Archiv der Pharmazie最新文献

Five novel 1,2,3-triazole/arylidenehydrazide/thiazolidinone hybrid compounds (7–11) were synthesized and characterized using NMR, HRMS, IR, and HPLC purity analysis. The cytotoxicity of these compounds was evaluated on fibroblasts and THP-1 cells, showing that all compounds were nontoxic at the tested concentrations. The wound healing assay revealed that compounds 7, 9, and 10 significantly enhanced wound closure, with a 7.74%–32.69% improvement in treated cells. Compounds 8 and 11 showed moderate effects. Anti-inflammatory activity was assessed through qRT-PCR, demonstrating that compound 10 led to the most significant reduction in proinflammatory cytokines TNF-α, IL-1β, and NF-κB1. In addition, the expression of Iba1 protein in THP-1 cells confirmed that compound 8 showed the strongest anti-inflammatory effect, surpassing that of aspirin. Compound 10 showed the highest inhibition of NF-κB signaling and iNOS activity. Molecular docking studies revealed that compounds 10 and 11 had strong binding affinities to TNF-α and iNOS, with compound 11 showing the most stable interactions. Molecular dynamics simulations supported these findings, indicating that compound 11 demonstrated more stable binding to both targets. Overall, the results suggest that compounds 10 and 11 are promising anti-inflammatory candidates with potential for further development in therapeutic applications for inflammatory diseases.

Cardiovascular diseases (CVDs) are the primary causes of death globally. Risk factors such as aging, poor lifestyle, and genetics significantly influence how these diseases progress, with oxidative stress being an important factor in their pathogenesis. Thioredoxin-interacting protein (TXNIP), a redox regulator, has emerged as a crucial mediator in oxidative stress-mediated CVD. TXNIP is a pro-oxidant that disrupts thioredoxin (TRX) antioxidant function and produces a redox imbalance that triggers vascular damage, endothelial dysfunction, and CVD progression. TXNIP has been shown to trigger the release of the proinflammatory cytokines IL-1β and IL-18, by activating inflammatory signaling through the NLRP3 inflammasome. By altering the interaction between TRX and ASK1, TXNIP regulates apoptosis and pyroptosis, which triggers cell death following oxidative stress. The present review highlights TXNIP's role in the progression of CVD by regulating various signaling pathways such as TXNIP/SIRT1/FOXO1, TXNIP/Redd1, TLR4/NF-κB/TXNIP/NLRP3, and NRF2/TXNIP. The review further explores TXNIP's potential as a therapeutic target in CVD intervention.

3-Phosphoglycerate dehydrogenase (PHGDH) is a key enzyme in the serine biosynthesis pathway, supporting cancer cell growth, survival, and proliferation. Its overexpression is frequently observed in aggressive cancers such as breast cancer, melanoma, and glioma, where it drives tumor growth, metastasis, and resistance to oxidative stress. Targeting PHGDH with small-molecule inhibitors has emerged as a promising therapeutic strategy. Notable inhibitors like NCT-503, CBR-5884, Azacoccone E, and Ixocarpalactone A, along with covalent inhibitors such as Withangulatin A, exhibit potent anticancer activity by limiting serine availability and inducing apoptosis. Gene-silencing techniques, including RNA interference (RNAi) and CRISPR/Cas9, further validate PHGDH as a therapeutic target. Advances in computational methods and structure–activity relationship (SAR) analysis have accelerated the discovery of selective PHGDH inhibitors, offering insights into binding mechanisms and facilitating rational drug design. However, cancer cells can activate alternative metabolic pathways, such as glutaminolysis, to evade PHGDH inhibition. Thus, combination therapies targeting multiple metabolic nodes are being explored to enhance efficacy and overcome resistance. Ongoing research focuses on optimizing PHGDH inhibitors through virtual screening, QSAR modeling, and clinical trials, aiming to integrate them into precision oncology and develop effective therapies for patients with high PHGDH expression or specific metabolic profiles.

Seven new quinoline derivatives with different functional groups at positions 2, 3, and 4 were synthesized and subsequently assessed for their biological activities. Four synthesized compounds exhibited significant cytotoxic effects against A549 and MCF7 cells. Compound 4f demonstrated IC₅₀ values comparable to that of the standard drug doxorubicin and showed a similar selectivity profile, exhibiting low toxicity toward healthy NIH3T3 cells. Furthermore, compound 4f displayed a strong EGFR inhibition profile with an IC₅₀ value of 0.015 ± 0.001 µM. Molecular docking studies revealed that 4f forms strong interactions with key amino acids on the active site of EGFR. Additionally, DFT analyses were conducted to calculate dipole moments, HOMO-LUMO energy gaps, and molecular electrostatic potential maps. Theoretical and experimental NMR chemical shift values showed a high correlation and confirmed the consistency of the computational results. These results indicate the potential of quinoline derivatives, especially of compound 4f, as promising candidates for the development of chemotherapeutic agents.

The escalating threat of drug-resistant Mycobacterium tuberculosis (Mtb) necessitates the discovery of novel chemotherapeutic agents. In this study, a series of dihydroindazole-based derivatives were designed, synthesized, and evaluated for their antimycobacterial potential. Among the synthesized compounds, 8u exhibited the most potent in vitro activity against Mtb H₃₇Rv with a minimum inhibitory concentration (MIC) of 2 µg/mL, while 8i and 8q showed moderate activity (MIC = 8 µg/mL). Several analogs demonstrated MICs in the range of 16–32 µg/mL. 8u also displayed enhanced activity against single-drug-resistant Mtb strains, outperforming ethambutol and rifampicin. Structure–activity relationship analysis indicated that both the hydrazide linker and heteroaryl substitutions significantly influenced antimycobacterial activity. 8u was non-cytotoxic to Vero cells (CC₅₀ > 100 µg/mL), yielding a selectivity index (SI) > 50. Time–kill kinetics confirmed its bactericidal nature. Mechanistic investigations using molecular docking and 100-ns molecular dynamics simulations identified InhA as the probable molecular target. In silico ADMET predictions (QikProp and ProTox-3.0) supported favorable pharmacokinetic and toxicity profiles. Collectively, these findings highlight 8u as a promising lead for the development of next-generation anti-TB agents.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired insulin secretion, and dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as an effective therapeutic option. A new series of pyrrole-3-carboximidamide derivatives was designed, synthesized, and evaluated as DPP-4 inhibitors. Most of the synthesized compounds exhibited favorable inhibitory activity against the DPP-4 enzyme, and compounds 5f and 5g were found to be the most potent inhibitors with IC₅₀ values of 12.19 and 23.08 nM, respectively. In vivo studies in diabetic Wistar rats showed that daily administration of compound 5g for 2 weeks resulted in a significant decrease in blood glucose compared with the control group. Moreover, compound 5g was effective in reducing plasma glucose in an acute oral glucose tolerance test in NMRI mice. The antiglycemic effects of compound 5g were comparable with standard treatment by sitagliptin, with no effect on normoglycemic rats. Both the in vitro and in vivo antidiabetic properties suggest that compound 5g could be considered a promising candidate for development as an antidiabetic medication.

A series of taurinamide-based amides 1–19 were investigated for their effects on human (h) carbonic anhydrase (CA; EC 4.2.1.1) isoforms I, II, VA, VII, IX, and XII, which are all relevant for biomedical applications. According to inhibition data, most of the derivatives displayed affinity and selectivity for the hCA I isoform over the other isoforms tested, and compounds 1, 2, 4, 8, and 9 emerged as potent nanomolar inhibitors of hCA I and hCA IX, exhibiting K_I values in the range of 0.65–0.83 and 0.59–0.96 µM, respectively (asetazolamide K_I = 0.25 for CA I and K_I = 0.03 M for hCA IX). The X-ray structures of 15 and 18 in complex with hCA II provided detailed insights into the binding mode and molecular determinants. Substitution patterns were found to have a tuning effect on both affinity and selectivity toward specific isoforms, thus providing valuable insights for the design of new CA inhibitors.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype marked by pronounced intra-tumoral heterogeneity and frequent therapeutic resistance. In this study, we report the design, synthesis, and biological evaluation of a novel series of triazolopyrimidine–isatin hybrids against the TNBC cell lines MDA-MB-231 and MDA-MB-468. Among them, 9h emerged as the most promising candidate, exhibiting potent cytotoxic activity against TNBC cell lines. Notably, 9h demonstrated 5.7-fold greater potency than tamoxifen and slightly better efficacy than the reference drug cisplatin against MDA-MB-231 cells. Further, 9h induced a significant reduction in MDA-MB-231 cell viability through caspase-mediated apoptosis. Preliminary ADMET predictions were also carried out to assess pharmacokinetic properties.