European Journal of Medicinal Chemistry最新文献

{"title":"Corrigendum to: “Discovery and optimization of tetrahydroacridine derivatives as a novel class of antibiotics against multidrug-resistant gram-positive pathogens by targeting type I signal peptidase and disrupting bacterial membrane” [Eur. J. Med. Chem. ISSN 0223–5234, (283, 2025, 117101]","authors":"Xiaolin Lu , Jinhu Huang","doi":"10.1016/j.ejmech.2025.117916","DOIUrl":"10.1016/j.ejmech.2025.117916","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"296 ","pages":"Article 117916"},"PeriodicalIF":6.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516198","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":"Research progress on the structure and activity of phenylpropanoid glycosides","authors":"Guangyao Liu ,&nbsp;Errui Zhang ,&nbsp;Xi Xiang ,&nbsp;Yulong Zhu ,&nbsp;Houchao Tao ,&nbsp;Weiliang Gu","doi":"10.1016/j.ejmech.2025.117921","DOIUrl":"10.1016/j.ejmech.2025.117921","url":null,"abstract":"<div><div>Phenylpropanoid glycosides (PPGs) are a diverse class of naturally occurring compounds, demonstrating wide-ranging bioactivity across multiple pharmacological domains, including antioxidant, anti-inflammatory, antibacterials, anti-tumor, and platelet aggregation inhibitory effects. Composed of phenylpropanoid aglycones linked to various sugar moieties, these glycosides exhibit considerable structural diversity that influences their bioactivity. The unique structures and medicinal potential of PPGs have garnered extensive research interest. This article provides a systematic overview of recent progress in understanding the biological activities, identification of new structures and synthetic approaches of PPGs. By summarizing current findings, this review aims to support future research and development in PPG applications, particularly in the context of pharmaceutical applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117921"},"PeriodicalIF":6.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521125","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":"1,3-Thiazole nucleus as promising molecular platform against antimicrobial resistance: a recent overview in drug discovery","authors":"Gleyton L.S. Sousa,&nbsp;Douglas C.A. Pinto,&nbsp;Isadora M.G. Andrade,&nbsp;Gustavo S.G. de Carvalho,&nbsp;Fernando C. da Silva","doi":"10.1016/j.ejmech.2025.117917","DOIUrl":"10.1016/j.ejmech.2025.117917","url":null,"abstract":"<div><div>Antimicrobial resistance (AMR) has emerged as one of the foremost public health threats of the 21st century. The progressive decline in the efficacy of conventional antibiotics, combined with a scarcity of new drug classes approved in recent decades, has created a critical and alarming scenario. In this context, new biological, chemical, and artificial intelligence tools have played a fundamental role in supporting the discovery of compounds aimed at improving safety, efficacy, and broad-spectrum activity, addressing both AMR and the high costs associated with drug development. Recent data from the World Health Organization (WHO) highlight a list of priority pathogens intended to guide efforts in the search for new therapeutic options. Most compounds currently in preclinical and clinical development are small molecules with direct mechanisms of action. Within this landscape, the search for new molecular scaffolds has focused especially on derivatives of natural compounds and synthetic heterocyclic structures. Among these, derivatives containing the 1,3-thiazole core have stood out due to their synthetic versatility and ability to interact with various bacterial molecular targets. This review provides a comprehensive overview of different classes of thiazole derivatives with demonstrated activity against multidrug-resistant bacterial strains. Their mechanisms of action, relevant chemical, and pharmacological properties, as well as methodological approaches applied to the discovery of these bioactive compounds are discussed highlighting their potential in the development of new therapeutic alternatives to combat bacterial resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117917"},"PeriodicalIF":6.0,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516193","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":"Local enhancement of cationic charge density via polyamine side chain incorporation improves the selectivity of antimicrobial peptoids","authors":"Jinyoung Oh ,&nbsp;Su-Mi Choi ,&nbsp;Yeojin Yun ,&nbsp;Jieun Choi ,&nbsp;Annelise E. Barron ,&nbsp;Kyung-Hwa Park ,&nbsp;Jiwon Seo","doi":"10.1016/j.ejmech.2025.117920","DOIUrl":"10.1016/j.ejmech.2025.117920","url":null,"abstract":"<div><div>Antimicrobial resistance poses a critical threat to global health, necessitating the development of new therapeutics. Peptoids are synthetic analogs of peptides with an N-substituted glycine backbone and have been investigated for antimicrobial therapeutic applications due to their resistance to proteolysis and tunable structures. This study explores antimicrobial peptoids functionalized with polyamine side chains, leveraging the cationic nature of polyamines to enhance interactions with bacterial membranes. A structure-activity relationship (SAR) analysis was conducted to elucidate the influence of polyamine chain length and density on antimicrobial potency and selectivity. The optimized peptoids demonstrated potent activity against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains, while maintaining low cytotoxicity toward mammalian cells. Mechanistic studies demonstrated that these peptoids employ multiple killing mechanisms, including membrane disruption, oxidative damage, and intracellular aggregation of proteins and nucleic acids. This work highlights the potential of polyamine-functionalized peptoids for developing next-generation antimicrobial agents and provides insights into the design principles for enhancing their efficacy and safety.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117920"},"PeriodicalIF":6.0,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516199","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":"Lead optimization of a CHI3L1 inhibitor for Glioblastoma: Enhanced target engagement, pharmacokinetics, and efficacy in 3D spheroid models","authors":"Baljit Kaur,&nbsp;Hossam Nada,&nbsp;Longfei Zhang,&nbsp;Moustafa T. Gabr","doi":"10.1016/j.ejmech.2025.117924","DOIUrl":"10.1016/j.ejmech.2025.117924","url":null,"abstract":"<div><div>Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, necessitating the development of novel therapeutics with improved efficacy and pharmacokinetic (PK) profiles. CHI3L1 (chitinase-3-like protein 1) is a secreted glycoprotein overexpressed in GBM, where it promotes tumor progression and immune evasion; however, no small molecule CHI3L1 inhibitors with demonstrated in vivo efficacy in GBM models are currently available. Herein, we present the lead optimization of <strong>K284</strong> - a previously reported CHI3L1 inhibitor - toward its application in glioblastoma (GBM) therapy. We employed microscale thermophoresis (MST), surface plasmon resonance (SPR), and molecular docking to design and evaluate novel <strong>K284</strong> derivatives targeting GBM. Among the synthesized compounds, <strong>11g</strong> emerged as a promising candidate, exhibiting superior CHI3L1 binding affinity and improved PK parameters compared to <strong>K284</strong>. Notably, <strong>11g</strong> demonstrated extended plasma half-lives (t₁/₂ = 2.5 ± 0.2 h in human and 2.0 ± 0.1 h in mouse) and microsomal stability (t₁/₂ = 2.8 ± 0.5 h in human and 2.2 ± 0.4 h in mouse), along with reduced intrinsic clearance (Cl_int = 15 ± 1.2 mL/min/mg in mouse and 19 ± 1.1 mL/min/mg in human). The <strong>11g</strong> compound also showed improved solubility, favorable permeability, and decreased plasma protein binding. Safety profiling revealed lower cardiotoxic potential and reduced cytotoxicity toward normal human astrocytes relative to <strong>K284</strong>. Furthermore, in a 3D multicellular GBM spheroid model, <strong>11g</strong> induced dose-dependent cytotoxicity, reduced spheroid mass by over 50 %, and inhibited migration by approximately 60 %, whereas <strong>K284</strong> exhibited minimal activity. These findings underscore compound <strong>11g</strong> as a potent and multifaceted anti-GBM agent with favorable pharmacological and safety characteristics, warranting further in vivo investigation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117924"},"PeriodicalIF":6.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515598","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 and synthesis of Riluzole-Ciprofloxacin hybrids as selective MST3 inhibitors for cancer treatment","authors":"Deping Li ,&nbsp;Shuoqi Huang ,&nbsp;Jinjin Lai ,&nbsp;Jianxiong Yang ,&nbsp;Wenwu Liu ,&nbsp;Renze Yang","doi":"10.1016/j.ejmech.2025.117923","DOIUrl":"10.1016/j.ejmech.2025.117923","url":null,"abstract":"<div><div>The MST3 isozyme is integral to the modulation of cellular proliferation and apoptosis, with its dysregulation critically implicated in the tumorigenesis of high-grade neoplasms. Current investigations into MST3 inhibitors are in their initial stages, characterized by restricted structural diversity and suboptimal selectivity. Previous studies have shown that Riluzole and Ciprofloxacin have the potential to be repurposing into the tumor field. Notably, their hybridization may facilitate the formation of a continuous hydrogen bonding network between donor and acceptor moieties, thereby augmenting their applicability as novel kinase inhibitors. In this study, we designed and synthesized a series of Riluzole-Ciprofloxacin hybrids, subsequently identifying the lead compound <strong>LD-1</strong> (GI₅₀ = 683.1 nM in HepG2 cells) through an anti-proliferative screening process. Comprehensive kinase profiling and target inhibition assays revealed that <strong>LD-1</strong> functions as a potent and selective inhibitor of MST3, exhibiting an IC₅₀ value of 122.4 nM. Preliminary mechanistic studies indicated that <strong>LD-1</strong> reduced the expression levels of cleaved caspase-3 and Bcl-2, resulted in inducing HepG2 cells apoptosis. Meanwhile, it decreased the expression level of cyclin B1 in a concentration-dependent manner, leading to cell cycle at the G2/M transition. The <em>in vivo</em> experiments demonstrated that <strong>LD-1</strong> significantly suppressed tumor growth (TGI = 47.64 %) at a dosage of 40 mg/kg, coupled none obvious adverse reactions were observed. Collectively, <strong>LD-1</strong>, characterized by its novel structure, high potency, and selectivity as an MST3 inhibitor, showcases substantial potential for further investigation and therapeutic development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117923"},"PeriodicalIF":6.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515599","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 novel thiazolylhydrazone derivatives as potent anti-cancer agents inducing ferroptosis via direct NRF2 inhibition","authors":"Xiaolu Meng ,&nbsp;Tianqi Xu ,&nbsp;Lunan Xu ,&nbsp;Yixiang Du ,&nbsp;Fan Huo ,&nbsp;Anchang Jin ,&nbsp;Yajin Li ,&nbsp;Chao Yan ,&nbsp;Yaliang Zhang ,&nbsp;Tengfei Huang","doi":"10.1016/j.ejmech.2025.117912","DOIUrl":"10.1016/j.ejmech.2025.117912","url":null,"abstract":"<div><div>Nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) is a key transcription factor regulating antioxidant defense and iron metabolism. Its activation confers ferroptosis resistance to cancer cells and promotes tumor progression. In this study, we designed and synthesized a novel series of thiazolylhydrazone derivatives (<strong>1a</strong>-<strong>1g</strong>, <strong>2a</strong>-<strong>2e</strong>, and <strong>3a</strong>-<strong>3i</strong>) as NRF2 inhibitors and evaluated their antiproliferative activities against a panel of cancer cell lines. Among them, PhcY emerged as the most potent compound. Molecular docking studies demonstrated its strong binding affinity to the NRF2 active site, indicating direct inhibition. PhcY induced ferroptosis in MCF-7 breast cancer cells <em>via</em> NRF2 inhibition. Mechanistic investigations revealed that PhcY disrupted cellular iron homeostasis, facilitated ferritin degradation, and ultimately triggered ferroptosis. <em>In vivo</em>, PhcY demonstrated significant antitumor efficacy in MCF-7 xenograft-bearing mice at a dose of 10 mg/kg. These findings highlight the potential of thiazolylhydrazone derivatives, particularly PhcY, as NRF2-targeted ferroptosis inducers for cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117912"},"PeriodicalIF":6.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515600","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":"Recent advance of hypoxia-inducible factor prolyl hydroxylases inhibitors for anemia therapy","authors":"Dan Wang ,&nbsp;Wancheng Zhao ,&nbsp;Yang Wang ,&nbsp;Sha Ni,&nbsp;Chong Feng,&nbsp;Shenshen Yao","doi":"10.1016/j.ejmech.2025.117907","DOIUrl":"10.1016/j.ejmech.2025.117907","url":null,"abstract":"<div><div>Recent advancements in prolyl hydroxylase domain enzyme (PHD) inhibitors have revolutionized anemia treatment by targeting hypoxia-inducible factor (HIF) pathways. Initially, PHD enzymes were identified as critical regulators of HIF-α degradation under normoxia. The discovery of PHD inhibitors emerged from understanding their role in stabilizing HIF-α, which stimulates erythropoietin (EPO) production and iron metabolism, addressing anemia pathophysiology. Early inhibitors, such as FG-2216, demonstrated proof-of-concept but faced safety concerns, prompting structural optimization to enhance selectivity and pharmacokinetic profiles. Subsequent generations, exemplified by roxadustat, incorporated modifications to reduce off-target effects and improve oral bioavailability, achieving clinical efficacy in renal anemia. Optimization strategies focused on balancing potency, tissue specificity, and minimizing adverse effects. The iterative discovery-to-optimization process underscores the value of PHD inhibitors as templates for novel therapies targeting hypoxia-responsive diseases, while ongoing research addresses challenges in long-term safety and patient-specific response variability. This progress solidifies PHD inhibitors as pivotal tools for anemia management and broader therapeutic innovation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117907"},"PeriodicalIF":6.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515597","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 SA-8 as a potent SHP2-AUTAC degrader in cancer therapy","authors":"Haoze Song ,&nbsp;Xiaoxue Zou ,&nbsp;Jing Liang ,&nbsp;Han Huang ,&nbsp;Yang Liu ,&nbsp;Yuqin Zhang ,&nbsp;Yang Liu ,&nbsp;Lixia Chen ,&nbsp;Hua Li","doi":"10.1016/j.ejmech.2025.117918","DOIUrl":"10.1016/j.ejmech.2025.117918","url":null,"abstract":"<div><div>Src homology region 2-containing phosphatase 2 (SHP2) is overexpressed in various cancers and suppresses immune function while promoting tumor immune escape by regulating intracellular signaling pathways. Currently, the primary therapeutic strategies targeting SHP2 focus on inhibiting its catalytic activity or reducing its expression levels. However, SHP2 allosteric inhibitors face challenges in terms of efficacy, safety, and developmental difficulty when used as monotherapy. Consequently, several SHP2-PROTAC molecules have been developed. Given the limited substrate spectrum of ubiquitin-proteasome systems, we propose that autophagy-based degradation strategies possess greater advantages. Using SHP099 as the ligand of the protein of interest (POI), we designed and synthesized two series of SHP2-AUTACs. Among these, <strong>SA-8</strong> demonstrated the optimal biological activity, showing significant antitumor activity and potent SHP2 degradation capability. Mechanistic studies revealed that <strong>SA-8</strong> induced SHP2 degradation through ternary complex formation with both SHP2 and LC3, ultimately activating the autophagy-lysosome pathway. It was found that <strong>SA-8</strong> can dose-dependently induce apoptosis in HeLa cells. This work not only validates the practical utility of the AUTAC strategy but also offers a promising therapeutic approach for developing next-generation target degraders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117918"},"PeriodicalIF":6.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515828","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 novel Genipin derivative targeting YB-1 to enhance the P-glycoprotein-mediated paclitaxel sensitivity of paclitaxel-resistant non-small cell lung cancer","authors":"Lulu Deng ,&nbsp;Gonghan Zhang ,&nbsp;Maofei He ,&nbsp;Yuehu Wang ,&nbsp;Jiang Li ,&nbsp;Xinglian Xu ,&nbsp;Xiaojiang Hao ,&nbsp;Yanhua Fan ,&nbsp;Shuzhen Mu","doi":"10.1016/j.ejmech.2025.117910","DOIUrl":"10.1016/j.ejmech.2025.117910","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and its incidence rate and mortality are relatively high. Paclitaxel, a classic chemotherapy drug, has become one of the first-line drugs commonly used for patients with advanced NSCLC in clinical practice, but multidrug resistance has become a major factor seriously restricting its efficacy. Therefore, overcoming multidrug resistance to paclitaxel is an important issue that urgently needs to be addressed to improve its efficacy. In our study, twenty-three novel derivatives of Genipin were synthesized by using different intermediates of methylene indole ketones and Genipin. When they were combined with paclitaxel, most of them exhibited good reversal activity in P-gp-mediated paclitaxel-resistant non-small cell lung cancer cells (A549/Taxol cells). The most potent compound <strong>13</strong> could enhance the sensitivity of A549/Taxol cells with low cytotoxicity to paxlitaxel by targeting YB-1 and reducing the expression of total YB-1 protein and the level of YB-1 protein in the nucleus, thus inhibiting the expression and function of the downstream protein P-gp, further suppressing the efflux rate of paclitaxel and increasing the concentration of intracellular paclitaxel. In addition, tumour growth in paclitaxel-resistant lung cancer xenografts was significantly decreased by combination treatment with compound <strong>13</strong> and paclitaxel. H&amp;E staining of mouse organs and IHC analysis of A549/Taxol tumour tissues indicated that compound <strong>13</strong> could enhance the paclitaxel sensitivity of paclitaxel-resistant NSCLC, with low cytotoxicity. These results clearly indicate that compound <strong>13</strong>, by targeting YB-1, might be useful as a novel chemosensitizer in combination with paclitaxel to overcome MDR in the management of NSCLC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117910"},"PeriodicalIF":6.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515829","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}