European Journal of Medicinal Chemistry最新文献

{"title":"Fungal 4-Hydroxy-2-Pyridone alkaloids: Structures, synthesis, biosynthesis, and bioactivities (2010–2024)","authors":"Xiangliu Chen ,&nbsp;Xiaoyang Zhao ,&nbsp;Mengjing Cong ,&nbsp;Yiwei Hu ,&nbsp;Changsheng Zhang ,&nbsp;Yonghong Liu ,&nbsp;Yiguang Zhu ,&nbsp;Junfeng Wang","doi":"10.1016/j.ejmech.2025.117953","DOIUrl":"10.1016/j.ejmech.2025.117953","url":null,"abstract":"<div><div>Contents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117953"},"PeriodicalIF":6.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578178","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":"Structure-activity relationship studies of thiazole-based derivatives leading to the identification of novel and potent SARS-CoV-2 main protease inhibitors","authors":"Weile Yin ,&nbsp;Wai-Po Kong ,&nbsp;Siu-Lun Leung,&nbsp;Cheung-Hin Hung,&nbsp;Kwok-Yin Wong","doi":"10.1016/j.ejmech.2025.117952","DOIUrl":"10.1016/j.ejmech.2025.117952","url":null,"abstract":"<div><div>The COVID-19 pandemic has highlighted the need for effective antiviral agents targeting SARS-CoV-2. This study presents the development of thiazole-based inhibitors against SARS-CoV-2 Main Protease, a key enzyme for viral replication. Using Masitinib and MAC-5576 as leads, we designed 29 compounds featuring a pyridinyl ester for covalent binding to Cys145 and a thiazole core for S2 subsite interaction. Structure-activity relationship (SAR) analysis identified the pyridinyl ester as a critical pharmacophore, with the thiazole core providing superior inhibition compared to oxazole. Compound MC12 (IC₅₀ = 77.7 ± 14.1 nM) demonstrated inhibitory activities comparable to Nirmatrelvir (IC₅₀ = 58.4 ± 8.6 nM). Mass spectrometry and X-ray crystallography confirmed reversible covalent binding of MC compounds to SARS-CoV-2 Main Protease. These compounds also showed low cytotoxicity and dual inhibition of SARS-CoV and SARS-CoV-2 M^pro. Thiazole-based compounds thus emerge as promising leads for developing potent and safe SARS-CoV-2 M^pro inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117952"},"PeriodicalIF":6.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578522","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":"Leveraging machine learning predicted confidence for boosting assay submission and decision-making efficiencies","authors":"Davide Bassani,&nbsp;Michael Reutlinger,&nbsp;Holger Fischer","doi":"10.1016/j.ejmech.2025.117947","DOIUrl":"10.1016/j.ejmech.2025.117947","url":null,"abstract":"<div><div>Machine learning (ML) has become very popular, and its benefits are widely recognized within the scientific community. The ability of ML approaches to leverage large datasets to find patterns among composite single data points has made these approaches widespread across different fields. Small molecule pharmaceutical research has experienced the advantages of these methods for tasks such as molecular property prediction, secondary pharmacology analysis, <em>de novo</em> generation, and compound clustering. Coupling efficient ML models with robust uncertainty quantification methods gives the additional advantage of discriminating among predictions to identify the ones that can be truly reliable. Herein, the Roche experience with ML uncertainty quantification for influencing decision making in pharmacokinetic assay submission is described. After setting up an initial threshold for error acceptance via nonadditivity analysis, the combined efforts of ML and experimental scientists developed an optimal uncertainty threshold in ML models. By excluding compounds with predicted properties that were within a confidence level equal to or greater than the agreed one, the analysis highlights how significant numbers of molecules could potentially be excluded from assay submission (up to 25 % of the normal submission rate), allowing significant time and cost savings for the organization.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117947"},"PeriodicalIF":6.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568748","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":"Sirtuin 3 as a promising target in disease therapy: Model action and drug discovery","authors":"Dongmin Yu","doi":"10.1016/j.ejmech.2025.117929","DOIUrl":"10.1016/j.ejmech.2025.117929","url":null,"abstract":"<div><div>Sirtuin 3 (SIRT3) belongs to the Class III histone deacetylase (HDACIII) family and is an enzyme of significant importance in epigenetic regulation. Many studies have demonstrated that the aberrant expression of SIRT3 is closely associated with a variety of diseases, including inflammation, cancer, cardiovascular diseases, and disorders of the central nervous system disorders. SIRT3 is involved in the regulation of multiple intracellular processes, such as cell migration and apoptosis, and thus, has emerged in recent years as a promising therapeutic target for disease treatment. This review first summarizes the structure of SIRT3 and its pharmacological actions, followed by an analysis of the cocrystal structures of representative SIRT3 inhibitors/activators. Subsequently, we focus on the development of SIRT3 modulators (including inhibitors and activators) from a drug-design perspective in recent years. Finally, we present challenges encountered in the discovery of small-molecule modulators targeting SIRT3 and potential future developments.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117929"},"PeriodicalIF":6.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566461","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":"Novel boron-modified aza-BODIPY photosensitizers for low-dose light-dependent anti-cancer photodynamic therapy","authors":"Mei Hu,&nbsp;Xiaochun Dong,&nbsp;Weili Zhao","doi":"10.1016/j.ejmech.2025.117934","DOIUrl":"10.1016/j.ejmech.2025.117934","url":null,"abstract":"<div><div>The aggregation-induced decrease in photosensitization activity is one of the major challenges limiting the clinical application of photosensitizers (PSs). Thus, developing highly efficient PSs for anti-cancer photodynamic therapy (PDT) remains an urgent need. To address this challenge, we designed and synthesized a novel family of efficient aza-BODIPY PSs by inhibiting aggregation with a boron-modified strategy. These novel aza-BODIPY PSs demonstrated significantly enhanced <em>in vitro</em> photodynamic efficacy. Of particular note was derivative <strong>A1</strong>, which emerged as a highly promising NIR PS with high singlet oxygen yield (rel.rate = 1.79) that obviously superior to the reported compound <strong>BDP 4</strong> (rel.rate = 1.23) in PBS. Additionally, <strong>A1</strong> showed exceptional cytotoxicity against various cells (IC₅₀ &gt; 4.5 nM) at a low light dose of 21.6 J/cm². <em>In vivo</em> anti-tumor experiments showed that significant tumor growth suppression following intravenous administration of <strong>A1</strong> (2 mg/kg) and subsequent irradiation (21.6 J/cm², <em>λ</em> = 660 nm), outperforming well-known PSs such as <strong>ADPM06</strong> and <strong>Ce6</strong>. Both <em>in vitro</em> and <em>in vivo</em> studies revealed that <strong>A1</strong> exhibited an excellent PDT effect at remarkable low drug and light doses.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117934"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566643","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 Thieno[3,2-d]pyrimidine derivatives as potent RIPK2 inhibitors with Prominent In vitro and In vivo anti-inflammatory efficacy","authors":"Haoyu Zhao ,&nbsp;Rongrong Sun ,&nbsp;Lijuan Chen ,&nbsp;Yong Chen","doi":"10.1016/j.ejmech.2025.117932","DOIUrl":"10.1016/j.ejmech.2025.117932","url":null,"abstract":"<div><div>Acute liver injury (ALI) is a major pathological event in various liver diseases and remains a significant global medical challenge in terms of prevention and treatment. RIPK2, as a novel therapeutic target, has shown promise in the treatment of various inflammatory diseases, and it also holds potential for addressing acute liver injury. In this study, starting from a patent compound, computer-aided drug design and targeted structural optimization were employed to develop a new RIPK2 inhibitor with a thieno[3,2-<em>d</em>]pyrimidine core scaffold. Compound <strong>HY3</strong> exhibited an IC₅₀ of 11 nM against RIPK2, with high selectivity for RIPK2 over RIPK1. <strong>HY3</strong> demonstrated favorable pharmacokinetic properties, with a bioavailability of 46.6 %, and displayed significant anti-inflammatory and hepatoprotective effects in an APAP-induced ALI model. These promising results suggest that <strong>HY3</strong> warrants further preclinical and clinical development as a potential treatment for ALI.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117932"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566646","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":"KRASG12D selective VHL-PROTAC with sparing KRASWT and other KRAS mutants","authors":"Eunhye Jeon ,&nbsp;Chan Kim ,&nbsp;Minjoo Ko ,&nbsp;Taeyul K. Kim ,&nbsp;Juhyeon Bae ,&nbsp;Jae Won Oh ,&nbsp;Kwang Pyo Kim ,&nbsp;Han Sang Kim ,&nbsp;Taebo Sim","doi":"10.1016/j.ejmech.2025.117928","DOIUrl":"10.1016/j.ejmech.2025.117928","url":null,"abstract":"<div><div>KRAS^G12D is the most prevalent KRAS mutant in various cancers. We report the KRAS^G12D selective PROTAC, CH091138 (<strong>6</strong>), identified through SAR studies. <strong>6</strong> selectively degrades exogenous and endogenous KRAS^G12D but not KRAS^WT or other KRAS mutants. Furthermore, global proteomic analysis shows that KRAS is most significantly downregulated in AsPC-1 cells. Mechanistic studies reveal that the degradation depends on the VHL-mediated ubiquitin-proteasome system. The binding site of <strong>6</strong> was identified by NMR studies, and docking studies explain <strong>6</strong>-mediated interaction between KRAS^G12D and VHL leads to KRAS^G12D selectivity. <strong>6</strong> suppresses the proliferation of AsPC-1 cells and the growth of colon cancer patient-derived organoids (PDOs) harboring KRAS^G12D but not PDOs with KRAS^WT. Notably, <strong>6</strong> reduces tumor growth in an AsPC-1 xenograft mouse model. Collectively, we report KRAS^G12D selective PROTAC and propose potential hypotheses for the selectivity. Also, our study reveals that PROTAC-mediated degradation of KRAS^G12D is an attractive anti-cancer strategy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117928"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566641","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":"Poly(ADP-ribose) polymerase-1 (PARP1)-based dual inhibitors targeting cancer synthetic lethality (2022-present): advances and perspectives","authors":"Guo-Wei Ye ,&nbsp;Yu-Qing Zhang ,&nbsp;Meng-Lan He ,&nbsp;Meng-Qian Yu ,&nbsp;Shun-Ran Li ,&nbsp;Bo-Qun Du ,&nbsp;Nian-Dong Mao ,&nbsp;Yuan Gao ,&nbsp;Xiang-Yang Ye","doi":"10.1016/j.ejmech.2025.117937","DOIUrl":"10.1016/j.ejmech.2025.117937","url":null,"abstract":"<div><div>Poly(ADP-ribose) polymerase 1 (PARP1), a critical enzyme in DNA damage repair (DDR) and genome stability maintenance, has emerged as a pivotal therapeutic target in oncology. PARP1 inhibitors (PARPi) exploit synthetic lethality to selectively target homologous recombination repair (HRR)-deficient cancer cells, revolutionizing treatment for patients with breast cancer susceptibility gene 1/2 (BRCA1/2) mutations and other DNA repair defects. However, monotherapy resistance and limited efficacy in broader patient populations necessitate innovative strategies. Recent advances highlight the promise of dual-targeting inhibitors that simultaneously inhibit PARP1 and additional oncogenic drivers (e.g. GFR, CDK, NRP1, Polθ, ALR2, Ras or FTase) to amplify antitumor effects and overcome resistance mechanisms. This review comprehensively examines dual inhibitors relevant to PARP1 in literature not covered in the last review, analyzing their design rationales, structure-activity relationships (SARs), pharmacological activities and synthetic pathways, and more. Furthermore, the challenges in balancing dual inhibitors' potency, in obtaining optimal pharmacokinetics, and in minimizing off-target effects also were discussed. By integrating mechanistic insights with drug discovery trends, this work provides a roadmap for developing next-generation PARP1-based therapies, offering strategic guidance to enhance therapeutic outcomes and expand clinical applicability in heterogeneous malignancies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117937"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566659","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 structure-activity relationship study of novel hydantoin-based inhibitors targeting mutant isocitrate dehydrogenase 1 (mIDH1)","authors":"Dong Luo ,&nbsp;Maojie Zhang ,&nbsp;Zizhen Liang ,&nbsp;Linling Gan ,&nbsp;Yun He ,&nbsp;Shao-Lin Zhang","doi":"10.1016/j.ejmech.2025.117945","DOIUrl":"10.1016/j.ejmech.2025.117945","url":null,"abstract":"<div><div>Mutations in isocitrate dehydrogenases (IDHs) are frequently observed in various malignancies. These mutations confer a neomorphic enzymatic activity, leading to the reduction of α-KG to the oncometabolite 2-HG. The aberrant accumulation of 2-HG inhibits α-KG-dependent histone and DNA demethylases, thus contributing to tumorigenesis. Consequently, considerable efforts have been directed toward the development of selective inhibitors targeting mutant IDHs. Herein, we report a high-throughput virtual screening campaign utilizing a chemical library of 1795658 compounds, which led to the identification of a promising IDH1 R132H inhibitor. Subsequent structure-based optimization yielded compounds <strong>13e</strong> and <strong>16a</strong>, which displayed potent inhibition of IDH1 R132H (IC₅₀ = 0.26 and 0.22 μM) and IDH1 R132C (IC₅₀ = 1.1 and 0.93 μM), while showing negligible activity against wt-IDH1 and wt-IDH2. Furthermore, both compounds effectively suppressed intracellular 2-HG production in U87-MG R132H cells (EC₅₀ = 0.55 and 1.45 μM). Additionally, <strong>13e</strong> and <strong>16a</strong> exhibited moderate antiproliferative effects against U87-MG R132H and HT-1080 cells, while exhibiting low cytotoxicity toward normal human cells even at concentrations up to 40 μM.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117945"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566644","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":"1,2,4-Oxadiazoles in medicinal chemistry: trends of the last years","authors":"Anastasia Cherkasova ,&nbsp;Roberta Astolfi ,&nbsp;Maxim Nawrozkij ,&nbsp;Boris Gladkikh ,&nbsp;Eleonora Proia ,&nbsp;Lidia Giuliani ,&nbsp;Dante Rotili ,&nbsp;Rino Ragno ,&nbsp;Roman Ivanov","doi":"10.1016/j.ejmech.2025.117935","DOIUrl":"10.1016/j.ejmech.2025.117935","url":null,"abstract":"<div><div>1,2,4-Oxadiazoles have emerged as a significant class of heterocyclic compounds in medicinal chemistry due to their diverse biological activities and versatile applications in drug discovery. Herein is reported an in-depth analysis of the structural properties, synthetic methodologies, and pharmacological significance of 1,2,4-oxadiazoles. The compound's unique five-membered ring containing three heteroatoms offers remarkable stability and tunable physicochemical properties, making it an attractive scaffold for the development of novel therapeutic agents, as confirmed by already approved drugs.</div><div>The review highlights the broad spectrum of biological activities associated with 1,2,4-oxadiazoles, including antimicrobial, anti-inflammatory, anticancer, antiviral, and central nervous system related activities. These diverse effects underscore the scaffold's potential for targeting multiple disease pathways. Several studies demonstrate that structural modifications on the oxadiazole ring can significantly influence its pharmacokinetic and pharmacodynamic profiles, enabling the design of selective and potent drug candidates.</div><div>Additionally, it has explored recent advances in synthetic strategies for constructing the 1,2,4-oxadiazole core, such as cyclization reactions involving amidoximes, nitrile oxides, and other precursors. Modern approaches using transition-metal catalysis, microwave-assisted synthesis, and green chemistry techniques are also discussed, emphasizing their importance in improving efficiency and scalability for pharmaceutical applications.</div><div>Furthermore, the role of 1,2,4-oxadiazole as bioisostere replacement for esters and amides is highlighted, particularly in enhancing metabolic stability and modulating target selectivity. Application of computational methods, including molecular docking and QSAR modeling, have been also covered in understanding ligand-receptor interactions and guiding lead optimization.</div><div>This review underscores the growing prominence of 1,2,4-oxadiazoles in modern drug design and their potential to address unmet medical needs. With continued research and innovation, these scaffolds are poised to play a pivotal role in the next generation of therapeutic agents across multiple disease areas.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117935"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566642","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}