Archiv der Pharmazie最新文献

{"title":"Discovery of VEGFR-2 Inhibitors From Leonurus japonicus via Integrated Genetic Authentication, Molecular Networking, and In Silico Analysis","authors":"Thiyagarajan Raviraj,&nbsp;Chen-Lin Yu,&nbsp;Aekkhaluck Intharuksa,&nbsp;Shang-Chih Lai,&nbsp;Vidya Febrasca Tenderly,&nbsp;Yen Chi Loo,&nbsp;Pin-Wei Chen,&nbsp;Shih-Wei Wang,&nbsp;Kartiko Arif Purnomo,&nbsp;Soundar Rajan Kulandhaivel,&nbsp;Sedin Renadi,&nbsp;Stephen Lirio,&nbsp;Yuan-Bin Cheng,&nbsp;Yu-Liang Yang,&nbsp;Tsong-Long Hwang,&nbsp;Fang-Rong Chang,&nbsp;Michal Korinek","doi":"10.1002/ardp.70249","DOIUrl":"10.1002/ardp.70249","url":null,"abstract":"<p>Angiogenesis, regulated by vascular endothelial growth factor (VEGF), is crucial in tumor growth, metastasis, and inflammation. <i>Leonurus japonicus</i> Houtt., a traditional Chinese herb, was investigated for its anti-angiogenic potential. DNA sequencing confirmed its identity, distinguishing it from the common morphological misidentification with <i>Leonurus sibiricus</i> by the public. Using UHPLC-MS/MS and GNPS (Global Natural Products Social) molecular networking on the active methanol partition, over 6000 nodes were grouped into 273 clusters. Diterpenoids and flavonoids were targeted. Six compounds were successfully isolated from <i>L. japonicus</i>, including four labdane-type diterpenoids (<b>1</b>–<b>4</b>) and two flavonoids (<b>5</b>, <b>6</b>) using column chromatography. Compound <b>1</b>, (–)-8<i>S</i>-acetoxy-15,16-epoxy-8,9-seco-13(16),14-labdadiene, was a new stereoisomer, while Compound <b>6</b>, nevadensin, was reported for the first time from this species. Compounds were characterized by NMR, ESI-MS, and ECD. At 50 μM, Compounds <b>1</b>, <b>4</b>, and <b>5</b> exhibited inhibitory effects in endothelial progenitor cell (EPC) tube formation. Molecular docking and dynamics simulations supported this anti-angiogenic activity. Compound <b>1</b> showed the highest VEGFR-2 binding affinity (−9.24 kcal/mol), comparable to sunitinib (−9.52 kcal/mol), further verified by an immunoblotting assay. This study demonstrated the successful integration of GNPS and bioactivity-guided isolation for identifying natural VEGFR-2 inhibitors. Our findings highlight Compounds <b>1</b> and <b>4</b> as promising lead candidates for anti-angiogenic therapy.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719536","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":"Issue Information: Arch Pharm (8/2026)","authors":"","doi":"10.1002/ardp.70316","DOIUrl":"https://doi.org/10.1002/ardp.70316","url":null,"abstract":"","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652475","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":"Targeting Human Protein Kinase CK2 by a Library of Indeno[1,2-b]Indoles: Contribution of Thermal Shift Assay to Pre-Screening and Co-Crystallization to Post-Screening","authors":"Matheus M. Guimarães,&nbsp;Christian Werner,&nbsp;Belen Leroy,&nbsp;Johana Charles,&nbsp;Jean Guillon,&nbsp;Noël Pinaud,&nbsp;Angélique Mularoni,&nbsp;Marc Jean-Baptiste,&nbsp;Perrine Ximenes,&nbsp;Alexander Gast,&nbsp;Helge Prinz,&nbsp;Dagmar Aichele,&nbsp;Alan G. Gonçalves,&nbsp;Christelle Marminon,&nbsp;Zouhair Bouaziz,&nbsp;Joachim Jose,&nbsp;Jean-Guy Delcros,&nbsp;Karsten Niefind,&nbsp;Marc Le Borgne","doi":"10.1002/ardp.70312","DOIUrl":"https://doi.org/10.1002/ardp.70312","url":null,"abstract":"<p>Protein kinase CK2 is the subject of numerous studies in medicinal chemistry due to its involvement in the development of several diseases, primarily cancers. Its overexpression in tumor cells is related to key processes such as tumor immune evasion and cell proliferation. The scientific approach of this study aims to investigate the thermal shift assay (TSA) as a pre-screening tool and to complement it with a co-crystallization approach in post-screening. Therefore, the synthesis of seven small-molecule CK2 inhibitors derived from indeno[1,2-<i>b</i>]indoles was supplemented by 18 related derivatives from our in-house compound library. The 25 molecules belong to four sub-scaffolds, namely 4<i>b</i>,9<i>b</i>-dihydroxy-4<i>b</i>,5,6,7,8,9<i>b</i>-hexahydroindeno[1,2-<i>b</i>]indole-9,10-dione (D-0), 5,6,7,8-tetrahydroindeno[1,2-<i>b</i>]indole-9,10-dione (D-1), 9-hydroxy-5<i>H</i>-indeno[1,2-<i>b</i>]indol-10-one (D-2), and 5<i>H</i>-indeno[1,2-<i>b</i>]indole-6,9,10-trione (D-3). The most active CK2 inhibitors identified by capillary electrophoresis (CE)-based assay belong to the D-1 sub-scaffold. In the TSA, these compounds also generate significant shifts of the melting temperature (Tm) of CK2, indicating a clear correlation between the results of the CE-based assay and those of the TSA. The contribution of co-crystallization in post-screening also demonstrated the effectiveness of D-1 sub-scaffold compared with D-0 sub-scaffold.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652466","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":"4-(5′-Dimethylamino)-Naphthalenesulfonyl-2(3H)-Benzoxazolone (W3D) Ameliorated COPD Lung Injury Through Regulating Macrophage Polarization Mediated by Glycolysis","authors":"Qikai Su,&nbsp;Yichen Yang,&nbsp;Zhichao Ren,&nbsp;Qing-shan Li,&nbsp;Rui Ge,&nbsp;Li Tang","doi":"10.1002/ardp.70311","DOIUrl":"10.1002/ardp.70311","url":null,"abstract":"<div>\u0000 \u0000 <p>Chronic obstructive pulmonary disease (COPD) remains a significant global health challenge, which urges the discovery of novel drugs. In this article, we investigated the therapeutic potential and action mechanism of a new benzoxazolone derivative, 4-(5′-dimethylamino)-naphthalenesulfonyl-2(3<i>H</i>)-benzoxazolone (W3D), synthesized by our research team, against COPD both in vivo and in vitro. The results demonstrated that W3D could down-regulate inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and MMP-9, thereby reducing airway inflammation and improving lung function, which together alleviated lung injury in COPD. Meanwhile, W3D increased the expression of tight junction proteins claudin-1 and occludin and attenuated the activation of the Toll-like receptor 4/nuclear factor kappa B (TLR4)/NF-κB) signaling pathway to maintain the integrity of bronchial epithelial cells. Additionally, W3D restored the expression of glycolytic enzymes such as LDHA, PKM2, and HK2 to modulate lactate levels, thereby correcting glycolytic pathway dysregulation. W3D decreased intracellular lactate content, down-regulated global Kla levels and H3K18la expression, and regulated macrophage polarization in cigarette smoke extract (CSE)-induced macrophages. Furthermore, these therapeutic effects of W3D were compromised in the presence of the glycolytic inhibitor 2-deoxy-<span>d</span>-glucose (2-DG), indicating that W3D regulated macrophage polarization by inhibiting glycolysis. Our results demonstrated that glycolysis was activated in macrophages exposed to CSE and served as a key role in the macrophage polarization process. Inhibiting glycolysis in macrophages might be a potential therapeutic direction for COPD. In addition, given the confirmed protective effect against COPD, W3D could serve as a promising lead compound for further structural modifications of innovative drugs.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519725","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":"Thiazole-Derived Dual EGFR/CDK-2 Inhibitors: Rational Design, Synthesis, In Vitro Anticancer Evaluation, Mechanistic Profiling, and Computational Binding Analysis","authors":"Rowida Nasr,&nbsp;Mohamed S. Nafie,&nbsp;Hesham Haffez,&nbsp;Mohamed Ahmed A. Moustafa,&nbsp;Mohamed M. El-kerdawy,&nbsp;Ahmed R. Ali","doi":"10.1002/ardp.70308","DOIUrl":"10.1002/ardp.70308","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>New series of thiazole analogues were designed, synthesized, and tested for their potential anticancer activity. All the synthesized compounds were biologically tested against HCT-116 and MCF-7 cell lines. Compounds <b>14d</b>, <b>14h</b>, and <b>14i</b> were determined to be the most active members in this series against HCT-116 cancer cell lines with a considerable safety profile. The three lead compounds were further investigated for their inhibitory activities against EGFR and CDK-2. Compound <b>14i</b> exhibited the most potent inhibition, with IC₅₀ values of 0.056 and 0.215 µM against EGFR and CDK-2, respectively, suggesting a possible association between kinase inhibition and the observed cellular activity. Compounds <b>14d</b>, <b>14h</b>, and <b>14i</b> induced early apoptosis (14.40%–18.09%) and G₂/M arrest (51.55%–66.15% population) in HCT-116 cells, with minimal necrosis. Additionally, the screened compounds upregulated pro-apoptotic factors (Bax, cytochrome c, and cleaved caspase-3), while downregulating pro-survival/anti-apoptotic markers (p-AKT1, Bcl-2) and the angiogenic factor VEGF, offering preliminary insight into the potential mechanism of action. EGFR and CDK-2 were among the most prominent genes identified in the network pharmacology analysis of the tested compounds. Molecular docking and molecular dynamics simulations suggested favorable binding modes of compound <b>14i</b> within the active sites of EGFR and CDK-2, with stable interaction patterns observed during the simulation period. Furthermore, compounds <b>14d</b>, <b>14h</b>, and <b>14i</b> showed encouraging in silico ADMET and drug-likeness profiles. Overall, these findings highlight the thiazole series as promising lead compounds with potential dual inhibitory activity, warranting further optimization and mechanistic validation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467924","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":"Total Synthesis of Marine Natural Product Sunshinamide via Macrolactonization","authors":"Yi Lu,&nbsp;Yuanmu Zhang,&nbsp;Hanqi Wang,&nbsp;Ya Gao,&nbsp;Ahmed Sabt,&nbsp;Wei Zhang,&nbsp;Xinsheng Lei","doi":"10.1002/ardp.70306","DOIUrl":"10.1002/ardp.70306","url":null,"abstract":"<div>\u0000 \u0000 <p>A new approach for the synthesis of marine natural product Sunshinamide has been developed, featuring macrolactonization as a key step. The important synthetic strategy is to first construct the unique 8-membered cyclic dithiazocane in the earlier stage and finally carry out macrolactonization according to Shiina's method. Compared with the reported macrolactamization of a linear precursor, the macrolactonization bearing the cyclic dithiazocane scaffold resulted in a lower macrocyclization yield, implying that the cyclic dithiazocane might not offer a more favorable conformational constraint for macrocyclization.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454087","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":"Recent Overview on the Molecular Hybrids Integrated With Benzosuberone/Benzo[7]annulene Derivatives as Multi-Target Therapeutics","authors":"Mohamed S. Nafie,&nbsp;Kamal M. Dawood,&nbsp;Mohamed K. Diab,&nbsp;Ashraf A. Abbas","doi":"10.1002/ardp.70300","DOIUrl":"10.1002/ardp.70300","url":null,"abstract":"<div>\u0000 \u0000 <p>Benzosuberone is a promising scaffold with a remarkably varied pharmacological profile that has been attracting significant interest in the potential development of anticancer agents. This review focuses on the historical interest, diversity of chemical structures, and different medicinal applications of benzosuberone derivatives, particularly as agents with potential anticancer activity. We investigated the relationship between structure modification and biological activity by focusing on the molecular hybrids of the present hit with various functionalities or heterocycles, which led to improved cytotoxicity against several cancer cell lines, and miscellaneous biological activities such as antimicrobial, antiviral, neurological, antiparasitic, anti-diabetic, and antitubercular activities. Detailed in vitro analyses showed promising cytotoxicity against breast, lung, and colon cancers, presenting IC₅₀ values in the low micromolar and submicromolar ranges and low toxicity profiles concerning normal cells. Novel approaches, including the hybrid molecule, combinatory therapy, and nano-formulation, are suggested to go beyond the current obstacles and expand the applications of benzosuberone-based derivatives toward clinical applications. This combined study demonstrates that the benzosuberone scaffold is a privileged structure in the search for miscellaneous biological drugs with high therapeutic potential.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454079","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":"Mutation-Induced Pocket Deactivation: How Ser353/Pro245 Alters KCa2.2 vs. KCa3.1 Ligand Selectivity","authors":"Matteo Gozzi,&nbsp;Joana Massa,&nbsp;Oliver Koch","doi":"10.1002/ardp.70299","DOIUrl":"10.1002/ardp.70299","url":null,"abstract":"<p>The K_Ca2.2 and K_Ca3.1 channels are fundamental regulators of membrane potential and calcium signalling and promising targets to treat diseases such as spinocerebellar ataxia and cancer. To fully exploit their therapeutic potential, and to continue studying their pathophysiological role, it is crucial to develop selective modulators for each of these two channels. Here, we present a computational study to identify the molecular determinants behind the selectivity of two recently reported K_Ca2.2 modulators, namely, N-(2,1,3-benzoxadiazol-4-yl)-3-(4-methoxybenzene-1-sulfonamido)benzamide and N-(2,1,3-benzoxadiazol-4-yl)-4-(trifluoromethyl)benzamide. We leveraged a protocol combining in silico mutagenesis, molecular dynamics simulations, and protein–ligand docking to analyse the pockets targeted by these ligands. We identified the Ser353/Pro245 substitution to be the main driver of the distinct pocket shapes in K_Ca2.2 and K_Ca3.1 channels, ultimately defining modulator selectivity. This approach provides novel insights into the structural differences of this binding site across potassium channel subtypes, proposing potential selectivity determinants of the modulators targeting this pocket.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454091","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":"Evaluation of Novel Cloxyquin Analogs for K2P18.1 Channel Modulation","authors":"Jasmin Sörgel,&nbsp;Marcel Kloth,&nbsp;Henning Klaasen,&nbsp;Sven G. Meuth,&nbsp;Thomas Budde,&nbsp;Bart Jan Ravoo,&nbsp;Julian A. Schreiber","doi":"10.1002/ardp.70310","DOIUrl":"10.1002/ardp.70310","url":null,"abstract":"<p>K_2P18.1 (TRESK) displays one of the most unusual two pore domain potassium channels, that is associated with different neurological and immune-related diseases emphasizing the therapeutic potential of K_2P18.1 activators. Previous studies identified cloxyquin and nitroxoline as lead compounds that do not alter the function of other K_2P channels. Although their 8-OH group is crucial for channel activation, 8-hydroxyquinolines are known for various effects including metal chelation and antibacterial properties increasing the risk of side effects. Therefore, we synthesized 14 quinoline derivatives to search for other tolerated substitutions in 8-position. Activity determination using two-electrode voltage clamp (TEVC) revealed that four derivatives achieved moderate inhibitory or stimulatory activity. Among these, benzaldimine <b>3d</b> represents a new extended scaffold that unexpectedly increases K_2P18.1 channel activity by about 60% at 100 µM. Docking studies suggest that despite the enlarged structure, <b>3d</b> is still able to achieve in silico interactions with important amino acids from the cloxyquin binding site. However, its usability in vitro is limited by hydrolysis leading to a compound half-life of 39 min in aqueous solutions. Nevertheless, the identification of a possible scaffold extension for K_2P18.1 channel activators opens a new opportunity for future compound diversification.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454031","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":"Issue Information: Arch Pharm (7/2026)","authors":"","doi":"10.1002/ardp.70309","DOIUrl":"https://doi.org/10.1002/ardp.70309","url":null,"abstract":"","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148533161","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}