superior drug-like characteristics. This study provides a promising ATX inhibitor for PF therapy.

l-Ascorbic acid exhibits paradoxical behavior as both antioxidant and pro-oxidant in cancer treatment, with mechanisms and optimal dosing remaining unclear. This in vitro study investigated l-ascorbic acid's effects on healthy lymphocytes and HL-60 leukemia cells using concentrations of 0.5–2 mg/mL for 6 and 24 h. Analyses included cell viability, gene expression, DNA damage, mutagenicity, and oxidative stress markers. The results demonstrated a dose-dependent increase in the metabolic activity of HL-60 cells, with a ~ sixfold increase observed at 2 mg/mL (p ≤ 0.001), and opposing modulation of FAS/catalase gene expression between the two cell types. In healthy lymphocytes, both genes were suppressed with increasing exposure, while HL-60 cells exhibited significant early induction (29-fold for FAS and 47-fold for catalase, p ≤ 0.001). l-Ascorbic acid concentrations (0.5–2 mg/mL) exhibited no significant genotoxicity in healthy cells, increased antioxidant status in healthy lymphocytes, and elevated oxidative stress (a 1.4-fold increase in the oxidative stress index at 24 h, p ≤ 0.001) in HL-60 cells. Ames testing confirmed non-mutagenicity, while plasmid analysis revealed bimodal effects, being pro-oxidant at an intermediate dose and protective at a high dose. These findings suggest that l-ascorbic acid requires cell-type-specific application in hematological malignancies and may offer a therapeutic window in leukemia treatment protocols, providing a foundation for optimizing combination strategies with conventional chemotherapeutics.

Through applying the hybridization technique, new coumarin derivatives (2–17) were prepared with substitution at coumarin C-3 utilizing various heterocyclic derivatives, aiming to afford multi-target carbonic anhydrases (CAs) IX/XII and topoisomerase II (Topo II) inhibitors with potent antiproliferative activity. Eight different cell lines were used to evaluate the growth inhibition percentages (GI%) of cancer cells determined by coumarin analogues 1–17. Analogues 16 and 17 had the most substantial cytotoxic effects, achieving mean GI% of 86.59% and 85.74%, respectively, exceeding doxorubicin (Dox), which demonstrated a mean GI% of 69.15. Furthermore, the CAs IX/XII and Topo II inhibitory potentials for compound 17 were evaluated according to the protein expression analysis in the MG-63 cancer cells. Analogue 17 downregulated the expression of CA IX, CA XII, and Topo II proteins by 0.43-, 0.51-, and 0.56-fold change, respectively, indicating frontier inhibitory potentials. Additionally, analogue 17 achieved upregulation of apoptotic proteins (Caspases 3, 7, and 9, and BAX by 1.52-, 3.10-, 1.67-, and 1.90-fold change, respectively). On the contrary, compound 17 induced downregulation of the antiapoptotic proteins BCL-2, MMP2, and MMP9 by 0.44-, 0.38-, and 0.45-fold change, respectively. Besides, compound 17 achieved an arrest at the G0–G1 phase of the cell cycle and elevated the cellular levels from 65.75% of the control cells to 92.54%. Finally, three molecular docking processes of the superior analogue 17 toward CA IX, CA XII, and Topo II targets were performed to investigate its molecular interactions.

Nitazoxanide (NTZ), an FDA-approved drug, served as the framework for synthesizing 22 new broad-spectrum antimicrobial agents from 4-aminosalicylic acid via protection–deprotection, Staudinger reduction, Clauson–Kaas pyrrole synthesis, and nucleophilic substitution. These compounds were evaluated for antibacterial, antimycobacterial, and antitrypanosomal activities. Several compounds, particularly 10, 11, 13, and 22, surpassed the antibacterial activity of NTZ and its active metabolite tizoxanide (TIZ) against all tested pathogens, with MICs ranging from 1.025 to 9.81 μM. Compounds 10 and 13 were twice as potent as ciprofloxacin against Klebsiella pneumoniae, while 11 and 17 were equipotent against Pseudomonas aeruginosa (MIC 5.34 μM). Compounds 11 and 14 matched ciprofloxacin against Staphylococcus aureus (MIC 3.20 and 2.98 µM), whereas 13 and 21 were 1.5- and 2.5-fold more potent against Enterococcus faecalis, respectively. Compound 10 outperformed ciprofloxacin against Helicobacter pylori (MIC 1.025 μM). Compounds 6 (MIC 9.46 μM) and 7 (MIC 16.78 μM) outperformed NTZ against Mycobacterium tuberculosis, and compound 3 emerged as a promising antitrypanosomal agent (MICs 2.59–4.73 μg/mL) against six Trypanosoma species. Cytotoxicity and pharmacokinetic studies confirmed the compounds’ favorable drug-like properties and high selectivity. Docking results showed strong binding to key targets like pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS), dihydrofolate reductase (DHFR), and ornithine decarboxylase (ODC). Overall, several NTZ derivatives, particularly compounds 3, 6, 10, 11, 13, and 22, showed potent broad-spectrum antimicrobial activity and offer convenient leads for further optimization.

The SARS-CoV-2 pandemic has spurred global efforts to develop therapeutic approaches. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and a key target for therapeutic development. In this study, 22 thiosemicarbazone derivatives were synthesized. Enzyme activity assays showed compound 3c exhibited obvious inhibition of Mpro, with an IC₅₀ value of 3.89 μM. The interaction mechanisms between thiosemicarbazone derivatives and Mpro were investigated using synchronous fluorescence, three-dimensional fluorescence, and circular dichroism spectroscopy. The fluorescence results indicate that static quenching is predominant. The equilibrium dissociation constant (K_d) of 2.3 μM between 3c and Mpro was obtained by microscale thermophoresis. This K_d value demonstrates the binding affinity of 3c for Mpro, consistent with the spectral results. Meanwhile, the binding modes and stability of thiosemicarbazone derivatives with Mpro were evaluated through molecular docking and molecular dynamics simulations, which also confirmed the stable binding between compound 3c and Mpro. This study provides valuable insights into the interaction mechanism between thiosemicarbazone derivatives and Mpro and provides clues for the design of Mpro inhibitors.

Inhibiting the p53-MDM2 interaction restores the function of the tumour suppressor protein, p53, and offers a promising avenue for anticancer therapies. Herein, a novel series of pyrazoline-derived compounds was developed and synthesised to serve as potential inhibitors of the p53-MDM2 interaction. Scaffold hopping was adopted via replacing the cis-imidazoline core of Nutlin-2 with a pyrazoline core, and molecular docking confirmed the binding orientation of the designed compounds at the p53-MDM2 interaction site. The antiproliferative activities of these compounds were evaluated against the NCI60 cell lines, where compounds 6c, 6d and 9d displayed the highest inhibitory activities. Subsequently, compound 6d was selected for the five-doses NCI60 cell panel assay to afford a mean GI₅₀ value of 8.39 μM. Moreover, 6d significantly reduced MDM2 expression and elevated the expression of p53 in an ELISA-based assay, yielding a biochemical IC₅₀ value of 13.8 μM against MDM2, which was confirmed by Western blot as well. Cytotoxicity study confirmed the selectivity of 6d towards cancerous cell lines over normal cell lines. Additionally, X-ray crystallography was used to check the stereochemistry of compound 6d. These newly identified MDM2 inhibitors represent promising candidates for the development of novel targeted anticancer agents.

Renal ischemia/reoxygenation triggers uremic encephalopathy (UE), culminating in cognitive and neural derangements. Despite its neuroprotective functions, the hippocampal repercussion of the estrogen receptor G protein-coupled estrogen receptor 1 (GPER1) in UE remains uncharted, alongside the prospective involvement of RUNX2. In Silico virtual screening suggested that prunetin (PRU) may activate GPER1 and inhibit RUNX2. To validate these findings in vivo, male Sprague Dawley rats were allocated into five groups: placebo-surgery (PS), PRU-treated PS, untreated UE, PRU-treated UE, and UE pretreated with G-15 (a selective GPER1 blocker) before PRU. Biochemically, PRU significantly restored hippocampal structure and behavioral functions impaired by UE, reduced serum IS levels, and replenished GPER1 expression. Additionally, it suppressed p-AKT, p-GSK3β, RUNX2, TLR4, and NF-κB, while enhancing cell survival by silencing the necroptotic signal (TICAM1/RIPK1/RIPK3/MLKL) and restoring caspase-8. PRU also counteracted mitochondrial dysfunction by downregulating PGAM5 and p-DRP-1. Crucially, these beneficial effects were nullified by G-15, confirming the role of activated GPER1 in mediating PRU's therapeutic effects. Collectively, PRU-induced GPER1 orchestrated neural integrity signal UE/AKT/GSK-3β/RUNX2, inflammatory axis UE/TLR-4/NF-κB, necroptosis pathway (TICAM1/RIPK1/RIPK3/MLKL), preventing mitochondrial dysfunction by suppressing the PGAM5/DRP-1 cue. These findings highlight the therapeutic potential of PRU in treating UE-related hippocampal damage through GPER1 activation.