European Journal of Medicinal Chemistry最新文献

{"title":"First Conjugates based on a Sigma Receptor Modulator and a Proteasome-Impairing Agent. Design, Synthesis and Exploratory Biological Evaluation in Cancer Cells.","authors":"Giacomo Rossino, Sara Salvi, Laura Molteni, Melania Elettra Vaccari, Roberta Listro, Pasquale Linciano, Daniela Rossi, Marcello Di Giacomo, Ludovica Aiello, Elena Tosca, Teresa Recca, Mariarosaria Miloso, Alessio Malacrida, Simona Collina","doi":"10.1016/j.ejmech.2026.119491","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119491","url":null,"abstract":"Cancer cells rely on a finely tuned proteostasis network to cope with high metabolic and proliferative demands. Targeting this vulnerability through the simultaneous modulation of both Sigma receptors (SRs) subtypes (i.e. S1R and S2R) and proteasome function represents an attractive and unprecedented strategy for the development of potential anti-cancer agents. The connection between Sigma receptor signalling and proteostasis suggested the design of conjugates combining a SRs modulator scaffold with a scaffold able to reduce proteasomal activity in cells. Here, we report the design, synthesis and exploratory biological evaluation of four conjugates (<ce:bold>15a-b</ce:bold> and <ce:bold>16a-b</ce:bold>) obtained by linking <ce:bold>RC-106</ce:bold> and <ce:bold>IP24</ce:bold> through PEG-based spacers, varying the attachment site on the <ce:bold>RC-106</ce:bold> scaffold and the linker length.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"81 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149358934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of 2-((4-(phenylsulfonyl)piperazin-1-yl)methyl)-1H-indole derivative B9, an Anti-Inflammatory Agent Targeting Acute and Chronic Inflammation for the Treatment of Acute Lung Injury and Diabetic Kidney Disease","authors":"Nan Huang, Miao Yuan, Zhihui Niu, Yulan Xu, Dan Tang, Ke Dong, Zhichao Chen, Yuehua Lv, Qi Chen, Ting Chen, Dongxue Fu, Yunchang Mo, Qian Zhou, Guang Liang, Qidong Tang, Qinxue Dai","doi":"10.1016/j.ejmech.2026.119487","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119487","url":null,"abstract":"Inflammatory diseases constitute a critical category of global health burdens. Acute lung injury (ALI) and diabetic kidney disease (DKD) are representative diseases of acute and chronic inflammatory diseases. Suppression of excessive pro-inflammatory cytokine release represents a promising therapeutic strategy. In this study, we designed and synthesized a series of indole-based derivatives to evaluate their anti-inflammatory potential. Biological evaluation in mouse macrophage (RAW264.7/J774A.1) and human monocytic (THP-1) cells identified compound <ce:bold>B9</ce:bold> as the most potent inhibitor on the release of cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Mechanistic studies demonstrated that <ce:bold>B9</ce:bold> suppressed inflammation by inhibiting the NF-κB/MAPK pathways. <ce:italic>In vivo</ce:italic> toxicity and tissue distribution study showed <ce:bold>B9</ce:bold> having favorable safety profile and high concentrations in lung/kidney. In mouse efficacy studies, <ce:bold>B9</ce:bold> exerted potent anti-inflammatory efficacy against lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced ALI. Moreover, <ce:bold>B9</ce:bold> conferred prominent renoprotective effects in both type 1 and type 2 DKD mouse models. However, the pharmacokinetic profile of <ce:bold>B9</ce:bold> remains suboptimal, warranting further investigation. These findings identified <ce:bold>B9</ce:bold> as a lead structure for further development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"6 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149358936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Green and Scalable Supercritical Fluid Chromatographic Resolution of 5-Nitroindoline Derivatives: Enantiomer-Specific Biological Evaluation and COX-2 Inhibition Insights","authors":"Upputuri Harikrishna, Vivek Hamse Kameshwar, Govinakere Mallegowda Dhanush, Prashantha Kalappa, Nandeesh Kebbahalli Nagalingaiah","doi":"10.1016/j.ejmech.2026.119484","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119484","url":null,"abstract":"We describe an integrated, environmentally conscious workflow that combines synthesis, enantioselective separation, and biological evaluation of 5-nitroindoline-based derivatives. Ten racemic compounds were synthesised &lt;ce:italic&gt;via&lt;/ce:italic&gt; a Petasis multicomponent reaction involving 5-nitroindoline, glyoxylic acid, and various (hetero)aryl boronic acids under trifluoroacetic acid (TFA) catalysis. Enantiomeric resolution was achieved using packed-column supercritical fluid chromatography (SFC) on immobilised and coated polysaccharide chiral stationary phases (Chiralpak IG, Chiral Art Amylose SA, and Chiralpak AS-H), employing CO&lt;ce:inf loc=\"post\"&gt;2&lt;/ce:inf&gt; with 30–40% isopropanol containing 0.5% isopropylamine (IPAm). Rapid screening delivered baseline resolution within 4–7 min under analytical conditions, which translated directly to 21 and 30mm i.d. preparative columns without loss of selectivity, enabling high-throughput isolation of both enantiomers. The racemic compounds and isolated enantiomers were comprehensively characterized by UPLC-QTOF, LC-MS, &lt;ce:sup loc=\"pre\"&gt;1&lt;/ce:sup&gt;H and &lt;ce:sup loc=\"pre\"&gt;13&lt;/ce:sup&gt;C NMR, FT-IR, CHNS analysis, HPLC purity, and specific optical rotation, followed by biological evaluation to assess enantiomer-dependent activity trends. Antibacterial screening against &lt;ce:italic&gt;Staphylococcus aureus&lt;/ce:italic&gt; and &lt;ce:italic&gt;Escherichia coli&lt;/ce:italic&gt; using the disk diffusion assay revealed moderate to significant antibacterial activity for several derivatives, with compounds 4a and 4b exhibiting the most pronounced inhibitory effects and enantiomer-dependent antibacterial behaviour. Furthermore, these derivatives demonstrated strong antibiofilm activity by significantly reducing biofilm formation and biomass in both bacterial strains. A series of enantiomerically enriched derivatives was further evaluated against COX-1 and COX-2 using molecular docking, MM/GBSA binding free-energy calculations, and molecular dynamics simulations. Compound 4a (R) showed selective preference for COX-2, with favorable docking affinity and thermodynamic stabilization. FMO analysis revealed that reduced HOMO–LUMO energy gap and enhanced electrophilicity contribute significantly to biological activity and intermolecular interactions. These findings identify 4a (+) as a promising scaffold for selective COX-2 inhibition and provide important structural and electronic insights for the development of novel anti-inflammatory and antibacterial agents. Overall, the study demonstrates a generalizable, mass-efficient, and scalable chiral separation strategy that minimizes organic solvent consumption while enabling access to stereo-chemically defined molecules for downstream biological investigations. The primary objective of this study was to develop a rapid, scalable, and environmentally sustainable supercritical fluid chromatographic (SFC) platform for the enantiomeric resolution of novel 5-nitroindoline derivatives. The isolated st","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149358944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct-to-Biology High-Throughput Optimization Enables Rapid Hit-to-Lead Discovery of Potent CDK2 Inhibitors","authors":"Huanmin Zhou, Zhidi Chen, Qingcheng Huang, Peijuan Chen, Yizhou Bian, Yu Wang, Yonghao Lin, Xiaozhen Zheng, Junyi Qiu, Xin Lu, Shuiping Fu, Shijie Chen, Dongxiang Liu, Cheng Luo, Ge Sun, Jin Lin","doi":"10.1016/j.ejmech.2026.119490","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119490","url":null,"abstract":"The growing demand for accelerated drug discovery has stimulated the development of Direct-to-Biology (D2B) strategies that integrate compound synthesis with immediate biological evaluation. Herein, we reported a D2B-enabled high-throughput optimization (HTO) platform that combined miniaturized parallel synthesis with fluorescence polarization (FP)-based <ce:italic>in situ</ce:italic> screening for the rapid discovery of cyclin-dependent kinase 2 (CDK2) inhibitors. Guided by structure-based design, a focused library of approximately 1,800 triazole derivatives was efficiently generated in 96-well microplates through copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) without purification. The resulting crude products were directly subjected to competitive FP assays, enabling rapid identification of active compounds through two rounds of biological screening. This workflow led to the discovery of LL-K2in10, which exhibited potent CDK2 inhibition with an IC<ce:inf loc=\"post\">50</ce:inf> value of 0.22<ce:italic>μ</ce:italic>M in the FP binding assay and 43.8nM in the enzymatic assay. Structural characterization of the CDK2–ligand complex revealed multiple hydrogen-bonding interactions responsible for the high binding affinity and provided a structural basis for the observed structure–activity relationships. Subsequent cellular studies provided evidence consistent with CDK2 target engagement, reduced Rb phosphorylation, decreased cell viability, and altered cell-cycle progression in OVCAR3 cells. Collectively, this study established an efficient HTO platform for rapid hit-to-lead optimization and demonstrated its utility for accelerating the discovery of CDK2 inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"81 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149358937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"A novel 20(R) dammarane panaxadiol-indole-2',3'-dione derivative was found to inhibit the growth and migration of colorectal cancer cells by inhibiting EGFR-mediated RalA/EMT pathway\" [Eur. J. Med. Chem. 298 (2025) 118005].","authors":"Hongyan Tan, Liyan Lv, Yue Chai, Jiayi Chai, Chunbo Huang, Linlin Han, Peng Wang, Yuqing Zhao","doi":"10.1016/j.ejmech.2026.119467","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119467","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":" ","pages":"119467"},"PeriodicalIF":6.7,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a highly potent DDR1/2 inhibitor with good kinase selectivity and strong anti-inflammatory efficacy in a mouse model of acute kidney injury","authors":"Michael Härter, Michael Koch, Jan Dreher, Anja Giese, Fabian Göricke, Klemens Lustig, Jürgen Klar, Ambra Pozzi, Corina M. Borza","doi":"10.1016/j.ejmech.2026.119470","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119470","url":null,"abstract":"Discoidin Domain Receptors 1 and 2 (DDR1/2) are receptor tyrosine kinases activated by collagen. Their upregulation and activation are observed in various human diseases, including kidney disease, with most evidence existing for DDR1. Several small-molecule DDR1 inhibitors have shown efficacy in diverse animal models of kidney injury and disease; yet none of them have entered clinical trials. Here, we report on the discovery of a new chemical series of small-molecule DDR inhibitors, based on a dihydropyridopyrimidinyl-benzamide scaffold, and its subsequent hit-to-lead optimization. The chemical series was identified from an in-house screening library by independent virtual and ultra-high throughput screening. The initial screening hit was optimized for potency, kinase selectivity and pharmacokinetic properties, and gave rise to a lead compound suitable for pharmacological <ce:italic>in vivo</ce:italic> studies. The lead compound BAY-852 inhibited collagen-induced receptor activation in kidney cells with IC<ce:inf loc=\"post\">50</ce:inf> values below 1 nM, consistent with the potencies in biochemical assays. In a model of ischemia reperfusion-induced acute kidney injury (AKI), BAY-852 – when administered <ce:italic>via</ce:italic> oral gavage at 2 mg/kg – blocked injury-induced DDR1 phosphorylation, reduced the levels of KIM-1, a marker of tubular injury, and reduced inflammatory cell infiltration. The low effective <ce:italic>in vivo</ce:italic> dose confirms the high potency and the excellent pharmacokinetic properties of BAY-852. Based on these results, the lead compound shows promise and warrants further exploration in animal models of human diseases where DDR1 is upregulated and activated.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149292304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis and SAR Studies of N’-(Heteroarylsalicylidene)- and N’-(Fused-heterobicyclosalicylidene)-N-arenecarbohydrazides as Next-Generation Broad-Spectrum Antifungal Agents","authors":"Ashna Garg, Nathalia Fidelis Vieira de Sa, Ananya Shibana Thennarasu, Kathryn Takemura, Gabriel S. Matos, Jacob Acosta, Neelu Singh, Caroline Correa De Almeida, Nivea Pereira De Sa, Maurizio Del Poeta, Iwao Ojima","doi":"10.1016/j.ejmech.2026.119426","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119426","url":null,"abstract":"The design, synthesis, biological evaluations and SAR study of <ce:italic>N’</ce:italic>-heteroarylsalicylidene- and <ce:italic>N′</ce:italic>-(fused-heterobicyclosalicylidene)-<ce:italic>N</ce:italic>-arenecarbohydrazides, as the next-generation broad-spectrum antifungal agents effective against fungal pathogens in WHO’s Fungal Priority Pathogen List (FPPL), are reported. A library of 58 compounds thus synthesized were examined for their potency against <ce:italic>C. neoformans, C. albicans</ce:italic> and <ce:italic>A. fumigatus</ce:italic> to select highly potent broad-spectrum lead compounds. Against <ce:italic>C. neoformans</ce:italic>, 52 out of 58 compounds show high potency and 7 compounds, bearing furan and thiazole on the ring B, exhibited extremely high potency (MIC<ce:inf loc=\"post\">80</ce:inf> 0.001∼0.007 μg/mL). A good number of compounds showed high potency against <ce:italic>C. albicans</ce:italic> (MIC<ce:inf loc=\"post\">80</ce:inf><ce:italic>≤</ce:italic> 0.5 μg/mL). In contrast, only 10 out of 58 compounds showed good activity against <ce:italic>A. fumigatus</ce:italic> (MIC<ce:inf loc=\"post\">80</ce:inf> &lt;1 μg/mL).","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"85 1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149292310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “ Engineering β-amino acid antimicrobial peptides with enhanced stability and potential efficacy against gram-negative bacterial infections” [Eur. J. Med. Chem. 310 (2026) 118802]","authors":"Jingyi Zhu, Luyang Gao, Wenjing Xue, Jing Zou, Jiahui Wang, Yashi Wang, Yun Zhang, Sanhu Gou, Hui Liu, Chao Zhong, Jingman Ni","doi":"10.1016/j.ejmech.2026.119444","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119444","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149233038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"AVP-GPT2: Prompt-conditioned fine-tuning of a GPT-2 protein language model for antiviral peptide identification\" [Eur. J. Med. Chem. 320 (2026) 119352].","authors":"Maryam, Hamza Zahid, Kil To Chong, Hilal Tayara","doi":"10.1016/j.ejmech.2026.119409","DOIUrl":"10.1016/j.ejmech.2026.119409","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":" ","pages":"119409"},"PeriodicalIF":6.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A hierarchical targeting one-for-all small-molecule enabling multimodal tumor therapy via energy blockade and heat-tolerance suppression","authors":"Zhizhe Li,Haonan Zheng,Yingying Ma,Tingting Li,Shuang Ma,Mi Li,Haiyan Xu,Shide Zheng,Hongqing Guo,Xinyu Wang,Weige Zhang,Qi Guan","doi":"10.1016/j.ejmech.2026.119299","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119299","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"74 1","pages":"119299"},"PeriodicalIF":6.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148895657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}