Archiv der Pharmazie最新文献

The MYC family of oncoproteins, a central regulator of cellular proliferation and metabolism, is aberrantly regulated in over 70% of human cancers, making them a significant target for therapeutic intervention. Yet, MYC intrinsically disordered conformation and exclusive nuclear localisation have led to its popularity as ‘undruggable’. This review provides an in-depth evaluation of the structure–activity relationship (SAR) of diverse small-molecule inhibitors designed to target the undruggable MYC. We highlighted a spectrum of chemical scaffolds, including indenoisoquinoline, dibenzoquinoxaline, isaindigotone, quindoline, berberine and iminobenzimidazole derivatives and many others. The described inhibitors act by two primary mechanisms: disrupting the essential MYC-MAX dimerisation and stabilising the c-Myc promoter G-quadruplex (G4) to suppress MYC transcription. Key SAR insights highlight the critical contributions in distinct structural motifs, including planar aromatic cores for π–π stacking, cationic side chains for electrostatic interactions and precisely positioned electron-donating or electron-withdrawing groups that determine inhibitory potency and selectivity. In silico docking studies highlighted the key interactions of the corresponding ligand molecules with the amino acid residues present within the active pocket of the MYC target. By systematically correlating chemical structure with biological activity across multiple classes through SAR and computational studies, this review establishes a robust framework to guide the rational development of next-generation MYC inhibitors with enhanced clinical potential.

Effective pain management in veterinary medicine often utilizes multi-drug formulations containing Metamizole sodium (MT), Paracetamol (PA), and Diclofenac (DI). However, severe spectral overlap makes their simultaneous quantification by spectrophotometry challenging, often requiring less green chromatographic methods. This study introduces AutoRegress, a novel Automated Machine Learning (AutoML) framework designed to overcome this limitation by automating the entire chemometric model development workflow. AutoRegress orchestrates a competitive evaluation of diverse regression algorithms and feature selection techniques, revealing that the optimal analytical model is analyte-specific—a key insight challenging the conventional ‘one-size-fits-all’ approach. The framework objectively identified a Lasso regression for MT, a non-linear Support Vector Regression (SVR) for PA, and a distinct Lasso model for DI. These tailored models demonstrated exceptional predictive accuracy (R² > 0.988) on an independent test set. By providing the robust computational solution needed to deconvolve the complex spectra, AutoRegress enables the use of a rapid, green analytical method. The primary contribution is a reproducible platform that automates complex model selection, provides deeper chemometric insights, and makes advanced analytical solutions more accessible for routine quality control.

Niflumic acid is a potent NSAID, while its long-term therapy can cause gastrointestinal complications. This study explores the prodrug approach of niflumic acid with natural antioxidant ethyl ferulate to improve its pharmacokinetics, thereby reducing gastrointestinal side effects. The primary objective was to develop niflumic acid prodrug with reduced gastric irritation, establish synthetic methods, characterize the prodrug, and evaluate their pharmacological activities. The prodrug was synthesized using the Steglich esterification method and characterized by IR, NMR, mass spectrometry, and elemental analysis. Further, in vitro hydrolysis, partition coefficient determination, protein binding studies, and in silico ADMET prediction were carried out. The pharmacological evaluation encompassed in vitro cytotoxicity assessments, anti-arthritic investigations, and in vivo studies on anti-inflammatory and ulcerogenic effects. The hydrolysis of the prodrug resulted in the release of niflumic acid in both simulated gastric fluid and simulated intestinal fluid, adhering to first-order kinetics, with a half-life of 230.4 min. Results showed that the prodrug exhibited higher lipophilicity, reduced gastric discomfort, and improved anti-inflammatory, cytotoxic, and anti-arthritic activities compared with niflumic acid. The bioconjugation of niflumic acid with ethyl ferulate significantly reduced gastrointestinal side effects while maintaining or enhancing therapeutic efficacy. The findings indicate that the synthesized prodrug represents a promising candidate for the advancement of safer and more effective anti-inflammatory therapies.

Acetylcholinesterase (AChE) is one of the most important therapeutic targets in the treatment of neurological disorders such as Alzheimer's disease. In recent years, studies on the use of carbonic anhydrase (CA) inhibitors in the treatment of Alzheimer's disease have attracted considerable attention. In this study, novel benzene/5-HMF-chalcone hybrids and their benzoate esters were synthesized. Furthermore, the AChE, carbonic anhydrases I and II (CA I and II) inhibition potentials of the compounds were evaluated through in vitro enzyme inhibition assays and molecular docking studies to identify new potential drug candidate molecules. According to the inhibition results, the K_i values of the synthesized compounds were found to be in the range of 1.51–2.91 nM against AChE, 26.15–68.66 nM against CA I, and 27.91–107.04 nM against CA II. Molecular docking studies revealed that the compounds bind to both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, with Glide scores ranging from –5.76 to –8.50 kcal/mol. In contrast, the molecules interacted with the active site of CA I/II by coordinating with the catalytic Zn²⁺ ion. All compounds complied with Lipinski's Rule of Five, indicating favorable drug-like properties. These results suggest that 5-HMF-chalcone hybrids and their benzoate derivatives could serve as promising scaffolds for the development of new anti-Alzheimer's agents. These findings suggest that 5-HMF-chalcone hybrids and their benzoate derivatives may be useful in establishing the structural basis of new anti-Alzheimer's agents.

The synthesis of azo-anchored imidazo[4,5-b]indoles represents a promising advancement in therapeutic and sensor technologies, offering significant potential in biomedical applications. This study presents a sustainable, high-yield approach grounded in green chemistry, employing minimal catalyst loading for ecological compatibility. The methodology involves condensing para-amino-functionalized azo benzene, aryl aldehydes, indoline-2,3-dione, and ammonium acetate using L-proline as a catalyst under ultrasonic irradiation at room temperature. The electrochemical characterization via. Cyclic voltammetry (CV) on a TiO₂.SiO₂-HMS/GCE electrode revealed enhanced electrocatalytic performance, with the effective surface area increasing from 0.031 cm² to 0.087 cm². Optimal activity was achieved at pH 6.54 with CTAB, providing a detection range of 1.0 × 10^–6 M to 5.0 × 10^–6 M, a detection limit of 1.50 × 10^–7 M, and a correlation coefficient of 0.992, indicative of irreversible reactions. Remarkably, DFT studies at the B3LYP/6-311 G level provided qualitative insights into the favorable electronic properties via. HOMO–LUMO analysis. Molecular docking predicted that compound 5(f) may interact favorably with the SARS-CoV-2 spike protein, showing better docking scores than Chloroquine and Hydroxychloroquine. Molecular dynamics (MD) simulations further confirmed the stability and persistence of these protein–ligand interactions over time. This prediction is further supported by its favorable pharmacokinetic profile and measurable in vitro cytotoxicity against HEK-293 cells, aligning computational findings with biological activity. This study highlights the dual functionality of these derivatives in sensor and therapeutic domains, adhering to green chemistry principles.

Paclitaxel is a frequently employed chemotherapeutic agent for nasopharyngeal carcinoma (NPC) patients, and tumor cell resistance to paclitaxel poses a significant challenge to NPC treatment. This study investigated the impact and potential mechanisms of folate-receptor 1 (FOLR1) on paclitaxel resistance in NPC cells. Levels of FOLR1 in NPC tissues and cells were measured using RT-qPCR. Protein expression was analyzed by Western blot. IC50 of paclitaxel-treated NPC cells was assessed by CCK-8. EdU and Colony formation assay detected cell proliferation. Apoptosis and pyroptosis were evaluated utilizing flow cytometry. Expression and localization of ITCH and FOLR1 were detected by immunofluorescence staining. Interaction between ITCH and FOLR1 was tested by co-immunoprecipitation (Co-IP). The immunoprecipitation assay evaluated FOLR1 ubiquitination levels. An NPC xenograft model was constructed in nude mice. FOLR1 was overexpressed in NPC and correlates with a poor prognosis in NPC patients. Low levels of cell pyroptosis and elevated FOLR1 expression were strongly associated with paclitaxel resistance in NPC. Knockdown of FOLR1 reduced the chemoresistance of 5–8 F/paclitaxel cells to paclitaxel. ITCH was associated with FOLR1 and enhanced its degradation through ubiquitination. ITCH reduced paclitaxel resistance in NPC cells via downregulation of FOLR1. FOLR1 increased resistance to paclitaxel by suppressing pyroptosis in NPC through an NLRP3-dependent mechanism. FOLR1 inhibited pyroptosis by inhibiting the mTOR pathway and promoting autophagy. Lowering FOLR1 expression suppressed tumor growth and boosted paclitaxel sensitivity in mice. FOLR1 plays a significant role in promoting chemoresistance of NPC cells to paclitaxel through NLRP3 signaling.

The emergence of the EGFR C797S mutation poses a significant challenge in the treatment of non-small cell lung cancer due to resistance to third-generation EGFR-tyrosine kinase inhibitors. This study introduces a novel and highly selective EGFR PROTAC, HBE-843, designed to degrade mutant EGFR while sparing wild-type EGFR. Our degrader not only effectively degrades the L858R but also shows promising activity against exon 19 deletion, T790M, and C797S, where it demonstrated low nanomolar GI₅₀ (26–103 nM) across all these EGFR mutant-harboring cell lines while sparing the wild-type. HBE-843 effectively reduced EGFR protein levels in mutant cells in a dose-dependent manner, with a DC₅₀ in the low nanomolar range (1.9–18 nM) and a D_max above 90%. Mechanistic studies showed that HBE-843 mediates EGFR degradation through the CRBN-associated proteasome pathway, preventing the activation of the ERK downstream signal and hindering cell growth. In vivo studies demonstrated a 112% tumor growth inhibition in L858R-induced cancers. These findings suggest that HBE-843 holds promise as a lead compound for developing new drugs to overcome C797S mutant-mediated resistance in clinical settings.

The Roseobacter clade, a versatile Rhodobacteraceae lineage, comprises up to 20% of marine bacteria and drives key biogeochemical cycles. Phaeobacter inhibens, a representative model species, is associated with the alga Emiliania huxleyi, exhibiting a dual lifestyle that alternates between promoting symbiotic growth and displaying pathogenicity during algal senescence. In this study, we investigated the metabolic responses of P. inhibens cultured with sinapic acid, an algal-derived lignin catabolite known to modulate algal–bacterial interactions. Detailed LC–MS/UV-guided analysis of the sinapic acid-treated culture identified 10 metabolites, including two new compounds, roseochelins C (1) and D (2). All isolated compounds were tested for anti-allergic effects in Th2 cell–mediated immune responses, and sinatryptin A (4) showed the strongest activity by reducing Th2 cytokine production and blocking Th2 differentiation through inhibition of the IL-4/STAT6–GATA3/IRF4 pathway. These findings expand the chemical diversity of algal–bacterial interactions, and anti-allergic assays of the isolated metabolites highlight the potential of Roseobacter-derived compounds as novel bioactive resources.