Archiv der Pharmazie最新文献

{"title":"Discovery of Novel Ligands for the Treatment of Cryptococcus neoformans Infection","authors":"Teresa Rocha,&nbsp;Catarina Alves,&nbsp;Carla Lima,&nbsp;Lisa Sequeira,&nbsp;Fernanda Borges,&nbsp;Fernando Cagide,&nbsp;Sofia Benfeito","doi":"10.1002/ardp.70324","DOIUrl":"https://doi.org/10.1002/ardp.70324","url":null,"abstract":"<div>\u0000 \u0000 <p>Fungal pathogens are an escalating global public health concern, particularly in the context of invasive and opportunistic infections. Cryptococcosis, primarily caused by <i>Cryptococcus neoformans var. grubii</i>, can affect multiple organs and often leads to life-threatening meningitis in immunocompromised individuals. Given limited antifungal therapies and emergence of resistance and toxicity-related constraints, the development of novel anti-cryptococcal agents remains an urgent priority. A library of innovative 3-hydroxypyridin-4(1<i>H</i>)-one-based hybrids (<b>5a–f</b>) was synthesized and evaluated for antimicrobial activity against clinically relevant Gram-positive and Gram-negative bacteria, as well as fungal species <i>Candida albicans</i> and <i>C. neoformans</i> var. <i>grubbi</i>. Safety was assessed through cytotoxicity studies in HEK293 and HepG2 cells and hemolytic evaluation, while iron-chelating capacity and lipophilicity were also investigated. All compounds formed stable iron(III) complexes and displayed no significant toxicity up to 25 μM. Series 1 compounds (<b>5a–c</b>) were less lipophilic than Series 2 (<b>5d–f</b>), mainly due to regioisomeric position of hydroxyl group on 2-methyl-4-pyridone scaffold, whereas fluorination increased lipophilicity in both series. Notably, compounds <b>5c–f</b> emerged as potent, selective, and nontoxic antifungal agents against <i>C. neoformans</i> var. <i>grubii</i> (MIC &lt; 16 µg/mL; CC₅₀ &gt; 32 µg/mL; HC₁₀ &gt; 32 µg/mL), highlighting the potential of 3-hydroxypyridin-4(1H)-one-based hybrids as a promising approach for cryptococcal meningitis therapy.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Issue Information: Arch Pharm (8/2026)","authors":"","doi":"10.1002/ardp.70329","DOIUrl":"https://doi.org/10.1002/ardp.70329","url":null,"abstract":"","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70329","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRET-Based Approaches for Ion Channels: Emerging Applications and Future Directions","authors":"Nadine Kock,&nbsp;Laura Heitzer,&nbsp;Joana Massa,&nbsp;Marvin Taterra,&nbsp;Marcel Bermúdez,&nbsp;Oliver Koch,&nbsp;Matthias Schiedel","doi":"10.1002/ardp.70325","DOIUrl":"https://doi.org/10.1002/ardp.70325","url":null,"abstract":"<p>Bioluminescence resonance energy transfer (BRET) is a technique based on energy transfer between a luminescent enzyme and a fluorescent acceptor. Since its first description in 1999, BRET has been widely applied in chemical biology research and drug discovery. Today, it is regarded as one of the most versatile methods for investigating the dynamics of ligand–protein and protein–protein interactions, both in cell-free systems and living cells. Owing to several advantages, including compatibility with high-throughput screening, suitability for cellular target engagement studies, and the ability to monitor real-time kinetics, BRET-based binding assays have become indispensable tools, particularly in early-stage drug discovery. Consequently, over the past decade these approaches have been extensively used for major drug target classes such as G protein-coupled receptors (GPCRs), kinases, and proteases. Despite the high relevance of ion channels as drug targets—approximately one-fifth of all approved drugs act on them—BRET-based assays have so far played only a limited role in this field. Here, we summarize recent applications of BRET-based methods for ion channels with a particular focus on approaches for studying ligand-ion channel interactions, highlighting current challenges and, more importantly, the significant potential of this technology to advance ion channel–focused drug discovery.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Activation-Dependent Anti-Liver Cancer Activity and Organ-Specific Toxicity of Retrorsine From Fanhuncao (Jacobaea cannabifolia and J. litvinovii).","authors":"Zhijie He, Zhongyu Tan, Lunrong Zhang, Yue Yin, Yedeli Yerjiang, Bo Bi, Jingshan Bao","doi":"10.1002/ardp.70326","DOIUrl":"https://doi.org/10.1002/ardp.70326","url":null,"abstract":"<p><p>Fanhuncao (Jacobaea cannabifolia and J. litvinovii) is a traditional Chinese herb with reported antitumor potential. Retrorsine, a pyrrolizidine alkaloid from Fanhuncao, requires CYP3A4‑mediated metabolic activation, but its dual outcomes (anti‑liver cancer efficacy vs. organ‑specific toxicity) remain unclear. To elucidate how CYP3A4-dependent activation of retrorsine drives both anti-liver cancer activity and organ-specific toxicity, and to identify differential cell death pathways in target organs. UPLC-HRMS profiled pyrrolizidine alkaloids in Fanhuncao. Cytotoxicity screening, molecular docking, and molecular dynamics identified retrorsine as the lead compound. Network pharmacology/toxicology predicted targets of dehydro-retrorsine. In vitro assays and Western blotting were performed on hepatoma cells. In vivo efficacy and toxicity were evaluated in H22 tumor-bearing mice. Retrorsine achieved significant tumor growth inhibition at high dose. Mechanistically, it simultaneously inhibited EGFR/PI3K/AKT/mTOR and NF-κB pathways while activating intrinsic mitochondrial apoptosis (altered Bax/Bcl-2, cytochrome c release, Caspase-9/3 activation). Retrorsine upregulated CYP3A4 in tumor cells, suggesting a potential self‑amplifying metabolic loop that requires further validation. However, this efficacy was accompanied by dose-dependent hepatorenal toxicity with organ-specific mechanisms: liver injury via oxidative stress and mitochondrial apoptosis; kidney injury via Caspase-3/GSDME-dependent pyroptosis. Retrorsine is a potent multi-target anti-liver cancer natural product, but its therapeutic window is narrowed by inseparable organ-specific toxicities (hepatic apoptosis vs. renal pyroptosis) arising from CYP3A4-dependent metabolic activation. Future decoupling strategies should focus on targeted delivery, structural modification, or combination therapies.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 9","pages":"e70326"},"PeriodicalIF":3.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First UV-Based Strategies Integrating Whiteness, Greenness, and Blueness Appraisals for Estimating Meloxicam and Tramadol Concurrently in Their Veterinary Mixture","authors":"Ahmed R. Mohamed,&nbsp;Eman Darweish,&nbsp;Sabry M. Attia,&nbsp;Tanveer Singh,&nbsp;Youstina M. Metias","doi":"10.1002/ardp.70323","DOIUrl":"10.1002/ardp.70323","url":null,"abstract":"<div>\u0000 \u0000 <p>Multimodal pain therapy, which combines drugs from different classes targeting distinct pain pathways, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), provides enhanced pain control in veterinary practice compared with single-agent therapy. Meloxicam (MXC), an NSAID, is frequently formulated with tramadol hydrochloride (TDH), a widely used opioid analgesic, for synergistic pain management. A comprehensive survey of the available literature revealed that no analytical method has yet been reported for the concurrent determination of meloxicam and tramadol. Therefore, this work introduces two facile and eco-friendly UV spectrophotometric methodologies for the simultaneous assay of meloxicam and tramadol in their pure forms and veterinary dosage forms. Due to the significant spectral overlap between meloxicam and tramadol, direct concurrent analysis is challenging. To resolve this spectral interference, Fourier deconvolution (FDC) and dual-wavelength (DWL) methods were developed, providing linear ranges of 2–25 µg/mL for meloxicam and 10–170 µg/mL for tramadol with satisfactory sensitivity. The proposed methods were validated according to ICH guidelines and statistically compared with the reported methods for the individual drugs using appropriate statistical tests. Furthermore, their environmental sustainability was comprehensively assessed using the AGREEprep metric, complemented by whiteness and practicality evaluations based on the RGB12 algorithm and the BAGI tool. The results demonstrate that the proposed UV methods are sustainable, sensitive, specific, and suitable for the routine simultaneous analysis of meloxicam and tramadol in veterinary dosage forms.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzophenone Derivatives as a New Class of Anti-Infectives Against Acanthamoeba spp","authors":"Tomas Rimkus,&nbsp;Hannes Geisler,&nbsp;Taha B. El-Jourani,&nbsp;Aurélien F. A. Moumbock,&nbsp;Matthias Schiedel,&nbsp;Stephan Reichl","doi":"10.1002/ardp.70321","DOIUrl":"https://doi.org/10.1002/ardp.70321","url":null,"abstract":"<p>The rare but sight-threatening ocular disease <i>Acanthamoeba</i> keratitis represents a therapeutic challenge due to its causative agents, <i>Acanthamoeba spp</i>., being able to penetrate the corneal epithelium and persist in the corneal stroma as dormant and highly resistant cysts. To combat the scarcity and limitations of current treatment options, we developed a new class of anti-infective agents against <i>Acanthamoeba spp</i>. based on Ro 48-8071 (<b>3</b>), a known inhibitor of the human oxidosqualene cyclase (hOSC). The compound design was guided by docking studies using a homology model of the cycloartenol synthase (CAS), which is the homolog of hOSC found in <i>Acanthamoeba spp</i>. and essential for the parasite's steroid biosynthesis. Among the synthesized Ro 48-8071 analogues, MSHG19 (<b>4f</b>) evoked the most potent activity against <i>Acanthamoeba hatchetti</i> leading to total eradication of trophozoites and cysts at single-digit micromolar concentrations, whereas having no effects within this concentration range on the viability of human corneal epithelial cells. With our initial set of synthesized compounds, we established a first structure–activity relationship model, which nicely aligns with the predicted binding mode of <b>4f</b> to CAS. Overall, the presented findings highlight the potential of benzophenones as a new class of anti-infectives for the treatment of <i>Acanthamoeba</i> keratitis.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Developments and Structure–Activity Relationships of BRAF Inhibitors for Cancer Drug Discovery","authors":"Xin-Ke Guo,&nbsp;Kadalipura P. Rakesh,&nbsp;Sahana Raju,&nbsp;Kothanahally S. Sharath Kumar,&nbsp;Hua-Li Qin","doi":"10.1002/ardp.70322","DOIUrl":"https://doi.org/10.1002/ardp.70322","url":null,"abstract":"<div>\u0000 \u0000 <p>Incorporating current structural and biochemical discoveries, this paper examines how B-RAF inhibitors control B-RAF, including their clinical efficacy, side effects, and important medicinal chemistry characteristics. It investigates the molecular insights that may direct the creation of more potent RAF inhibitors that can target different oncogenic B-RAF conformations. We have discussed the advantages and disadvantages of structurally varied next-generation RAF inhibitors that are presently undergoing preclinical and clinical trials. A few of these drug candidates have started clinical trials with promising outcomes. This review also covers the structure–activity relationship of promising bioactive B-RAF compounds, highlights advancements in the discovery and development of B-RAF inhibitors, and attempts to assist future drug discovery initiatives.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Modifications of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): New Horizons in Antimicrobial Drug Discovery","authors":"Ebru Koçak Aslan,&nbsp;Ayşe Karagüzel,&nbsp;Miyase Gözde Gündüz","doi":"10.1002/ardp.70319","DOIUrl":"https://doi.org/10.1002/ardp.70319","url":null,"abstract":"<p>Nonsteroidal anti-inflammatory drugs (NSAIDs) are traditionally recognized for their analgesic and anti-inflammatory effects, mediated by inhibition of cyclooxygenase (COX) enzymes. However, many NSAIDs have been shown to possess intrinsic antimicrobial effects beyond their classical properties. This unexpected activity, together with the rise of antimicrobial resistance, has positioned NSAIDs and their derivatives as promising scaffolds for antimicrobial drug discovery. Additionally, their well-established pharmacological profiles and chemical structures suitable for modification make NSAIDs attractive starting points for developing novel antimicrobial agents. This review, for the first time, focuses exclusively on molecular modifications directly applied to NSAIDs to develop new antimicrobial agents that combat the growing problem of antimicrobial resistance and overcome the limitations of current clinical therapies. These modifications include conjugating commercial NSAIDs with heterocyclic compounds (such as triazole, thiazolidinone, and benzimidazole), functional groups (including hydrazide-hydrazone, Schiff base, hydroxamic acid, amide, and thiosemicarbazide), and other drug molecules (fluconazole, sulfamethoxazole, isoniazid, etc.), resulting in the development of novel antimicrobial agents and an enhanced understanding of their structure–activity relationships. By integrating chemical and biological findings, this review highlights the potential of modifying NSAIDs as a viable strategy to expand the current antimicrobial arsenal and address the growing challenge of antimicrobial resistance.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70319","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular and Molecular Mechanisms of Berberine in Cancer Therapy: Recent Advances","authors":"Kang He,&nbsp;Bing-Rui Lu,&nbsp;Xu-Ying Shi,&nbsp;Run-Long Sui,&nbsp;Zhi-Gang Sun","doi":"10.1002/ardp.70313","DOIUrl":"10.1002/ardp.70313","url":null,"abstract":"<div>\u0000 \u0000 <p>In recent years, the role of traditional Chinese medicine (TCM) in comprehensive cancer treatment has become increasingly prominent, gradually emerging as an important adjunctive modality alongside conventional therapies such as surgery, chemotherapy, and radiotherapy, and attracting widespread attention. Berberine, an isoquinoline alkaloid extracted from natural plants such as <i>Coptis chinensis</i>, possesses broad-spectrum and potent pharmacological activities. A large body of evidence has demonstrated that berberine exerts definite antitumor effects in various cancer models, with its mechanisms of action spanning multiple dimensions, including cell-cycle arrest, induction of cell death, modulation of the tumor microenvironment (TME), inhibition of invasion and metastasis, and intervention in angiogenesis. Based on the latest research progress worldwide, this review focuses on key oncogenic signaling pathways and immune regulatory mechanisms to systematically elucidate the cellular and molecular mechanisms underlying the antitumor activity of berberine, and further discusses its clinical application potential and the challenges ahead. Although the clinical translation of berberine remains constrained by bottlenecks such as formulation optimization and bioavailability enhancement, its broad prospects in the field of cancer prevention and treatment establish it as a highly valuable TCM-derived antitumor candidate for further development.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venom-Derived Peptides in Breast Cancer: Pharmacological Mechanisms and Medicinal Chemistry-Guided Translational Development","authors":"Radwa A. Amen,&nbsp;Alyaa Farid,&nbsp;Mohamed A. Abdel-Rahman,&nbsp;Ahmed A. El-Sherif,&nbsp;Yaser M. Hassan,&nbsp;Nadia R. Shehata,&nbsp;Rana H. Ahmed,&nbsp;Wael M. El-Sayed","doi":"10.1002/ardp.70320","DOIUrl":"10.1002/ardp.70320","url":null,"abstract":"<div>\u0000 \u0000 <p>Breast cancer remains the most prevalent malignancy among women worldwide and continues to present major therapeutic challenges, including drug resistance, systemic toxicity, and limited long-term efficacy despite advances in multimodal treatment strategies. These limitations have intensified interest in venom-derived peptides as structurally diverse bioactive scaffolds with anticancer potential. This review evaluates venom-derived peptides in breast cancer from a medicinal chemistry and translational drug development perspective. A structured narrative synthesis of the literature was conducted, covering preclinical and early translational studies of peptides derived from snakes, spiders, scorpions, and bees, with emphasis on structure–function relationships, mechanisms of action, and optimization strategies. Unlike previous reviews that primarily focus on individual venom sources, this work integrates mechanistic pharmacology with peptide engineering and translational constraints to provide a unified drug-development framework across breast cancer subtypes. Venom-derived peptides exert anticancer effects through ion channel modulation, apoptosis induction, cell cycle arrest, angiogenesis inhibition, membrane disruption, and immune modulation, with reported selectivity toward malignant cells in triple-negative, HER2-positive, and hormone receptor-positive models. Despite encouraging preclinical evidence, clinical translation is limited by instability, immunogenicity, poor pharmacokinetics, delivery barriers, and manufacturing challenges. Emerging advances in peptide engineering, nanodelivery systems, and artificial intelligence-assisted design offer promising strategies to improve pharmacological performance and drug-like properties. Overall, this review provides a medicinal chemistry-guided framework that identifies the key steps and remaining challenges required to support the future development of venom-derived peptides as anticancer lead scaffolds for breast cancer.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}