European Journal of Medicinal Chemistry最新文献

{"title":"Preclinical evaluation of 68Ga-labelled Pt(IV)-DFO complexes as PET-imaging agents for osteosarcoma","authors":"Ines Lopez-Martinez,Lena Zachhuber,Giulia Ferrari,Daniela Prinz,Mario Laskaj,Maximilian Krisch,Eva-Maria Patronas,Diego Montagner,Marcus Hacker,Cécile Philippe,Claudia Kuntner,Thomas Wanek","doi":"10.1016/j.ejmech.2026.119302","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119302","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"16 1","pages":"119302"},"PeriodicalIF":6.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148895658","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 and Characterization of PGC-01: An Effective GSDMD-Targeting PROTAC","authors":"Qian-qian Wang, Rong-ying Hou, Yi-xuan Shua, Ya-fei Xu, Wen-jing Bian, Wen Xiao, Yu-qing Chen, Bing-yu Zhou, Yue Gao, Li Liu, Yu-hang Wang, Yi-bei Xiao, Cheng Jiang","doi":"10.1016/j.ejmech.2026.119294","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119294","url":null,"abstract":"As the key executioner protein of pyroptosis, GSDMD represents a promising yet underexplored therapeutic target for inflammatory diseases. In this study, we explored a PROTAC-based degradation approach targeting GSDMD for the treatment of pyroptosis-driven inflammatory conditions. Through screening of our in-house compound library, we identified a high-affinity GSDMD binder, <ce:bold>PGC</ce:bold> (K<ce:inf loc=\"post\">D</ce:inf> = 9.42 nM). Through rational design of linkers and systematic optimization of the E3 ligase attachment site, we constructed a series of PROTACs and identified <ce:bold>PGC-01</ce:bold> as a CRBN-recruiting and effective GSDMD degrader (DC<ce:inf loc=\"post\">50</ce:inf> = 3.32 μM, D<ce:inf loc=\"post\">max</ce:inf> = 85%). Functionally, <ce:bold>PGC-01</ce:bold> concentration-dependently suppressed nigericin-induced macrophage pore formation, cell death, and IL-1β release. In vivo, rectal administration of <ce:bold>PGC-01</ce:bold> dose-dependently alleviated clinical symptoms and pathological damage in a DSS-induced murine colitis model. Collectively, this study provides critical proof-of-concept that targeted degradation of GSDMD is a viable therapeutic strategy and positions <ce:bold>PGC-01</ce:bold> as a promising lead compound for the treatment of GSDMD-driven inflammatory diseases.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"492 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885570","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":"From indole to pyrrole-based inhibitors of the large GTPase, dynamin and the in-cell inhibition of clathrin mediated endocytosis","authors":"Beatrice Chiew, Nicholas S. O’Brien, Kate Prichard, Michael P. Hamilton, Mohammed K. Amin, Bryony Munro, Jakobi Stegh, Jing Xue, Phillip J. Robinson, Adam McCluskey","doi":"10.1016/j.ejmech.2026.119258","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119258","url":null,"abstract":"Four libraries of dynole 34-2 (<ce:bold>1</ce:bold>, (<ce:italic>E</ce:italic>)-2-cyano-3-(1-(3-(dimethylamino)propyl)-1<ce:italic>H</ce:italic>-indol-3-yl)-<ce:italic>N</ce:italic>-octylacrylamide) analogues were synthesized with a view of maintaining or improving dynamin inhibition and expanding the <ce:italic>in vivo</ce:italic> utility of dynole 34-2 – a ubiquitously used dynamin chemical probe. A total of 62 compounds were assessed for dyn I inhibition, 39 and 13 analogues were identified with dynI IC<ce:inf loc=\"post\">50</ce:inf> values of &lt;10 and &lt; 5 μM, respectively: equipotent to Dynole 34-2. Eight sub 5 μM potent analogues were screened for their ability to block in cell inhibition of clathrin mediated endocytosis (CME) with six analogues with IC<ce:inf loc=\"post\">50</ce:inf> values ≤ 20 μM. Moreover, five of these analogues displayed improved cLogPs and drug scores relative to dynole 34-2, with the most potent dynamin active analogue: (<ce:italic>E</ce:italic>)-3-(4-(3-chlorophenyl)-1-(3-(dimethylamino)propyl)-1<ce:italic>H</ce:italic>-pyrrol-3-yl)-2-cyano-<ce:italic>N</ce:italic>-octylacrylamide (<ce:bold>94</ce:bold>) Dyn I IC<ce:inf loc=\"post\">50</ce:inf> = 3.1 ± 0.9 μM; the most CME active analogue: <ce:italic>(E</ce:italic>)-2-cyano-3-(1-(3-(dimethylamino)propyl)-4-(3-hydroxyphenyl)-1<ce:italic>H</ce:italic>-pyrrol-3-yl)-<ce:italic>N</ce:italic>-octylacrylamide (<ce:bold>97</ce:bold>) with IC<ce:inf loc=\"post\">50CME</ce:inf> = 4.3 μM. Analogue <ce:bold>97</ce:bold> displayed the best combination of dyn and CME inhibition with IC<ce:inf loc=\"post\">50</ce:inf> values of 3.3 ± 2.3 and 4.3 μM, respectively.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885572","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":"Synthesis and biological activity of steroid conjugates of five-membered N-heterocycles with one or two nitrogen atoms: A review covering the years 2020-2025","authors":"Ali Abbas Abo Algon,Rita Skoda-Földes","doi":"10.1016/j.ejmech.2026.119300","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119300","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"80 1","pages":"119300"},"PeriodicalIF":6.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148895656","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":"Exploring the Role of Conformational Restriction in 5-Аlkyl-6-benzyl-2-{[(methylthio)methyl]thio}pyrimidin-4(3H)-ones: Effects in HIV-1 Infected Cells and Reverse Transcriptase Enzymes","authors":"Egor Degtyarenko,Gebremedhin Solomon Hailu,Emanuele Fabbrizi,Anastasia Golovina,Andrey Voronkov,Roberta Astolfi,Lidia Giuliani,Andrea Mancini,Maxim B. Nawrozkij,Vladimir Chernyshov,Clarissa Pupillo,Roberto Cirilli,Laura Bavagnoli,Rino Ragno,José A. Esté,Emmanuele Crespan,Francesco Fiorentino,Roman Ivanov,Antonello Mai,Dante Rotili","doi":"10.1016/j.ejmech.2026.119304","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119304","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"176 1","pages":"119304"},"PeriodicalIF":6.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148895660","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":"Precision chemoenzymatic tailoring of bioengineered low-molecular-weight heparins for protamine-reversible anticoagulation.","authors":"Lin Wang, Yali Wang, Fengyan Tang, Yanzhen Cheng, Ziyi Zhou, Qiuhan Xu, Jiukun Liu, Chunhui Liu","doi":"10.1016/j.ejmech.2026.119275","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119275","url":null,"abstract":"<p><p>Animal-derived low-molecular-weight heparins (LMWHs) are essential anticoagulants but are associated with supply chain vulnerabilities and contamination risks, alongside incomplete protamine reversibility in clinical practice. Herein, we report the precision chemoenzymatic tailoring of bioengineered LMWHs from Escherichia coli K5 capsular polysaccharide (heparosan) to achieve protamine-reversible anticoagulation. Through the integration of chemical N-deacetylation/N-sulfation, precisely regulated C₅-epimerization/2-O-sulfation, controlled β-eliminative depolymerization, and sequential enzymatic 6-O/3-O-sulfation, the molecular weight distribution and specific sulfation patterns were rationally modulated. The representative bioengineered product, L3S-2, exhibited potent anti-factor Xa activity, an optimized anti-factor Xa/anti-factor IIa ratio, and pharmacokinetic properties comparable to enoxaparin following subcutaneous administration. Crucially, L3S-2 demonstrated significantly improved protamine reversibility both in vitro and in vivo compared to commercial enoxaparin. In rat thrombosis models, L3S-2 potently inhibited venous and arterial thrombus formation, demonstrating efficacy comparable to enoxaparin. These findings establish a rational design framework for bioengineered anticoagulants, demonstrating that optimizing multivalent electrostatic interactions with protamine via tailored sulfation and molecular weight yields highly reversible agents with optimized therapeutic indices.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119275"},"PeriodicalIF":6.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878796","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":"Redundancy-aware AI-guided discovery and experimental validation of antimicrobial peptides for infected wound treatment.","authors":"Yabo Deng, Mengyun Gu, Xinlu Ren, Jianna Meng, Hai Guo, Yihao Xie, Yunxiang Yu, Zhou Zhang, Yi Zhou, Yunke Wu, Danna Chen, Zhiqiang Shen, Jiexi Yan, Jian Han, Wenjin Yan, Jinqi Huang","doi":"10.1016/j.ejmech.2026.119277","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119277","url":null,"abstract":"<p><p>Artificial intelligence (AI) is accelerating antimicrobial peptide (AMP) discovery, but prediction-centered workflows often overlook dataset redundancy, peptide synthesizability, and experimental anti-infective translation. Here, we developed a redundancy-aware AI-guided peptide discovery workflow integrating redundancy-controlled dataset construction, model interpretation, candidate screening, synthesis-linked experimental validation, and evaluation in an infected-wound model. A redundancy-retention (RR) dataset of 1861 peptides with E. coli MIC annotations was compared with CD-HIT-filtered CD60-CD90 datasets containing 439-1061 sequences. Redundancy control reshaped activity-density distributions, SHAP-derived feature dependence, and virtual-screening stringency. Screening 2.1 million random 13-mer peptides yielded 1763, 189, 157, 141, and 20 candidates from CD60, CD70, CD80, CD90, and RR workflows, respectively. Experimental synthesis and MIC testing showed that the RR-derived group had a higher mean crude yield and a higher hit rate against E. coli than the CD90-derived group (60% vs 20%; MIC ≤16 μM). The lead peptide A36 showed broad activity against the tested Gram-negative bacteria, inhibited drug-resistant clinical A. baumannii isolates, displayed low hemolysis and cytotoxicity, retained substantial integrity in serum and antibacterial activity after protease exposure, disrupted bacterial membranes, and reduced bacterial burden while promoting wound closure in an A. baumannii-infected wound model. These findings identify redundancy control as a practical factor influencing candidate selection, synthetic accessibility, and experimental hit recovery in AI-guided AMP discovery.</p>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119277"},"PeriodicalIF":6.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862888","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":"AI agent-based discovery of antimicrobial Peptides against multidrug-resistant Gram-negative bacterial infection","authors":"Yan Zhang, Xinyuan Zhang, Xiaojie Chen, Jingrui Chen, Lingcong Kong, Hongxia Ma","doi":"10.1016/j.ejmech.2026.119279","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119279","url":null,"abstract":"The emergence of multidrug-resistant gram-negative bacteria poses a severe threat to global public health, and the limitations of traditional antibiotics in efficacy and drug resistance have become increasingly prominent. This study integrated AI technologies, including RFdiffusion and ProteinMPNN, to design and screen a novel antimicrobial peptide, AMP-ZJLC586, which exhibited potent antimicrobial activity against multidrug-resistant gram-negative bacteria, with a minimum inhibitory concentration (MIC) ranging from 0.5 to 8 μg/mL, and has the characteristics of high stability and low cytotoxicity. In addition, it can also kill clinically isolated drug-resistant bacteria and inhibit the formation of their biofilms.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885575","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":"Development of GS-441524 Derivatives as Potent SARS-CoV-2 Mac1 Inhibitors via a Direct-to-Biology Approach","authors":"Kewen Peng, Suryadeep Chakraborty, Shamar D. Wallace, Jessica Caroline Gomes Noll, Jialin Shang, Xuan Lu, Annette Choi, Gary Whittaker, J. Christopher Fromme, Hening Lin","doi":"10.1016/j.ejmech.2026.119280","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119280","url":null,"abstract":"Targeting viral macrodomains (Mac) has emerged as a promising strategy for antiviral drug development, especially after the outbreak of COVID-19 that claimed millions of lives worldwide. Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mac1 inhibitors have been reported in the past few years. In the present work, we converted GS-441524 (IC<ce:inf loc=\"post\">50</ce:inf> of ∼10 μM for SARS-CoV-2 Mac1) to KP-S54 (<ce:bold>18c</ce:bold>), a potent inhibitor of both SARS-CoV-2 Mac1 (IC<ce:inf loc=\"post\">50</ce:inf>: 44 nM) and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 (IC<ce:inf loc=\"post\">50</ce:inf>: 91 nM) through an iterative direct-to-biology approach. This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative (<ce:bold>12p</ce:bold>) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"240 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885574","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":"Integrated Computational and Automated Flow Synthesis Platform for the Rapid Discovery of N-Benzylpiperidine Acetylcholinesterase Inhibitors.","authors":"A. Michelle Reinhardt, Anjo Theron, Asongwe Lionel Ateh Tantoh, Frederick P. Malan, Jenny-Lee Panayides, Darren L. Riley","doi":"10.1016/j.ejmech.2026.119259","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119259","url":null,"abstract":"The principal constraint on early-stage medicinal chemistry in an academic setting is rarely the supply of chemical ideas, but the cycle time required to convert them into tested compounds. Here we benchmark an integrated platform that couples ensemble virtual screening, automated continuous-flow library synthesis with inline scavenging, and biological profiling. The platform was evaluated deliberately on a target–scaffold combination for which the pharmacology is already established: the <ce:italic>N</ce:italic>-benzylpiperidine carboxamide class, identified in our earlier virtual screening campaign against acetylcholinesterase (AChE)[1] and structurally anchored to the approved therapeutic donepezil (<ce:bold>1</ce:bold>). This choice makes platform performance, the measured variable. An 84-member virtual library was designed, triaged by ensemble docking, and synthesised on an automated flow platform; 54 members were isolated in ≥95% purity. Single-point screening at 5 μM identified ten compounds with ≥70% AChE inhibition, and dose–response determination against electric eel AChE (<ce:italic>ee</ce:italic>AChE) gave three sub-200 nM inhibitors: <ce:bold>69</ce:bold> (91 nM), <ce:bold>8</ce:bold> (93 nM) and <ce:bold>12</ce:bold> (117 nM), each exceeding galantamine (237 nM) and approaching donepezil (<ce:bold>1</ce:bold>, 42 nM) under identical assay conditions. Cytotoxicity against VERO cells was uniformly low (IC<ce:inf loc=\"post\">50</ce:inf> &gt; 250 μM), giving selectivity indices above 2000. Molecular dynamics simulations and twelve single-crystal X-ray structures provide a structural basis for the observed structure–activity relationships, identifying a C–Br···O halogen bond to Asp72 as the origin of the <ce:italic>ortho</ce:italic>-bromo preference, and a binding-mode reversal that accounts for the loss of potency on benzylpiperazine extension. The complete cycle was executed in under three months by a three-person team. We report this as a measured platform capability rather than as accelerated drug discovery allowing the rapid generation of first-round leads.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885576","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}