Archiv der Pharmazie最新文献

{"title":"Design, Synthesis, and Anticancer Evaluation of Febuxostat-Based Triazolyl Derivatives","authors":"Yao Lu,&nbsp;Han Wang,&nbsp;Dong Yan,&nbsp;Baoyu He,&nbsp;Jingjing Guo,&nbsp;Xixi Hou,&nbsp;Ling Liu","doi":"10.1002/ardp.70263","DOIUrl":"10.1002/ardp.70263","url":null,"abstract":"<div>\u0000 \u0000 <p>Febuxostat, a selective xanthine oxidase inhibitor, was modified via 1,2,3-triazole-based molecular hybridization to generate a series of derivatives with potential anticancer activity. Among them, compounds <b>8c</b> and <b>8e</b> exhibited significant antitumor effects across multiple cancer cell lines, particularly in HepG2 cells, with IC₅₀ values of 6.96 ± 1.76 and 8.56 ± 1.93 μM, respectively. Colony formation assays confirmed that both compounds markedly inhibited tumor cell proliferation. Annexin V-FITC/PI and TUNEL assays further demonstrated that <b>8c</b> and <b>8e</b> induced DNA damage and apoptosis in HepG2 cells, as shown by increased γ-H2AX expression and enhanced DNA strand breaks. They also activated intrinsic apoptotic pathways, including the cleavage and activation of caspase-9, caspase-3, and PARP. In vivo, nude mouse xenograft experiments validated their antitumor efficacy, with elevated cleaved caspase-3 levels in tumor tissues. Collectively, these findings indicate that <b>8c</b> and <b>8e</b> possess strong therapeutic potential against liver cancer and exhibit promising efficacy and safety profiles.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148160935","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":"Structure–Activity Relationship Study on Ligands Activating the Voltage-Gated Potassium Channel KV7.1","authors":"Florian Roßner,&nbsp;Judith Schmidt,&nbsp;Guiscard Seebohm,&nbsp;Bernhard Wünsch","doi":"10.1002/ardp.70268","DOIUrl":"10.1002/ardp.70268","url":null,"abstract":"<p>K_V7.1 agonists are promising therapeutic agents for the treatment of hypertension, arrhythmia and preterm labor. The 3-(indol-3-ylmethyl) substituted 1,4-benzodiazepine (R)-L3 has been reported as a potent K_V7.1 activator. In this study, (R)-L3 was systematically modified at eight positions including the configuration at 3-position. For the synthesis of the designed 1,4-benzodiazepines <b>8</b> and <b>12</b>, 2-aminobenzophenones <b>4</b> were reacted with amino acid derived 1,3-oxazolidinediones <b>7</b> or <b>11</b>. The required 2-aminobenzophenones <b>4</b> were obtained regioselectively by Sugasawa reaction of anilines <b>2</b> and <b>3</b> with various substituted benzonitriles, using BCl₃ and AlCl₃. Racemization during deprotonation and alkylation of secondary lactams <b>8</b> and <b>12</b> was not observed. However, racemization occurred during conversion of lactam <b>8b</b> into thiolactam <b>17</b>. The enantiomers of thiolactam <i>rac</i>-<b>17</b> and triazole <i>rac</i>-<b>18</b> were separated by chiral HPLC. The ion channel modulatory activity of the resulting 1,4-benzodiazepines was evaluated by two-electrode voltage-clamp (TEVC) experiments. These TEVC experiments showed that (3<i>R</i>)-configuration and the indolylmethyl moiety at 3-position are essential for K_V7.1 activation. High activity was observed for secondary lactam <b>8b</b> and methylated lactam <b>9b</b>, but larger N-substituents reduced the channel activation. The thioamide (<i>R</i>)-<b>17</b> and the triazole (<i>R</i>)-<b>18</b> did not significantly activate the K_V7.1 channel. Replacement of the F-atom in 2-position of the 5-phenyl moiety by a proton or other halogen atoms reduced the K_V7.1 activity. However, the 9-hydroxy derivative <b>9i</b> appeared to exhibit higher agonistic activity (+68% activity increase at 1 µM) than (R)-L3 (<b>9b</b>, +45% at 1 µM). Moreover, higher phase I metabolic stability was observed for phenol <b>9i</b>.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70268","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148160887","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":"Silymarin and Its Isolated Flavanonol Lignans Are Liver X Receptor Antagonists","authors":"Nils C. Bandomir,&nbsp;Astrid Kaiser,&nbsp;Felix F. Lillich,&nbsp;Pascal Heitel","doi":"10.1002/ardp.70267","DOIUrl":"10.1002/ardp.70267","url":null,"abstract":"<p>Silymarin is a mixture of bioactive natural products from milk thistle (<i>Silybum marianum</i>) fruit extracts, which have a long history as a phytotherapeutic agent in treating various liver-related ailments. Even though important pharmacological effects of silymarin, such as the antioxidative properties, have been proven, the exact molecular mechanisms for its liver-protective action remain elusive. Here, we provide in vitro pharmacological data showing that silymarin, as a mixture and also its individual flavanonol lignans, antagonize liver X receptor (LXR). In HepG2 cells, the isolated silymarin flavanonol lignans showed LXR-mediated anti-steatotic effects that may play a crucial role in the hepatoprotective action of silymarin. Our findings underscore the potential of silymarin, both as a mixture and in the form of its isolated flavanonol lignans, as therapeutic agents for liver disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). There is an urgent need for well-designed clinical trials engaging standardized milk thistle fruit extract to explore its efficacy in MASLD.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148160860","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":"Molecular Insights and Repellent Efficacy of the Essential Oil and Major Compounds From Piper cyrtopodon (Miq.) C.DC (Piperaceae) Against Aedes aegypti (Linnaeus, 1762) (Culicidae)","authors":"Maria L. L. da Costa,&nbsp;Renata G. de Azevedo,&nbsp;Sergio M. Nunomura,&nbsp;Rita de C. S. Nunomura,&nbsp;Gemilson S. Pontes,&nbsp;Rosemary A. Roque,&nbsp;Tatiane P. de Souza,&nbsp;André C. de Oliveira","doi":"10.1002/ardp.70271","DOIUrl":"10.1002/ardp.70271","url":null,"abstract":"<p>Dengue, a mosquito-borne disease transmitted mainly by <i>Aedes aegypti</i>, remains a major global public health concern. In the Americas, over 13 million cases were reported in 2024 and more than 4 million in 2025, highlighting the urgent need for effective preventive strategies. Repellents are among the most practical tools to reduce mosquito–human contact. In this study, the essential oil (EO) from <i>Piper cyrtopodon</i> and cadina-1(10),4-diene showed the highest repellent efficacy (EC₅₀ = 2.68 and 2.31 mg/cm²), followed by germacrene D and δ-Elemene (EC₅₀ = 3.85 and 4.54 mg/cm²). All treatments maintained high repellency levels for up to 270 min under laboratory conditions, showing performance comparable to the reference compound DEET within the experimental conditions. Molecular docking with the mosquito odorant-binding proteins OBP1 and OBP22 suggested favorable binding interactions with the major compounds (–6.8 to –8.4 kcal/mol for OBP1 and –6.8 to –7.3 kcal/mol for OBP22), involving hydrophobic and aromatic contacts within the binding cavity. ADMET predictions indicated high lipophilicity, low aqueous solubility, and limited systemic absorption. No significant cytotoxicity was observed in Vero and PBMC cells up to 25 µg/mL for 72 h. These findings highlight the EO from <i>P. cyrtopodon</i> as a potential source of natural compounds with repellent activity, with emphasis on behavioral repellency under controlled laboratory conditions.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70271","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142074","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":"Therapeutic Potential of Indazole as a Promising Scaffold for Anticancer Drug Development: A Comprehensive Review","authors":"Ashish Vajidwal,&nbsp;Sanjeev Kumar Patel,&nbsp;NS Hari Narayana Moorthy,&nbsp;Akhilesh Tiwari","doi":"10.1002/ardp.70257","DOIUrl":"10.1002/ardp.70257","url":null,"abstract":"<div>\u0000 \u0000 <p>Indazole tautomers (1<i>H</i>- and 2<i>H</i>-) have emerged as privileged scaffolds in drug discovery due to their unique hydrogen-bonding properties, aromatic stability and ability to interact with many oncogenic targets. These structural characteristics of indazole derivatives make them a promising chemical moiety for the development of anticancer drugs. This review aims to elucidate the structural features of indazole derivatives that contribute to their anticancer potential while summarising recent advances in their biological evaluation. Recent studies have revealed that an indazole derivative exhibits several anticancer activities, including kinase inhibition, cell-cycle arrest, apoptosis, DNA interactions and modulation of critical oncogenic pathways. Computational studies supporting structural validation were also discussed to correlate the substitution pattern with biological potency. Discussed patents may highlight innovative synthetic strategies and hybrid molecular designs. In this review, the most active indazole-based compounds are discussed, along with their IC₅₀ values, key structural features and supporting biological evaluations (cell line studies, molecular targets: AURKs, CDKs, EGFR, FGFR, HIF-1, ER-α, MAPKs, PDKs and in vivo studies). Indazole derivatives with potent activity exhibit nano- to micromolar IC₅₀ values, with strategic substitutions markedly improving efficacy and selectivity, highlighting indazole as a potential anticancer scaffold.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142059","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 (6/2026)","authors":"","doi":"10.1002/ardp.70275","DOIUrl":"https://doi.org/10.1002/ardp.70275","url":null,"abstract":"","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148147157","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":"Microneedle-Assisted Skin Delivery of Immunotherapies for Melanoma","authors":"Issac V. Cherian,&nbsp;Md Mustahidul Islam,&nbsp;A. Akash,&nbsp;Abhishek Vijukumar,&nbsp; Janvi,&nbsp;Gautam Singh,&nbsp;Sourabh Kosey,&nbsp;Navjot Kaur Sandhu","doi":"10.1002/ardp.70265","DOIUrl":"10.1002/ardp.70265","url":null,"abstract":"<div>\u0000 \u0000 <p>Melanoma is one of the most aggressive and treatment-resistant skin cancers, and its long-term response to conventional therapies and systemic immune checkpoint blockade has limited efficacy because of immunosuppression induced by tumors and off-target toxicity. Transdermal microneedle (MN)-based drug delivery systems have emerged as an interesting alternative for localized, minimally invasive melanoma immunotherapy in recent years. This review is a critical analysis of the recent breakthroughs in MN-mediated immunotherapeutic models of melanoma, with a focus on the capability to: (1) regulate the tumor microenvironment (TME), (2) improve antitumor immunity, and (3) minimize the systemic adverse effects. The ability of various MN platforms, such as peptide supramolecular MNs, melanin-assisted immunotherapeutic patches, and self-locking MNs produced via micro-stereolithography, to provide sustained, spatially regulated delivery of immune checkpoint inhibitors, adjuvants, and tumor-associated antigens directly into the TME is discussed. A mechanistic understanding of immune activation cascades involving antigen-presenting cell interactions, T-cell priming, and immune memory establishment is illuminated. The review also examines strategies of synergistic combinations of MN-based immunotherapy with photothermal therapy and chemotherapeutic co-delivery to circumvent immune resistance and reprogram the immunosuppressive TME. Other important design factors, such as polymer composition, nanocarrier integration, and stimuli-responsive release mechanisms, are also discussed. There is comparative preclinical evidence that MN-based systems are superior to conventional intratumoral injections in terms of drug retention, immune cell infiltration, and tumor regression. Taken together, this review testifies to the high translational potential of microneedle technologies as highly accurate, patient-acceptable, and multifunctional vehicles of next-generation melanoma immunotherapy.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142137","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":"Synthesis and Biological Evaluations of New 4,5-Diphenyl-Imidazole-Indole-N-Phenylacetamide Derivatives Against α-glucosidase and Acetylcholinesterase.","authors":"Seyedeh Niloufar Ghafouri, Mohammad Halimi, Navid Dastyafteh, Catherine Behzad, Seyed Mostafa Ebrahimi, Marzieh Aghaei Khouzani, Milad Noori, Aydın Aktaş, Nastaran Sadeghian, Armin Dadgar, Bagher Larijani, Maryam Mohammadi-Khanaposhtani, Parham Taslimi, Omidreza Firuzi, Mohammad Mahdavi","doi":"10.1002/ardp.70294","DOIUrl":"https://doi.org/10.1002/ardp.70294","url":null,"abstract":"<p><p>A novel series of 4,5-diphenyl-imidazole-indole-N-phenylacetamide derivatives (6a-m) was designed, synthesized, and evaluated for their inhibitory activities against α-glucosidase and acetylcholinesterase (AChE). Among the thirteen derivatives, nine were more potent than the standard α-glucosidase inhibitor (acarbose), and eleven showed higher potency than the standard AChE inhibitor (tacrine). The most effective compound against α-glucosidase was compound 6l, which demonstrated a 2.1-fold higher potency compared to acarbose. The best compound against AChE was compound 6j, which was 16.9-fold more potent than tacrine. Given that the compounds showed stronger inhibitory activity against AChE than against α-glucosidase, compound 6j, identified as the best AChE inhibitor, was selected for further investigation. Kinetic studies revealed that compound 6j is a competitive inhibitor of AChE. Molecular docking and dynamics simulations confirmed the stability of compound 6j within the active site of AChE. Additionally, compound 6j demonstrated no cytotoxicity at its effective dose against AChE in the normal cell line NIH-3T3, confirming its favorable safety profile at high concentrations.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":"e70294"},"PeriodicalIF":3.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389488","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":"In Vitro, In Silico and Structure-Activity Relationship Evaluation of 3-Amino-thiophene-2-carbohydrazides as Lactoperoxidase Inhibitors.","authors":"Zeynep Köksal, Furkan Çakır, Halil Şenol, Mahmut Sami Erdoğan","doi":"10.1002/ardp.70295","DOIUrl":"https://doi.org/10.1002/ardp.70295","url":null,"abstract":"<p><p>In this study, 18 arylidenehydrazide derivatives (1-18) were systematically evaluated for their inhibitory activity against lactoperoxidase (LPO, EC 1.11.1.7). The inhibitory potential of the derivatives was investigated using in vitro spectrophotometric assays, yielding nanomolar-level K_i values. Among the tested compounds, compound 18 exhibited the most potent activity (IC₅₀ = 0.33 nM, K_i = 0.05 nM) through a competitive inhibition mechanism, whereas compound 10 demonstrated strong non-competitive inhibition (IC₅₀ = 0.52 nM, K_i = 0.20 nM). Complementary in silico analyses, including molecular docking, MM-GBSA calculations, and 250 ns molecular dynamics (MD) simulations, confirmed stable ligand-protein interactions at the active site for compound 18 and at a putative allosteric site for compound 10. The computational findings supported the experimental results by revealing favorable binding affinities driven by hydrogen bonding, π-π stacking, and halogen interactions, maintaining stable interaction profiles throughout the equilibrated simulation period. Furthermore, a structure-activity relationship (SAR) analysis revealed that specific molecular modifications markedly affected the inhibitory potency. In particular, the presence of a hydroxyl (-OH) group at the C1 position and a bromide (-Br) group at the C4 position significantly enhanced the inhibitory activity against LPO. Overall, this integrated experimental and computational study provides deep mechanistic insights into LPO inhibition and establishes a robust foundation for the rational design of novel arylidenehydrazide-based LPO inhibitors.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":"e70295"},"PeriodicalIF":3.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389464","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":"Small Molecules, Big Impact: Structural Innovations Driving PD-L1 Checkpoint Modulation.","authors":"Salma A Haggag, Mohammad Abdel-Halim, Ashraf H Abadi","doi":"10.1002/ardp.70292","DOIUrl":"https://doi.org/10.1002/ardp.70292","url":null,"abstract":"<p><p>Cancer immunotherapy enhances the body's ability to recognize and eliminate tumor cells, mainly by modulating immune checkpoints such as PD-1/PD-L1 and CTLA-4. Monoclonal antibody inhibitors targeting PD-1 or PD-L1 have transformed cancer care, but their high cost, IV administration, and immune-related toxicities have encouraged the development of small-molecule alternatives. Early PD-L1 small-molecule inhibitors, pioneered by Bristol Myers Squibb, block PD-1/PD-L1 interactions by occupying hydrophobic pockets on PD-L1, and SAR studies continue to refine their potency and selectivity. This review focuses on how the structural scaffolds of small-molecule PD-L1 inhibitors determine their mechanisms of action, protein interactions, and biological performance. We examine how different chemotypes influence dimerization of PD-L1, disruption of PD-1 binding, or engagement of additional immune-modulatory pathways. Special attention is given to scaffolds capable of acting through more than one mechanism, as these may offer broader or more durable immunomodulatory effects. We also compare how scaffold design correlates with activity across in vitro assays, co-culture immune models, and in vivo tumor systems, highlighting the physicochemical features that enable or limit translatability. Finally, we discuss emerging clinical efforts, the challenges underlying trial failures, and how refined structural design may guide the next generation of small-molecule PD-L1 inhibitors.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":"e70292"},"PeriodicalIF":3.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389494","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}