Archiv der Pharmazie最新文献

Benz/imidazole-2-thione/selone-based triazoles, particularly their thione and selone analogs, are gaining attention for anticancer drug development due to their structural diversity and biological activity. However, their potential as targeted inhibitors of cancer-related proteins remains underexplored. This study reports the design, synthesis, and evaluation of novel benz/imidazole-2-thione/selone-based triazoles, focusing on cyclin-dependent kinase 1 (CDK1), a key regulator of cancer cell proliferation. The compounds were synthesized via a multistep approach involving imidazolium salt intermediates, followed by sulfur or selenium incorporation. Structural confirmation was achieved using FT-IR, NMR, and mass spectrometry. Molecular docking against CDK1, TERT, and VEGFR2 revealed strong binding affinities (−9.7 to −7.3 kcal/mol), with CDK1 selected for further in vitro study using MCF-7 breast cancer cells. Molecular dynamics (MD) simulations confirmed stable CDK1 binding for Compounds 2, 4, and 9, although Compound 9 showed conformational instability after 60 ns. ADMET profiling indicated favorable drug-likeness and permeability but highlighted metabolic liabilities and hERG inhibition risks, particularly for Compounds 4 and 9. The target prediction and pathway enrichment analyses predict that benz/imidazole-2-thione/selone-based triazoles exert their pharmacological effects primarily through the regulation of GPCR signaling pathways, likely via direct interaction with key regulators such as RGS8 and RGS4. In vitro assays demonstrated dose-dependent cytotoxicity, with Compound 4 showing the highest potency (IC₅₀ = 106.12 ± 1.03 µg/mL), followed by 9 and 2. These findings suggest that benz/imidazole-2-thione/selone-based triazoles are promising CDK1 inhibitors and support their further optimization as targeted breast cancer therapies.

A novel series of benzimidazole-based derivatives (5a–g), (6a–b), and (7a–b) were designed, synthesized, and evaluated for their potential as dual inhibitors of EGFR and HER-2. The synthesized compounds were subjected to in vitro screening against a panel of selected human cancer cell lines. Additionally, their cytotoxicity was assessed using normal human mammary epithelial cells (MCF-10A) to evaluate their safety profile. Among the tested derivatives, compounds 5b, 5f, and 6a demonstrated the most pronounced antiproliferative activity, exhibiting IC₅₀ values of 6, 8, and 5 µM, respectively. These values reflect a potency at least fourfold greater than that of the reference drug Doxorubicin (IC₅₀ = 33 µM). EGFR and HER-2 enzyme inhibition assays were conducted to explore the potential molecular targets responsible for the observed anticancer effects. Notably, compound 6a (R₁ = phenyl, thiosemicarbazide) exhibited superior efficacy against the MCF-7 breast cancer cell line, with an IC₅₀ of 5 µM, approximately six times more potent than Doxorubicin. Conversely, compound 7b, with an IC₅₀ value of 85 µM against MCF-7 cells, was the least active, underscoring the critical role of the phenyl moiety in antiproliferative activity. Furthermore, a molecular docking study was conducted to investigate the binding interactions of 6a within the active sites of EGFR and HER-2, providing insight into its potential mechanism of action.

Cancer remains a major global health challenge, responsible for millions of deaths each year. The limitations of current therapies, including adverse effects and drug resistance, have intensified the search for safer, more effective alternatives, particularly from natural sources. Alantolactone, a sesquiterpene lactone extracted from Inula helenium and related medicinal plants, has emerged as a promising anticancer candidate due to its diverse pharmacological actions. Although notable anticancer properties have been reported, its full therapeutic potential, mechanisms of action, and translational relevance remain insufficiently explored and scattered across the literature. This review provides a comprehensive synthesis of current evidence on alantolactone's anticancer effects. It examines its sources, phytochemical features, structure–activity relationships, bioavailability challenges, mechanistic pathways, and preclinical findings, alongside perspectives for future clinical application. Evidence shows that alantolactone modulates multiple molecular targets and signaling cascades, including NF-κB, STAT3, MAPK, and apoptotic regulators. It demonstrates strong cytotoxic activity across diverse cancer cell lines and tumor-bearing animal models. However, barriers such as low systemic bioavailability, limited pharmacokinetic profiling, and the absence of human clinical data impede its therapeutic development. Alantolactone nonetheless holds significant promise as a multi-targeted anticancer compound with encouraging preclinical outcomes. Further research is required to address pharmacological limitations and establish safety and efficacy in clinical contexts. This review highlights alantolactone's potential contribution to future cancer therapy and emphasizes the need for interdisciplinary research to support its clinical translation and formulation advancement.

Cystitis, characterized by bladder inflammation, represents a significant clinical challenge in cancer chemotherapy, particularly with cyclophosphamide administration. Drug repurposing, which involves applying existing pharmaceuticals to new therapeutic areas, offers increased efficiency, reduced costs, and lower risks. This study investigated the molecular mechanisms underlying the uro-protective application of lacosamide, an FDA-approved antiepileptic drug, against cyclophosphamide-induced cystitis via suppression of the Notch-1/NICD/NF-κB inflammatory pathway. Network pharmacology analysis identified key molecular targets and pathways involved in lacosamide's protective mechanisms, followed by molecular docking studies that validated the binding interactions between lacosamide and target proteins. In vivo validation was performed using adult male Wistar rats with cyclophosphamide-induced cystitis. Network analysis revealed Notch-1 as a primary target for lacosamide's uroprotective action. Experimental validation demonstrated that lacosamide pretreatment significantly attenuated oxidative bladder injury by decreasing malondialdehyde levels while enhancing superoxide dismutase activity and reduced glutathione content. Lacosamide substantially downregulated pro-inflammatory mediators including TNF-α, IL-1β, and IL-6 via NF-κB suppression. Additionally, lacosamide suppressed the Notch-1/NICD/NF-κB pathway, elevated Bcl-2 expression, and reduced Bax protein and caspase-3 levels. Histopathological examination corroborated biochemical findings. Lacosamide demonstrates significant uro-protective efficacy through coordinated anti-inflammatory, antioxidant, and anti-apoptotic mechanisms through modulation of Notch-1/NICD/NF-κB pathway.

Malaria, caused by Plasmodium falciparum and other species, remains a significant global health issue, transmitted by infected Anopheles mosquitoes. According to the WHO 2024 report, malaria affected 249 million individuals and resulted in 608,000 deaths between 2000 and 2022. The rise of drug resistance in both Plasmodium species and Anopheles mosquitoes has significantly complicated the malaria treatment, necessitating the development of novel therapeutic agents. This review highlights recent advancements in the design of anti-malarial drugs, with a particular focus on heterocyclic compounds reported in 2023, in continuation of our previous works on updates on anti-malarial agents reported since 2016. Among these, artemisinin derivatives have shown remarkable efficacy, while other heterocyclic classes—such as benzofuran, β-lactam, coumarin, indole, morpholine, piperazine, pyrimidine, pyrrole, quinazoline, quinoline, thiazole, and triazoles—are emerging as promising alternatives. These compounds target essential parasite functions such as heme metabolism, RBC invasion, and oxidative stress pathways, with several new hybrid molecules combining multiple mechanisms of action to counter drug resistance. This review provides an overview of recent developments in these heterocyclic-based anti-malarial agents, summarizing their chemical structures, mechanisms of action, and therapeutic potential. By focusing on innovations reported in 2023, this study aims to orient the ongoing research in the pursuit of safer and more effective treatments for malaria.

The development of theranostic probes with tumor-specific targeting and high therapeutic efficacy remains a pivotal challenge in precision oncology. Herein, we have successfully developed a new cyclooxygenase-2 (COX-2)-targeted probe compound 2 derived from Rofecoxib. Compound 2 facilitated tumor visualization by a sixfold fluorescence enhancement upon COX-2 binding, while it exhibited minimal background fluorescence under physiological conditions. Moreover, compound 2 monotherapy achieved 53% tumor regression (p < 0.01). When combined with a programmed cell death protein 1 (PD-1) inhibitor (RMP1-14), concurrent blockade of the COX-2/prostaglandin E2 (PGE2) and PD-1/programmed death-ligand 1 (PD-L1) axes achieved 95% tumor regression (p < 0.001). Compound 2 involves activating fluorescence by targeting tumor markers COX-2 as well as enhancing therapeutic efficacy. We believe this approach could provide insights for advancing cancer diagnosis and treatment technologies.

The rise of multidrug-resistant pathogens, including MRSA, underscores the urgent need for novel antibacterial agents with minimum resistance potential and enhanced potency. Herein, we report the design and synthesis of novel phenylvinylsulfonate-anchored azetidin-2-ones 8a–h & 9i–j via the reaction of (E)-2-phenylethene-1-sulfonyl chloride with differently substituted 3-hydroxy azetidin-2-ones. Structural confirmation was achieved by ¹H NMR, ¹³C NMR, HRMS, and stereochemical elucidation based on the J-coupling values of C3–H and C4–H. Among the series, compound 9j exhibited the most potent antibacterial activity against MRSA (MIC: 7.5 μg/mL), outperforming Tetracycline. Mechanistic investigation using ROS quantification (DCFH-DA assay) revealed markedly elevated intracellular ROS (OD: 71,467), suggesting a possible ROS-mediated bacterial damage mechanism. Molecular docking interactions further supported the strong binding of 9j to penicillin-binding protein 2a (PBP2a, PDB: 1VQQ) with a docking score of –6.68 kcal/mol. Additionally, 9j exhibited selective cytotoxicity toward HCT-116 colon cancer cells with an IC₅₀ value of 9.82 ± 0.21 μM while maintaining moderate viability (~52%) in NIH-3T3 normal fibroblast cells. Collectively, these findings highlight phenylvinylsulfonate-anchored azetidin-2-ones as promising antibacterial agents with a ROS-driven mechanism and supplementary selective cytotoxic potential.

A series of ester derivatives of (6-methyl-4-phenyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl)(piperidin-1-yl) methanone (6a–6k) have been synthesized using a solvent and catalyst-free one-pot two-step synthetic method. These 11 molecules have been characterized by spectroscopic techniques such as FT-IR, NMR (¹H and ¹³C), and single-crystal x-ray structural analysis. The Hirshfeld surface and 2D fingerprint plot elucidated the intermolecular interactions and their contribution to crystal packing. Furthermore, the computational calculations, such as FMOs and MEP, revealed the global reactivity descriptors and sites for noncovalent interactions, such as hydrogen bonding, respectively, in these pharmacophores. Among these derivatives, the 6h molecule, which bears –CF₃ on the phenyl ring, has piperidine substitution on the ester group and contains a thiourea moiety, demonstrated the best larvicidal activity against Anopheles arabiensis, achieving a 94% mortality rate compared to the standard sample Temephos (98%).