Archiv der Pharmazie最新文献

Neglected tropical diseases remain a major global health challenge, highlighting the need for new antiparasitic agents. In this study, a series of substituted 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperidine-4-carboxamides was designed, synthesized, and evaluated for in vitro antileishmanial and antitrypanosomal activity. Compound 18 emerged as the most promising derivative, showing submicromolar activity against all tested parasites with acceptable selectivity toward THP-1 cells. Mechanistic studies in T. b. brucei bloodstream cells revealed a reversible cytostatic effect rather than apoptosis, and assessment of cellular and mitochondrial ROS levels indicated that oxidative stress was not a primary contributor to activity. In silico ADME analysis supported the drug-likeness of the synthesized compounds. Taken together, these findings identify 18 as a valuable lead for further antiparasitic drug development.

This study reports the synthesis of some novel chalcone (C1-C3) and 3,5-disubstituted pyrazoline derivatives (P1-P3), structurally based on aminophenyl and trifluoromethylphenyl groups. Their potential as antidiabetic agents was evaluated through in vitro inhibition of α-amylase and α-glucosidase enzymes and supported by molecular docking studies. Among all the compounds, P2 showed potent dual inhibition, with IC₅₀ values of 9.35 and 2.10 µM against α-amylase and α-glucosidase, respectively, comparable to or better than the standard inhibitor acarbose. Kinetic studies revealed that P2 acts via a non-competitive mechanism for both enzymes. Docking analysis was performed for all of the molecules. These findings suggest that especially P2 has significant potential as a lead compound for further antidiabetic drug development.

Proteolysis targeting chimeras (PROTACs) and molecular glues induce ligand-mediated ternary complexes between an E3 ubiquitin ligase and a protein of interest, but their in silico modeling remains challenging due to conformational flexibility and weak protein-protein interfaces. Recent diffusion-based AI structure prediction models enable the direct prediction of protein-ligand complexes. Here we benchmarked AlphaFold 3 and Boltz-2 for predicting PROTAC- and molecular glue-mediated ternary complexes using a reproducible evaluation workflow. We curated a dataset of 40 experimentally resolved complexes from the Protein Data Bank, including 25 PROTAC and 15 molecular glue systems. Structural accuracy was assessed using complex RMSD and DockQ scores relative to the corresponding crystal structures and compared to model-internal confidence metrics. Both models outperform other current approaches in both accuracy and runtime. Boltz-2 shows higher prediction accuracy assessed by complex RMSD and DockQ scores. Predictions are generally more accurate for VHL-based PROTACs than for CRBN-based PROTACs. Predictions for molecular glue complexes show good overall accuracy. Error analysis indicates that prediction failures predominantly arise from misoriented global arrangements and twisting in flexible ternary complexes, while individual protein and ligand structures are often accurately modeled. Limitations in the generalizability of the models could also be observed, especially for more recently released structures. These findings suggest that diffusion-based AlphaFold-type models show promise in the structure-based prediction of PROTAC- and molecular glue-mediated ternary complexes.

Isoniazid (INH) and rifampicin (RIF) are cornerstone first-line antituberculosis drugs, yet their clinical utility is often limited by drug-induced liver injury (DILI). Understanding the mechanistic basis of INH and RIF-induced hepatotoxicity is essential for developing effective preventive and therapeutic strategies. This review provides a comprehensive overview of hepatic metabolism and bioactivation pathways of INH and RIF, highlighting how their co-administration potentiates synergistic hepatotoxic effects. We further explore genetic polymorphisms in drug-metabolizing enzymes and epigenetic modifications, including DNA methylation and histone remodeling, which modulate susceptibility to hepatotoxicity. Special attention is given to the epigenetic regulation of key detoxification enzymes such as cytochrome P450 2E1 (CYP2E1), N-acetyltransferase 2 (NAT2), glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase (GST) theta 1 (GSTT1), UDP glucuronosyltransferase family 1 member A1 (UGT1A1), and nuclear factor-erythroid 2-related factor 2 (NRF2) pathway. Additionally, we examined immune-mediated mechanisms, including hapten formation, Tool-like receptor-4 (TLR4) driven innate immune responses, and human leukocyte antigen (HLA) associated adaptive recognition, which integrated with toxic insults under the dual-hit hypothesis. By elucidating the interplay between metabolism, genetics, epigenetics, and immune pathways, this review highlights emerging insights into the pathogenesis of INH and RIF-induced hepatotoxicity, offering potential avenues for precision risk assessment and hepatoprotective interventions.

The pyrazolopyrimidines are a significant category of heterocyclic fused compounds that have gained growing interest owing to their wide range of biological functions as well as their synthetic all-purpose. The review draws attention to the current advances (2019-2025) in the synthesis, structural rearrangement, and pharmacological assessments of pyrazolopyrimidines with particular focus on pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives. The latter scaffolds have also been efficiently and sustainably approached through recent synthetic methodologies, such as multicomponent reactions, microwave-assisted synthesis, and green chemistry methodologies. Several derivatives have been shown to have strong anticancer, antimicrobial, anti-inflammatory, and antiviral effects, usually through the action on important enzymes, including CDK2, FLT3, VEGFR-2, PIM-1, and Topoisomerase IIa.

Anticoagulant-dependent pseudothrombocytopenia (PTCP) is an in vitro artifact that leads to falsely low platelet counts. To evaluate the efficacy of Amikacin in reversing platelet (PLT) clumping induced by various anticoagulants, including EDTA, heparin, and sodium citrate. we collected 26 blood samples demonstrating EDTA-dependent pseudothrombocytopenia. Amikacin solution (50 μL of 50 mg/L) was added to 500 μL of whole blood from each sample. Complete blood count (CBC) analysis was performed at 5, 30, 60, 240 min, and 24 h post-treatment. Additionally, five samples exhibiting PLT aggregation dependent on multiple anticoagulants (EDTA, heparin, and sodium citrate) were treated with Amikacin, and PLT counts were compared across the different anticoagulant tubes. For the Amikacin-treated EDTA tubes, differential leukocyte counts (DLC) were analyzed and compared with untreated controls, with validation by flow cytometry. Amikacin treatment significantly increased PLT counts in EDTA-dependent samples compared with untreated controls (p < 0.001), with the maximum effect observed at 240 min. In samples with multi-anticoagulant dependency, PLT counts in heparin- and sodium citrate-anticoagulated tubes remained significantly lower than those in EDTA tubes after Amikacin treatment (p < 0.01). Furthermore, in Amikacin-treated EDTA blood, the proportions of neutrophils and basophils were significantly increased (p < 0.0001), whereas the proportions of lymphocytes and monocytes decreased (p < 0.01). Amikacin effectively reverses EDTA-dependent PLT clumping within 240 min, but only partially resolves aggregation induced by heparin or sodium citrate. Moreover, the use of Amikacin in EDTA-anticoagulated blood compromises the accuracy of CBC differential counts, rendering such samples unsuitable for routine hematological analysis.

Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment.

Indicaxanthin, a prominent betalain pigment known for its bioactivity and safety, has long been valued in traditional medicine for its antioxidant and anti-inflammatory effects. The leading cause of liver failure and dysfunction is hepatic ischemia-reperfusion (I/R) injury, which frequently happens during hemorrhagic shock, hepatectomy, and liver transplantation. Given the increasing global incidence of hepatic disorders, especially those involving ischemic damage and inflammation-mediated apoptosis, there is a pressing need for therapeutic agents that can target key molecular pathways. Liver ischemia and injury often result in the upregulation of inflammatory cascades, notably involving NF-κB p65, and pro-apoptotic markers such as caspase-3, both of which play central roles in hepatocellular injury. We constructed a protein-protein interaction (PPI) network integrating predicted indicaxanthin targets with liver ischemia-related proteins. The network identified NF-κB p65 and caspase-3 as central hubs, functionally associated with pro-inflammatory and apoptotic pathways. Gene Ontology and KEGG enrichment analyses further implicated TNF, IL-17, and Toll-like receptor pathways, highlighting the broader regulatory role of indicaxanthin in hepatic stress signaling. Molecular docking against NF-κB p65 (RelA) revealed a strong binding affinity (-6.89 kcal/mol), with key hydrogen bond interactions involving Lys221, Arg246, Val244, and Gln241. Subsequent molecular dynamics (MD) simulations confirmed the structural stability of the complex, showing low RMSD drift, consistent hydrogen bonding, compact ligand behavior, and favorable energy profiles over 100 ns. Furthermore, hepatic IRI was induced in male Wistar rats, and then the hepatoprotective effect of indicaxanthin was studied at histopathological, molecular, and biochemical levels.

AXL and c-Met have been identified as pivotal oncogenic factors in non-small cell lung cancer (NSCLC), their downstream signaling pathways exhibit substantial cross-talk, and the simultaneous inhibition of both factors has demonstrated substantial anti-tumor efficacy. Molecular targeted therapy is characterized by its high precision and low toxicity, which confers a significant advantage in the management of NSCLC. Extensive research has explored the co-targeting of AXL and c-Met in both preclinical and clinical contexts, primarily emphasizing small-molecule inhibitors. This review systematically examines the structure, function, regulatory mechanisms, and signaling pathways of AXL and c-Met. It then highlights recent advancements in small molecule co-targeted inhibitors of AXL and c-Met, detailing their mechanisms of action in NSCLC treatment, and summarizes the results of relevant clinical trials. AXL and c-Met significantly influence NSCLC cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), and drug resistance, all of which adversely affect patient prognosis. Co-targeting of AXL and c-Met is considered a promising therapeutic strategy for NSCLC.

A small library of differently substituted chromones was successfully synthesized and structurally characterized. All compounds were evaluated for their inhibitory potency and selectivity toward human cancer-associated carbonic anhydrase isoforms IX and XII, as well as the off-target isoforms I and II. Compounds 4a, 4g, 4j, and 4k selectively inhibited cancer-associated isoforms IX and XII, with no activity against the off-target isozymes I and II. Among them, compound 4k was the most potent and isozyme-selective inhibitor, with K_i 0.31 µM for hCA IX and 0.24 µM for hCA XII. To estimate drug-likeness, in silico ADMET predictions were performed, indicating that all compounds possess physicochemical and pharmacokinetic properties within the acceptable ranges. Molecular docking studies on the hCA IX isoform highlighted an optimal orientation within the binding pocket, with the chromene moiety positioned toward the zinc ion. In cellular assays 4a, 4g, 4j, and 4k selectively inhibited metabolic activity in HepG2 cells expressing hCA IX in normal conditions, whereas no activity was observed in Caco-2 cells lacking hCA IX expression.