Archiv der Pharmazie最新文献

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.

Four previously unreported tigliane diterpenes (1, 2, 4, and 6), along with two known tiglianes (3 and 5), were isolated from the latex of Euphorbia palustris and Euphorbia lucida. The structures of the isolated compounds were elucidated by spectroscopic techniques. Antiviral activity assays for compounds 1‒4 and 6 against HIV-1 and HIV-2 replication were performed on a CD4⁺ T cell line, MT-4 cells. The compounds were tested for their ability to inhibit infection by the HIV-1 strain NL4.3 and the HIV-2 strain ROD. Compound 6 showed no activity against either strain, while compound 4 was only slightly active against HIV-2 (EC₅₀ = 12.778 µM). Compounds 1, 2, and 3 were able to inhibit both HIV-1 and HIV-2 infections. Among them, compound 2 was the most potent, with EC₅₀ values of 0.069 µM for HIV-1 NL4.3 and 0.023 µM for HIV-2 ROD. The PBMC toxicity profile for compound 2 is also more favorable compared with MT-4 cells with CC₅₀ = 50 μM.

A series of fifteen 1,2,3-triazole derivatives 6(a–o) were developed and evaluated for their inhibitory effects on carbohydrate-hydrolyzing enzymes implicated in Type 2 diabetes management. The compounds were assessed through in silico studies (including molecular docking and ADME predictions) and in vitro assays such as α-amylase, α-glucosidase, and antioxidant activities. Notably, the compounds 6a, 6d, 6g, 6h, 6k, 6l, and 6n exhibited dual inhibition against both enzymes. Among them, compound 6a exhibited the most potent α-glucosidase inhibition (IC₅₀ = 22.15 ± 0.75 µM), comparable to the reference drug acarbose (IC₅₀ = 21.07 ± 0.05 µM). Meanwhile, compound 6h demonstrated strong α-amylase inhibition (IC₅₀ = 84.46 ± 1.14 µM) compared with standard acarbose (IC₅₀ = 87.62 ± 0.47 µM). Cytotoxicity studies of the most active compounds 6a and 6h indicated moderate cytotoxicity, with IC₅₀ values of 32.87 ± 1.2 µM and 32.42 ± 1.5 µM, respectively, suggesting a reasonable safety margin compatible with continued drug development. The DPPH assay revealed moderate to good activity for all compounds 6(a–o), with IC₅₀ values ranging from 39.60 ± 0.15 to 99.45 ± 0.12 µM. These findings support the therapeutic potential of these compounds as antidiabetic agents.

Microtubules are crucial for various cellular processes, including cell division, where they form highly dynamic spindle fibers for chromosomal alignment and segregation. Interference with microtubule dynamics through microtubule targeting agents (MTAs) blocks progression through mitosis, ultimately resulting in apoptosis. Although MTAs have been effectively used as a frontline treatment for various cancers, multidrug resistance (MDR) often limits their effectiveness. This study focuses on selenadiazoles, a group of organic selenium compounds with anticancer activities. Eighteen novel 1,2,5-selenadiazole derivatives were synthesized, three of which (9d, 9f, and 9i) showed potent antiproliferative activity in HCT116 colorectal cancer cells. Treatment of cells with 9f (SSE1706), one of the most potent compounds (GI₅₀ value of 1.89 ± 0.99 µM), disrupted mitotic spindle formation, leading to G2/M arrest. 9f inhibited microtubule polymerization in cell-based assays, and long-term treatment with 9f stabilized p53 and induced apoptosis. Moreover, 9f effectively inhibited the growth of mouse and human colon cancer-derived organoids. Finally, 9f exhibited potent antiproliferative activity against MDR-1 overexpressing KB-V1 cells, highlighting its potential to overcome MDR. These findings suggest 9f as a lead compound for further optimization studies, particularly targeting MDR.

Despite notable advancements in conventional cancer therapies, challenges such as drug resistance, adverse effects, and high treatment costs remain significant obstacles. This situation calls for exploring new therapeutic options. One promising approach is drug repurposing, which uses existing medications with known effects to identify new anticancer agents. Isotretinoin (13-cis-retinoic acid), a vitamin A derivative typically used to treat severe acne, shows considerable potential as an anticancer agent. Recent studies suggest that isotretinoin has the potential to enhance the efficacy of cancer treatment and contribute to cancer inhibition by targeting specific molecular pathways. This review explores isotretinoin's chemistry, pharmacokinetics, and toxicity, emphasizing its role in cancer treatment through clinical and preclinical studies while elucidating its anticancer mechanisms. Both preclinical and clinical studies have revealed that isotretinoin can effectively inhibit the growth of tumor cells, induce apoptosis, and help regulate cellular differentiation in a range of cancers, including neuroblastoma, glioblastoma, breast, skin, lung, ovarian, cervical, and head and neck cancers. Isotretinoin works against cancer through several mechanisms. It activates retinoic acid receptors (RARs), suppresses oncogenic signaling pathways, and influences gene transcription related to cell cycle control and apoptosis. Moreover, combining isotretinoin with other treatments, like interferon-alpha, chemotherapy drugs, or other targeted inhibitors, can create synergistic effects that improve treatment effectiveness and potentially lessen side effects. Although isotretinoin holds great promise, we still need more research to address its limitations, such as its toxicity, risks during pregnancy, and differing responses in various cancer types. Current research focuses on optimizing isotretinoin-based therapies by refining dosage regimens to maximize efficacy and enhancing formulation strategies for improved absorption and reduced side effects. Ultimately, the use of isotretinoin in cancer treatment demonstrates the potential of repurposing established drugs and paves the way for more accessible and cost-effective cancer therapies.