European Journal of Medicinal Chemistry最新文献

{"title":"Design, synthesis, and neuroprotective evaluation of chiral butylphthalide-ligustrazine hybrids via the Keap1-Nrf2 pathway in ischemic stroke","authors":"Chenwei Zuo ,&nbsp;Haochen Xie ,&nbsp;Haoyue Shen,&nbsp;Jiaxin Wang,&nbsp;Guangyu Li,&nbsp;Quanxing Hou,&nbsp;Guibo Sun,&nbsp;Yu Tian","doi":"10.1016/j.ejmech.2025.118438","DOIUrl":"10.1016/j.ejmech.2025.118438","url":null,"abstract":"<div><div>As a racemate, 3-<em>n</em>-butylphthalide (<strong>NBP</strong>) can be separated into its <em>S</em>- and <em>R</em>-enantiomers, with <strong><em>S</em>-NBP</strong> reported to exhibit superior bioactivity. To develop more potent anti-stroke agents with enhanced bioavailability, we therefore employed <strong><em>S</em>-NBP</strong> as the lead compound. Through structural modification and hybridization with ligustrazine (<strong>TMP</strong>), 20 novel <em>S</em>-NBP-TMP hybrids were designed and synthesized. <em>In vitro</em> screening for neuroprotection using OGD/R-injured HT22 cells and primary hippocampal neurons identified compounds <strong>S8g</strong>, <strong>S8h</strong>, and <strong>S8i</strong>. At 12.5 μM, these compounds significantly enhanced cell viability recovery compared to both their racemates and <strong>NBP</strong>. Among them, <strong>S8i</strong> exhibited the most potent neuroprotective activity, outperforming even <strong><em>S</em>-NBP</strong>. Subsequent mechanistic studies demonstrated that <strong>S8i</strong> effectively attenuated OGD/R-induced mitochondrial damage and oxidative stress, while also reducing both neuronal apoptosis and necrosis. Molecular docking revealed that <strong>S8i</strong> effectively occupies the Keap1 binding pocket for Nrf2 and forms four hydrogen bonds with Arg380, Arg415, and Ser555. Moreover, <strong>S8i</strong> exhibits favorable BBB permeability, as its <em>Pe</em> value (21.95 × 10⁻⁶ cm/s) significantly exceeds the penetration threshold. <em>In vivo</em> studies demonstrated that <strong>S8i</strong> ameliorated cerebral ischemia-reperfusion injury, restored cerebral blood flow, and protected cerebral vasculature in MCAO/R model mice. Furthermore, at doses of 30 and 60 mg/kg, <strong>S8i</strong> exhibited significantly superior efficacy to <strong>NBP</strong> (90 mg/kg). Additionally, <strong>S8i</strong> downregulated Keap1 expression and upregulated the expression of Nrf2 and its downstream factors, HO-1 and NQO-1 <em>in vivo</em>. In summary, <strong>S8i</strong> demonstrates significantly enhanced neuroprotection versus its racemate, <strong>NBP</strong>, and <strong><em>S</em>-NBP</strong>, positioning it as a highly promising lead compound for ischemic stroke therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118438"},"PeriodicalIF":5.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657638","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":"Natural and synthetic compounds targeting ferroptosis in esophageal squamous cell carcinoma: Research progress and application potential","authors":"Nana Wu ,&nbsp;Guanhua Wang ,&nbsp;Jinnuo Wang ,&nbsp;Meixuan Wu ,&nbsp;Xian Wang ,&nbsp;Junting Ma ,&nbsp;Wei He","doi":"10.1016/j.ejmech.2025.118448","DOIUrl":"10.1016/j.ejmech.2025.118448","url":null,"abstract":"<div><div>Esophageal Squamous Cell Carcinoma (ESCC) is a prevalent malignant tumor of the human digestive system, characterized by high incidence and mortality rates. Most patients are diagnosed at advanced stages, marked by metastasis and drug resistance, significantly limit the efficacy of conventional therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by dysregulated iron metabolism, lipid peroxidation, and compromised antioxidant defense system, has shown great potential in inhibiting the biological activity of cancer cells and improving prognosis. Thus, inducing ferroptosis could become a promising approach for cancer treatment. Bioactive small‐molecule compounds, both natural and synthetic, offer unique advantages in the treatment of ESCC due to their distinct properties and potential efficacy. Modulating tumor cells survival via ferroptosis—whether through natural or synthetic agents—represents a crucial direction for precision ESCC therapy. In this review, we systematically outline the core mechanisms of ferroptosis and the roles of ferroptosis in ESCC. We also summarize a range of natural and synthetic compounds that target ferroptosis in ESCC cells, discussing their mechanisms of action and therapeutic potential. This review demonstrates that targeting ferroptosis with natural and synthetic compounds could be effective for ESCC treatments, and highlights a promising therapeutic avenue that could be utilized to prevent ESCC. This review article aims to shed light on developing novel therapeutic regimens by pharmacological induction of ferroptosis to treat ESCC efficiently in the future.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118448"},"PeriodicalIF":5.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657654","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 of conditional and tumor-activated PROTACs for selective degradation in lung cancer","authors":"Lin Lin ,&nbsp;Fushuang Zheng ,&nbsp;Hongyi Wei ,&nbsp;Xiaojie Wu ,&nbsp;Hengyi Yan ,&nbsp;Yuanyuan Ding","doi":"10.1016/j.ejmech.2025.118432","DOIUrl":"10.1016/j.ejmech.2025.118432","url":null,"abstract":"<div><div>Lung cancer remains the leading cause of cancer-related mortality worldwide, with limited therapeutic options for patients harboring drug-resistant or undruggable targets. PROteolysis TArgeting Chimeras (PROTACs) have emerged as a promising strategy to selectively degrade oncogenic drivers; however, their clinical translation is hampered by systemic toxicity, off-target effects, and poor pharmacokinetics. To address these limitations, conditional and tumor-activated PROTACs have been developed, enabling spatiotemporal control of protein degradation within the tumor microenvironment. Recent advances include light-responsive PROTACs, glutathione- and ROS-activated degraders, enzyme-cleavable linkers, and nanocarrier-based prodrugs that enhance tumor selectivity. In lung cancer, these strategies show particular promise against KRAS, EGFR, and SMARCA2/4-driven malignancies, while also offering synergy with immunotherapy and chemotherapy. This review highlights current design principles, emerging applications, and future perspectives for conditional and tumor-activated PROTACs, underscoring their transformative potential in precision oncology.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118432"},"PeriodicalIF":5.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651302","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 Pyrrolidine-2,5-dione Scaffold PICK1 PDZ Inhibitors as Anti-ischemic Stroke Agents","authors":"Yichen Jiang, Qi Liu, Ting Zhu, Ruiguo Liang, Yujiao Qin, Xiya Guo, Jiacheng Wang, Ping Li, Jie Zhou, Han Ju, Mingxin Dong","doi":"10.1016/j.ejmech.2025.118410","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118410","url":null,"abstract":"Targeting PICK1 presents a promising therapeutic strategy for ischemic stroke. Through multi-level virtual screening, we identified a pyrrolidin-2-one-based hit <strong>3a</strong>. Its optimized derivative, <strong>6b</strong>, demonstrated potent PICK1 PDZ binding affinity (<em>K</em>_i = 27.73 μM) and robust neuroprotection in glutamate-induced HT22 cell and primary neuron models, improving cell survival. Mechanistically, <strong>6b</strong> attenuated ROS production and significantly modulated apoptosis-related proteins, downregulating the levels of pro-apoptotic factors Caspase-3 and Bax, while upregulating the anti-apoptotic protein Bcl-2. Critically, siRNA-mediated knockdown of PICK1 completely abolished the neuroprotective effects of <strong>6b</strong>, confirming that its action is explicitly mediated through PICK1 inhibition. Furthermore, <strong>6b</strong> exhibited high membrane permeability and, in a middle cerebral artery occlusion model, significantly reduced the cerebral infarct area by 32.51%. Collectively, our findings underscore compound <strong>6b</strong> as a highly promising, novel neuroprotective agent for ischemic stroke treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651301","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 discovery of guaianolide ‐ eudesmanolide heterodimers as CDK2 inhibitors for the treatment of hepatocellular carcinoma","authors":"Tian-Ze Li ,&nbsp;Feng-Jiao Li ,&nbsp;Min-Min Hu ,&nbsp;Feng-Dan Huang ,&nbsp;Yun-Bao Ma ,&nbsp;Yao Yang ,&nbsp;Yong-Cui Wang ,&nbsp;Ji-Jun Chen","doi":"10.1016/j.ejmech.2025.118412","DOIUrl":"10.1016/j.ejmech.2025.118412","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, creating an urgent need for novel therapeutic agents with unique mechanisms. Inspired by the antiHCC properties of natural sesquiterpenoid dimers and to overcome their limited structural diversity and availability, 26 new guaianolide–eudesmanolide heterodimers were synthesized <em>via</em> Diels–Alder reactions. AntiHCC assay suggested 19 analogues showed better inhibitory activity than sorafenib on HepG2, SK-Hep-1, and Huh7 cells. Surprisingly, chlorinated dimer <strong>10</strong> showed exceptional activity with IC₅₀ values 3.9–6.1 fold superior to sorafenib, inhibited migration and invasion, and induced apoptosis. CDK2 was identified as the target of compound <strong>10</strong> as confirmed by CETSA, DARTS, and functional knockdown assays. Molecular docking and molecular dynamics simulations predicted that compound <strong>10</strong> acted as a novel non-ATP-competitive inhibitor of CDK2. Compound <strong>10</strong> inhibited CDK2/Cyclin A2 with an IC₅₀ value of 236.7 nM, disrupted their interaction, promoted CDK2 degradation <em>via</em> the lysosomal pathway, and ultimately induced G0/G1 phase cell cycle arrest and cellular senescence. <em>In vivo</em>, dimer <strong>10</strong> at 30 and 60 mg/kg inhibited tumor weight up to 64 % and 69 % without detectable toxicity, and IHC analysis confirmed <em>in vivo</em> target engagement. This study identified compound <strong>10</strong> as a potential antiHCC agent targeting CDK2, and warrants further investigation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118412"},"PeriodicalIF":5.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651013","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":"ATTEC-mediated degradation of BCR-ABL in chronic myeloid leukemia cells","authors":"Zhiyan Wang ,&nbsp;Tingting Xu ,&nbsp;Yiying Che ,&nbsp;Jun-An Ma ,&nbsp;Runqi Jin ,&nbsp;Boao Mao ,&nbsp;Xinru Lai ,&nbsp;Kunrong Mei ,&nbsp;Hongxia Zhao ,&nbsp;Zhiguang Yuchi","doi":"10.1016/j.ejmech.2025.118430","DOIUrl":"10.1016/j.ejmech.2025.118430","url":null,"abstract":"<div><div>Chronic myeloid leukemia (CML) is driven by the BCR-ABL oncoprotein, which exerts both kinase-dependent and kinase-independent oncogenic functions. However, current tyrosine kinase inhibitors (TKIs) fail to eliminate its non-catalytic activities. Here, we report the rational design and synthesis of autophagosome-tethering chimeras (ATTECs) that selectively degrade BCR-ABL via the autophagy-lysosome pathway. By conjugating the BCR-ABL inhibitor dasatinib with the LC3B-binding ligand <strong>GW5074</strong>, we engineered eight distinct ATTEC variants with diverse linkers. Among them, <strong>DS-PPE-GW</strong>, featuring a piperidine-based linker, exhibited the most potent antiproliferation activity in K562 CML cells, with an IC₅₀ of 9.62 nM and a DC₅₀ of 11.6 nM, achieving over 90 % BCR-ABL degradation. This degradation suppressed phosphorylation of STAT5, a downstream substrate of BCR-ABL, and significantly inhibited cell proliferation. The activity of <strong>DS-PPE-GW</strong> was further enhanced by the autophagy activator rapamycin, confirming its autophagy dependence. Notably, <strong>DS-PPE-GW</strong> did not increase global autophagic flux, suggesting selective engagement of pre-existing autophagosomes. These findings demonstrate that strategically designed ATTECs can efficiently degrade BCR-ABL, targeting both its catalytic and non-catalytic functions, and provide a promising strategy for next-generation CML therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118430"},"PeriodicalIF":5.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657655","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":"Fused thiophene – benzimidazole conjugates targeting EGFR: Design, synthesis, anticancer evaluation and their mechanistic insights","authors":"Munugala Chandrakanth ,&nbsp;Sehal Mishra ,&nbsp;Kankipati Gayathri ,&nbsp;Rajasekhara Reddy Katreddy ,&nbsp;Sampathkumar Ranganathan ,&nbsp;Arya C G ,&nbsp;Ramesh Gondru ,&nbsp;Subbiah Rajasekaran ,&nbsp;Janardhan Banothu","doi":"10.1016/j.ejmech.2025.118435","DOIUrl":"10.1016/j.ejmech.2025.118435","url":null,"abstract":"<div><div>The development of potent epidermal growth factor receptor (EGFR)-targeted anticancer agents continues to be a major priority in medicinal chemistry. In the present study, a series of rationally designed acetamide-linked fused thiophene–benzimidazole hybrids (<strong>3a–h, 4a–h, 5a–h,</strong> and <strong>6a–i</strong>) were synthesized and comprehensively characterized using ¹H NMR, ¹³C NMR, and HRMS; compound <strong>6d</strong> was further validated by single-crystal X-ray diffraction. The <em>in vitro</em> anticancer potential of the synthesized derivatives was evaluated against PANC-1 (human pancreatic cancer cells), A549 (adenocarcinomic human alveolar basal epithelial cells), and BEAS-2B (normal human bronchial epithelial cells) cell lines. Among them, compound <strong>4d</strong> exhibited remarkable potency and selectivity toward PANC-1 cells (IC₅₀ = 0.067 ± 0.019 μM; BEAS-2B, IC₅₀ = 101.93 ± 2.21 μM, SI = 1521.34), whereas compound <strong>6d</strong> demonstrated pronounced cytotoxicity against A549 cells (IC₅₀ = 0.82 ± 0.02 μM) with moderate selectivity (BEAS-2B, IC₅₀ = 19.06 ± 0.58 μM, SI = 23.24). Mechanistic investigations in A549 cells revealed that both <strong>4d</strong> and <strong>6d</strong> induced cell cycle arrest, apoptosis, and alterations in the expression of markers of cell cycle regulators and apoptosis. Furthermore, Western blot analysis revealed that both compounds significantly inhibited the phosphorylation of the EGFR (pEGFR) and also upregulated the expression of LC3B-II (a key marker of autophagy) and cyclin-dependent kinase inhibitor p27, suggesting that activation of autophagy and cell cycle arrest occurred, respectively, thereby inhibiting EGFR phosphorylation and activating downstream cellular responses similar to those of Erlotinib. In addition, the target prediction, followed by molecular docking results, showed strong binding affinities of both compounds toward the EGFR tyrosine kinase domain (PDB ID: 1M17, 2ITY, 2J5F). <em>In silico</em> ADME profiling further highlighted favourable pharmacokinetic properties, reinforcing the potential of <strong>4d</strong> and <strong>6d</strong> as promising lead candidates. Collectively, these results establish fused thiophene–benzimidazole hybrids as selective EGFR-targeted anticancer agents with strong therapeutic promise.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118435"},"PeriodicalIF":5.9,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619412","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":"Targeting Chikungunya virus entry: Enantiomeric separation, synthesis of derivatives, and structure-activity relationship of E1-E2 envelope glycoprotein inhibitors","authors":"Daniela M. Fidalgo ,&nbsp;Eliana Castro ,&nbsp;Agostina Mazzeo ,&nbsp;Tamara J.B. Vazquez ,&nbsp;Leandro Battini ,&nbsp;Daniel Vladimir ,&nbsp;Malena Tejerina Cibello ,&nbsp;Facundo N. Gallo ,&nbsp;Maximilian A. Rey ,&nbsp;Sara A. Thannickal ,&nbsp;Sophie N. Spector ,&nbsp;Florencia Di Salvo ,&nbsp;María E. Monge ,&nbsp;Kenneth A. Stapleford ,&nbsp;Diego E. Alvarez ,&nbsp;Mariela Bollini","doi":"10.1016/j.ejmech.2025.118427","DOIUrl":"10.1016/j.ejmech.2025.118427","url":null,"abstract":"<div><div>Chikungunya virus (CHIKV) remains a global health concern partly due to the lack of effective antiviral strategies to control its current global expansion. In this study, we report the design, synthesis, and biological evaluation of a novel series of small-molecule CHIKV entry inhibitors targeting the viral E1-E2 envelope glycoprotein complex. Starting from a previously identified racemic β-amino alcohol compound (<strong>1</strong>) with low micromolar antiviral activity, we performed enantiomeric separation, absolute configuration assignment, and biological evaluation of (<em>R</em>)-<strong>1</strong> and (<em>S</em>)-<strong>1</strong>. Both enantiomers retained activity, with (<em>S</em>)-<strong>1</strong> showing slightly greater potency (EC₅₀ = 6 ± 1 μM) than <em>(R)</em>-<strong>1</strong> (EC₅₀ = 14 ± 4 μM).</div><div>A library of 40 derivatives was synthesized to explore structure–activity relationships (SAR), focusing on four key regions: the amino/hydroxyl groups (<strong>AH</strong>), the piperidine core (<strong>PC</strong>), the left-hand side (<strong>LHS</strong>), and the right-hand side (<strong>RHS</strong>) of the molecule. SAR analysis revealed that the central piperidine scaffold and the hydrogen-bonding capability of the amino and hydroxyl groups were essential for antiviral activity. Bulky or strongly electron-withdrawing substituents on the <strong>RHS</strong> often increased cytotoxicity. In contrast, several <strong>LHS</strong> modifications enhanced potency or selectivity.</div><div><em>In vitro</em> ADME profiling of compound <strong>1</strong> and selected derivatives showed favorable chemical and plasma stability and moderate-to-high permeability in the PAMPA assay. However, solubility was limited under neutral conditions, anticipating the need of adequate formulation strategies for <em>in vivo</em> administration. Metabolic stability varied across the series, with certain derivatives showing resistance to CYP-mediated oxidation.</div><div>These findings validate the CHIKV E1-E2 heterodimer as a promising antiviral target and identify a set of selective, stable, and synthetically tractable inhibitors suitable for further preclinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118427"},"PeriodicalIF":5.9,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619400","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":"Indole hybrids: Emerging therapeutic candidates for breast cancer (2023–2025)","authors":"Shanshan Huang ,&nbsp;Zhi Xu","doi":"10.1016/j.ejmech.2025.118449","DOIUrl":"10.1016/j.ejmech.2025.118449","url":null,"abstract":"<div><div>Breast cancer inflicts severe multidimensional harm on physical health, mental well-being, and quality of life, with its impacts spanning localized tissue damage, systemic complications, and long-term functional impairment. Breast cancer remains the most frequently diagnosed cancer and the second leading cause of cancer-related mortality among women worldwide, with its epidemiological burden exhibiting substantial regional variation. Current chemotherapy drugs for breast cancer face critical dilemmas, including widespread primary and secondary drug resistance, as well as severe side effects that harm quality of life and compliance. Additionally, these drugs show limited curative effects in advanced breast cancer, where achieving a cure remains difficult and treatment primarily focuses on controlling tumor progression and extending survival, an area still in need of improvement for long-term outcomes. Indole hybrids have emerged as a highly promising class of therapeutic agents for breast cancer therapy, distinguished by their unique structural design that integrates an indole core with diverse pharmacophores to synergize antitumor activities, enhance subtype selectivity, and surmount key limitations of conventional treatments. Their versatility enables targeted intervention across multiple breast cancer subtypes by modulating critical oncogenic pathways, making them a focal point in preclinical and early clinical research. The present manuscript aims to summarize the current landscape of indole hybrids with therapeutic potential against breast cancers and address their structure-activity relationships and mechanisms of action, covering literature published since 2023, to inform the further rational design of novel candidates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118449"},"PeriodicalIF":5.9,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651014","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":"Thiazolyl 4-carboxylate ketone as a new warhead for a highly potent SARS-CoV-2 main protease inhibitor","authors":"Maria A. Theodoropoulou ,&nbsp;Haifa El Kilani ,&nbsp;Christiana Mantzourani ,&nbsp;Dirk Jochmans ,&nbsp;Johan Neyts ,&nbsp;Kaixuan Zhang ,&nbsp;Judith Röske ,&nbsp;Maroula G. Kokotou ,&nbsp;Rolf Hilgenfeld ,&nbsp;George Kokotos","doi":"10.1016/j.ejmech.2025.118436","DOIUrl":"10.1016/j.ejmech.2025.118436","url":null,"abstract":"<div><div>The SARS-CoV-2 main protease (M^pro), an enzyme essential for viral replication and lacking a human homologue, has emerged as a highly attractive target for the development of novel antiviral agents. Although several M^pro inhibitors have been developed — some receiving regulatory approval — their use is sometimes limited by drug-drug interactions. In this study, we designed and synthesized peptidomimetic SARS-CoV-2 M^pro inhibitors incorporating a novel thiazolyl 4-carboxylate ketone warhead, previously employed by our group in the development of cytosolic phospholipase A₂ inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory potency against SARS-CoV-2 M^pro, and a highly potent M^pro inhibitor (GK730) was identified (IC₅₀ 5.75 nM). The melting temperature of the M^pro-GK730 complex revealed high stability, consistent with the high inhibitory potency. The X-ray crystal structures of inhibitors GK729 and GK730 bound to M^pro were determined, providing insights into the binding interactions and mechanism of action. Studies on the host cell proteases cathepsin B and L showed that GK730 did not inhibit cathepsin B, while exhibited weak inhibition of cathepsin L. Furthermore, GK730 demonstrated an EC₅₀ value of 5.70 μM against a wild-type SARS-CoV-2 strain in Vero E6 cells and minimal cytotoxicity (CC₅₀ value greater than 100 μM).</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118436"},"PeriodicalIF":5.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614053","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}