European Journal of Medicinal Chemistry最新文献_第10页

Development of a P2X3 receptor antagonist derived from eliapixant with improved properties for the treatment of chronic cough 从Eliapixant衍生的P2X3受体拮抗剂的开发，具有改善治疗慢性咳嗽的性能

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-07 DOI: 10.1016/j.ejmech.2025.118116

Yang Zang , Qun Li , Yang Li , Xiaohua Ding , Ruibin Liu , Lifei Liu , Hongna Sun , Lihan Qu , Xuejun Zhang

引用次数: 0

Enoxacin–fatty acid conjugates: Synthesis and assessment of antibacterial and anticancer potentials 依诺沙星-脂肪酸缀合物：抗菌和抗癌潜力的合成和评价

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-07 DOI: 10.1016/j.ejmech.2025.118143

Karolina Jałbrzykowska , Alicja Chrzanowska , Karolina Buchajska , Barbara Żyżyńska-Granica , Angelika Pawlicka , Jolanta Smok-Kalwat , Marta Struga , Piotr Roszkowski

引用次数: 0

Design, synthesis, and biological evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors 2,6 -二取代吲哚衍生物作为METTL3抑制剂的设计、合成和生物学评价

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-06 DOI: 10.1016/j.ejmech.2025.118134

Ruoyang Miao , Chunxia Liu , Xianbin Li , Ning Wang , Linnan Zhao , Guanghe Zhu , Ruiying Zhu , Han Wei , Weiyan Cheng , Xin Tian

{"title":"Design, synthesis, and biological evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors","authors":"Ruoyang Miao , Chunxia Liu , Xianbin Li , Ning Wang , Linnan Zhao , Guanghe Zhu , Ruiying Zhu , Han Wei , Weiyan Cheng , Xin Tian","doi":"10.1016/j.ejmech.2025.118134","DOIUrl":"10.1016/j.ejmech.2025.118134","url":null,"abstract":"<div><div>METTL3 (Methyltransferase Like 3) has garnered significant attention in recent years due to its pivotal role in RNA methylation modification, emerging as a novel and highly promising therapeutic target for the treatment of cancer. Here, we report the optimization and evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors. The representative compound <strong>16e</strong> showed an IC<sub>50</sub> value of 0.49 ± 0.30 nM against METTL3. Molecular dynamics simulation confirmed that the binding of <strong>16e</strong> to METTL3. <em>In vitro</em> assays, <strong>16e</strong> significantly reduced m<sup>6</sup>A levels in acute myeloid leukemia MOLM-13 cells and ovarian cancer SKOV3 cells, markedly inhibited cell proliferation, induced cells apoptosis, suppressed cells migration, and downregulated the expression of m<sup>6</sup>A downstream target genes c-MYC and BCL2. Additionally, compound <strong>16e</strong> showed favorable pharmacokinetic characteristics and good antitumor efficacy in a SKOV3 xenograft model. Collectively, this study provides a promising candidate compound for the development of new therapeutics for cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118134"},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003389","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}

引用次数: 0

Mitigating SARS-CoV-2–exacerbated neuroinflammation and Alzheimer's pathology: Synthesis of quinoline-based dual inhibitors targeting cysteine and aspartyl proteases 缓解sars - cov -2加重的神经炎症和阿尔茨海默病病理：合成以喹啉为基础的半胱氨酸和天冬氨酸蛋白酶双抑制剂

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-06 DOI: 10.1016/j.ejmech.2025.118144

Abid Hussain Khan , Anees Saeed , Amal Balqees Gondal , Fahad Hussain , Ayesha Tahir , Iltaf Shah , Umer Rashid , Abbas Hassan

{"title":"Mitigating SARS-CoV-2–exacerbated neuroinflammation and Alzheimer's pathology: Synthesis of quinoline-based dual inhibitors targeting cysteine and aspartyl proteases","authors":"Abid Hussain Khan , Anees Saeed , Amal Balqees Gondal , Fahad Hussain , Ayesha Tahir , Iltaf Shah , Umer Rashid , Abbas Hassan","doi":"10.1016/j.ejmech.2025.118144","DOIUrl":"10.1016/j.ejmech.2025.118144","url":null,"abstract":"<div><div>Viral and neurodegenerative proteases, such as the cysteine protease and aspartyl protease, offer strategic targets in a multitarget therapeutic approach for Alzheimer's disease, especially when viral infection may exacerbate neurological degeneration. To establish a multitarget therapeutic for treating Alzheimer's disease, we chose β-secretase (BACE-1), an aspartyl protease, and the SARS-CoV-2 main protease (Mpro), a cysteine protease, as dual targets. In search of BACE-1 and M<sup>pro</sup> inhibitors, a set of novel quinoline-4-carboxamide derivatives (<strong>2a-k, 3a-c, 4a-d, 5a-c, 6a-c</strong>) was synthesized using the Suzuki coupling reaction in good to excellent yields. All the synthesized compounds were screened in vitro for their potential inhibitory activities against two proteases. Compounds <strong>2e</strong>, <strong>6b</strong>, and <strong>6c</strong> emerged as dual inhibitors of both proteases. Furthermore, a kinetic study revealed the mechanism of BACE-1 inhibition by compound <strong>6c</strong>. Safety profiling of the most potent dual inhibitor <strong>6c</strong> was performed via an <em>in vivo</em> acute cytotoxicity assay on Swiss albino mice. Molecular docking studies were conducted against aspartyl protease (2HM1) and cysteine protease (6XHM) to elucidate the binding interaction of synthesized quinoline derivatives. The compound <strong>6c</strong> exhibited strong binding affinities through multiple hydrogen bonds, π-Sulfur and π-π stacking interactions, within key subpockets of both targets, supporting inhibitory potential. These studies revealed that the lead compound <strong>6c</strong> could be a good drug candidate with further structural modifications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118144"},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003511","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}

引用次数: 0

Discovery of novel indazole derivatives as type Ⅰ PRMTs inhibitors for the treatment of triple-negative breast cancer 发现新型茚唑衍生物Ⅰ型PRMTs抑制剂治疗三阴性乳腺癌

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-06 DOI: 10.1016/j.ejmech.2025.118123

Qiangsheng Zhang , Shuyan Zhou , Xueying Chen , Luoting Yu , Xianli Zhou

{"title":"Discovery of novel indazole derivatives as type Ⅰ PRMTs inhibitors for the treatment of triple-negative breast cancer","authors":"Qiangsheng Zhang , Shuyan Zhou , Xueying Chen , Luoting Yu , Xianli Zhou","doi":"10.1016/j.ejmech.2025.118123","DOIUrl":"10.1016/j.ejmech.2025.118123","url":null,"abstract":"<div><div>Type I protein arginine methyltransferases (PRMTs) play significant roles in various diseases, including cancer. The inhibition of type I PRMTs significantly suppresses the growth of breast cancer, particularly triple-negative breast cancer (TNBC). The development of potent and selective type I PRMTs inhibitors has become a research hotspot in recent years. In this study, a series of six-membered fused five-membered heterocyclic derivatives were designed via a scaffold hopping strategy. Through structural optimization, the pyrazole derivative <strong>B9</strong>, namely SKLB06329, was obtained. This compound exhibited inhibitory activity against Type I PRMTs at the nanomolar to low nanomolar level and showed good selectivity for PRMT5/7 and various lysine methyltransferases. SKLB06329 could significantly inhibit the proliferation of TNBC cells, induce apoptosis, and suppress the expression of asymmetric dimethylarginine (ADMA) within cells. When administered intravenously, it demonstrated favorable pharmacokinetic properties. SKLB06329 can serve as an effective lead compound for further research, providing a new strategy for the treatment of TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118123"},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003512","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}

引用次数: 0

4-substituted (1,2,5-oxadiazol-3-yl)benzamides and -benzene sulfonamides as antiplasmodial agents 4-取代（1,2,5-恶二唑-3-基）苯酰胺和-苯磺酰胺作为抗疟原虫药物

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-06 DOI: 10.1016/j.ejmech.2025.118150

Theresa Hermann , Patrick Hochegger , Robert Saf , Eva-Maria Pferschy-Wenzig , Monica Cal , Pascal Mäser , Robert Weis

{"title":"4-substituted (1,2,5-oxadiazol-3-yl)benzamides and -benzene sulfonamides as antiplasmodial agents","authors":"Theresa Hermann , Patrick Hochegger , Robert Saf , Eva-Maria Pferschy-Wenzig , Monica Cal , Pascal Mäser , Robert Weis","doi":"10.1016/j.ejmech.2025.118150","DOIUrl":"10.1016/j.ejmech.2025.118150","url":null,"abstract":"<div><div>The 1,2,5-oxadiazol MMV665805 from Medicines for Malaria Venture's Malaria Box Project is the lead compound of herein presented study. It exhibits very promising activity against the blood stages of the strain NF54 of <em>Plasmodium falciparum</em>. Twenty-five new derivates were prepared by replacing the initial left-hand side 3,4-diethoxyphenyl ring as well as introducing various benzamido and benzenesulfonamido substituents in position 3 of the furazan. Thereby, an insightful series of valuable structure-activity-relationships was elaborated. Compounds were furthermore analyzed for their compliance with Lipinski's rules for drug-likeness. Additionally, passive permeability was determined experimentally. A 3-amino-<em>N</em>-[4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl]benzamide not only complies perfectly with Lipinski's rules, most notably, it possessed excellent antiplasmodial activity against the chloroquine-sensitive strain <em>P. falciparum</em> NF 54 (IC<sub>50</sub> = 0.035 μM). Furthermore, it is nearly nontoxic for rat L-6 cells (IC<sub>50</sub> = 186.2 μM) resulting in a marvelous selectivity index of 5319.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118150"},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003509","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}

引用次数: 0

Aurora A degradation by HSP90 interactome-mediating PROTACs in A549 and paclitaxel-resistant A549 cells HSP90相互作用体介导的PROTACs在A549和紫杉醇抗性A549细胞中降解Aurora A

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-06 DOI: 10.1016/j.ejmech.2025.118141

Xiao-Yi Deng , Hao Xu , Yi-Xuan Peng, Yu-Yao Guo, Rui-Fan He, Gui Lu

{"title":"Aurora A degradation by HSP90 interactome-mediating PROTACs in A549 and paclitaxel-resistant A549 cells","authors":"Xiao-Yi Deng , Hao Xu , Yi-Xuan Peng, Yu-Yao Guo, Rui-Fan He, Gui Lu","doi":"10.1016/j.ejmech.2025.118141","DOIUrl":"10.1016/j.ejmech.2025.118141","url":null,"abstract":"<div><div>Lung cancer has one of the higher incidence and mortality rates worldwide. The development of drug resistance poses a significant challenge to lung cancer treatment. Aurora A kinase, a member of the Aurora family of proteins, has been identified as a key regulator of the cell cycle and mitotic spindle assembly, and overexpression is frequently observed in tumors. Kinase-independent oncogenic functions may be responsible for low clinical response rates, which are difficult to target the conventional small molecules. Targeting both the catalytic and non-catalytic functions of Aurora A may be a viable approach. In this study, we have designed and synthesized a series of novel Aurora A protein degradation-targeted chimeras (Aurora A-<strong>PROTAC</strong>s) based on the HSP90 interactome. Unlike existing Aurora A <strong>PROTAC</strong>s, the new <strong>AurAP</strong>s series utilizes HSP90, which is highly expressed in tumor cells, as the ligand to recruit the HSP90/E3 ubiquitin ligase complex. <strong>AurAP</strong>s induced the degradation of the target protein Aurora A by “hijacking” the HSP90/E3 complexes, effectively increasing the targeting of tumors. <em>In vitro</em> biochemical and cellular assays showed that <strong>AurAP14</strong> effectively degraded Aurora A kinase, inhibited the proliferation of most human tumor cells and effectively attenuated the development of paclitaxel-resistant lung cancer cells. In addition, <strong>AurAP14</strong> significantly inhibited the tumor growth of NSCLC and drug-resistant NSCLC xenograft tumor mice. The results from this study indicate that <strong>AurAP14</strong> represents a promising delivery strategy for the sequential elimination of multiple functions of oncogenic proteins and the attenuation of chemotherapy-induced drug resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118141"},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003510","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}

引用次数: 0

Targeting galectin-4 with glycoconjugates of varying architectures: a multivalency étude with accent on anti-tumor effect and protection against apoptosis 用不同结构的糖缀合物靶向半乳糖凝集素-4：一种以抗肿瘤作用和保护细胞凋亡为重点的多价调制体

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-06 DOI: 10.1016/j.ejmech.2025.118149

Andrea Vopálenská , Soňa Balogová , Michaela Hovorková , David Vrbata , Jakub Červený , Lucie Petrásková , Helena Pelantová , Pavlína Nekvasilová , Kristýna Slámová , Josef Cvačka , Anna Shaliutina-Loginova , Vladimír Křen , Pavla Bojarová

{"title":"Targeting galectin-4 with glycoconjugates of varying architectures: a multivalency étude with accent on anti-tumor effect and protection against apoptosis","authors":"Andrea Vopálenská , Soňa Balogová , Michaela Hovorková , David Vrbata , Jakub Červený , Lucie Petrásková , Helena Pelantová , Pavlína Nekvasilová , Kristýna Slámová , Josef Cvačka , Anna Shaliutina-Loginova , Vladimír Křen , Pavla Bojarová","doi":"10.1016/j.ejmech.2025.118149","DOIUrl":"10.1016/j.ejmech.2025.118149","url":null,"abstract":"<div><div>Galectin-4 (Gal-4) is a protumorigenic protein that strongly participates especially in gastrointestinal cancer and is increasingly recognized as a therapeutic target in gastrointestinal malignancies, where its dysregulated expression contributes to tumor progression and immune modulation. Its abundance and the extent of its involvement in these pathologies are comparable with its much better-studied counterparts, galectin-1 and -3. However, to date, no systematic effort has been made to design efficient defined Gal-4 inhibitors with a potential therapeutic effect. In this work, we present a library of biocompatible multivalent Gal-4 inhibitors with diverse architectures to investigate how different modes of multivalent presentation of a common ligand, lactose, influence the binding affinity to Gal-4. The most efficient scaffold was then loaded with a high-affinity tetrasaccharide ligand of Gal-4, derived from lacto-<em>N</em>-tetraose, to further enhance Gal-4 binding. The resulting glycopolymer exhibited outstanding performance in inhibiting Gal-4-induced apoptosis of T lymphocytes, and, in addition, it efficiently scavenged Gal-4 from the surface of cancer cells. Both of these processes are relevant for tumor immune evasion. Given the high biocompatibility, and low toxicity of the POx carrier, this glycopolymer has a strong potential as a candidate for further development of glycotherapeutics against Gal-4-associated diseases such as gastrointestinal cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118149"},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003391","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}

引用次数: 0

Approved alkyne-containing drugs: A review of their pharmacokinetic properties and therapeutic applications 已批准的含炔药物：药代动力学性质及治疗应用综述

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-05 DOI: 10.1016/j.ejmech.2025.118118

Jing Wang , Aiguo Gu , Huangdi Feng , Chuang Liu , Peng Li , Junhai Huang

引用次数: 0

Targeting calreticulin (CALR) in tumors: Cellular mechanisms, structural insights and ligand development advances 靶向钙网蛋白（CALR）在肿瘤中的作用：细胞机制、结构见解和配体发展进展

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-09-05 DOI: 10.1016/j.ejmech.2025.118122

Qikun Yin , Qinqin Song , Lili Sun , Jiaguo Lu , Xiaolin Zhang

引用次数: 0