European Journal of Medicinal Chemistry最新文献_第9页

Multicationic Ruthenium Phthalocyanines as Photosensitizers for Photodynamic Inactivation of Multiresistant Microbes 多阳离子酞菁钌作为多耐药微生物光动力失活的光敏剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-27 DOI: 10.1016/j.ejmech.2024.117214

Ana Belén Domínguez, Daniel Ziental, Jolanta Długaszewska, Lukasz Sobotta, Tomás Torres, M. Salomé Rodríguez-Morgade

{"title":"Multicationic Ruthenium Phthalocyanines as Photosensitizers for Photodynamic Inactivation of Multiresistant Microbes","authors":"Ana Belén Domínguez, Daniel Ziental, Jolanta Długaszewska, Lukasz Sobotta, Tomás Torres, M. Salomé Rodríguez-Morgade","doi":"10.1016/j.ejmech.2024.117214","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117214","url":null,"abstract":"Four photosensitizers PS1a-PS4a consisting in multicationic Ruthenium(II) Phthalocyanines (RuPcs) have been evaluated in photodynamic inactivation (PDI) of multiresistant microorganisms. The RuPcs, bearing from 4 to 12 terminal ammonium salts, have been designed to target the microorganisms cytoplasmic cell membrane and display high singlet oxygen quantum yields. In addition, PS3a and PS4a were conceived to exhibit multi-target localization by endowing them with amphiphilic character, using two different structural approaches. Under low light regimes, the two hydrophilic PS1a and PS2a, as well as the amphiphilic PS3a show much stronger response against gram-positive MRSA than that observed for the typical phthalocyanines designed for PDI, namely zinc(II) and palladium(II) complexes, as well as free-base Pcs. Besides, PS1a, PS2a and PS3a show remarkably high activity against the gram-negative E. coli, although weak fungicidal character against fluconazole-resistant C. albicans. Contrasting, the structurally different, amphiphilic PS4a shows only slight activity for Gram-positive bacteria, despite its ability to cross cell membrane and reach internal organelles. Still, PS4a shows a positive synergistic effect against MRSA when combined with doxycycline, exhibiting an increased activity from about 1.5 to about 4.9 log reduction under the light dose of 30 J/cm2 and the 0.125 mg/L subinhibitory dose of doxycycline.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888997","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

Synthesis and Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain 新型HDAC6锌指泛素结合域抑制剂的合成及功能筛选

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-27 DOI: 10.1016/j.ejmech.2024.117208

Silke Geurs, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, Jorick Franceus, Tom Desmet, Kristof Van Hecke, Dorien Clarisse, Karolien De Bosscher, Matthias D’hooghe

{"title":"Synthesis and Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain","authors":"Silke Geurs, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, Jorick Franceus, Tom Desmet, Kristof Van Hecke, Dorien Clarisse, Karolien De Bosscher, Matthias D’hooghe","doi":"10.1016/j.ejmech.2024.117208","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117208","url":null,"abstract":"Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy. Despite the importance of the UBD in proteostasis and viral infection, its pharmacological inhibition has been minimally explored thus far, with research largely focused on the deacetylase domain. We synthesized a diverse library of new compounds designed to target the HDAC6-UBD, termed HZUBi, with varied core structures including quinazolinone, oxindole and tetrahydrothiopyrano[4,3-b]indole, aimed at enhancing UBD interaction and extending into the side pocket. New structure-activity relationships were established, computational docking and molecular dynamics studies were performed and the functional impact of selected inhibitors was assessed in the context of multiple myeloma and viral infection. Several new HZUBi could displace a ubiquitin peptide from HDAC6-UBD in a differential manner, although to a lower extent than the literature reference compound HZUBi-3e. Despite exhibiting in vitro target engagement, neither HZUBi-3e nor its ester prodrug HZUBi-1e enhanced proteasome inhibitor-mediated multiple myeloma cell killing. Finally, none of the screened HZUBi triggered anti-viral activity.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888940","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

Recent advances in developing targeted protein degraders 靶向蛋白降解剂的研究进展

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-27 DOI: 10.1016/j.ejmech.2024.117212

Binbin Cheng, Hongqiao Li, Xiaopeng Peng, Jianjun Chen, Chuxiao Shao, Zhihua Kong

引用次数: 0

Design, synthesis and evaluation of pyrimidine derivatives as sedative-hypnotic agents 嘧啶衍生物镇静催眠剂的设计、合成及评价

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-27 DOI: 10.1016/j.ejmech.2024.117213

Tao Xu, Fangfang Li, Zifan Feng, Chenyu Dang, Yang Yang, Jinrong Wang, Cai-Xia Zang, Xiu-Qi Bao, Shi-Shan Yu, Dan Zhang, Ru-Bing Wang

{"title":"Design, synthesis and evaluation of pyrimidine derivatives as sedative-hypnotic agents","authors":"Tao Xu, Fangfang Li, Zifan Feng, Chenyu Dang, Yang Yang, Jinrong Wang, Cai-Xia Zang, Xiu-Qi Bao, Shi-Shan Yu, Dan Zhang, Ru-Bing Wang","doi":"10.1016/j.ejmech.2024.117213","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117213","url":null,"abstract":"Insomnia is a mental disorder in which drugs only alleviate the symptoms but also produce adverse effects. Therefore, developing innovative sedative-hypnotic agents is urgent. In this work, twenty-five novel heteroatomic compounds were designed, synthesized, and screened for their sedative activities, structurally featuring the fusion of pyrimidine and carbazole or benzothiazole. Most of the synthesized compounds showed distinct sedative activities in vivo. Among them, 4l displayed excellent sedative and hypnotic properties in the dose range of 0.1 - 2.5 mg/kg, and was superior to diazepam at 5 mg/kg. Mechanism studies showed 4l induced sedative-hypnotic effects via activating cAMP/PKA/CREB signaling pathway. Moreover, 4l possessed appropriate blood brain barrier permeability and excellent bioavailability (F: 74.5 ± 4.5%). Thus, 4l was identified as the lead compound owing to its favorable potency and pharmacokinetic profiles, providing alternative for insomnia drugs development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888941","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

Novel antileukemic compound with sub-micromolar potency against STAT5 addicted myeloid leukemia cells 一种新型抗白血病化合物，具有亚微摩尔效力，可对抗STAT5成瘾的髓系白血病细胞

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-26 DOI: 10.1016/j.ejmech.2024.117211

Marion Polomski, Marie Brachet-Botineau, Benjamin Victoir, Cécile Croix, Fabrice Gouilleux, Gildas Prié

{"title":"Novel antileukemic compound with sub-micromolar potency against STAT5 addicted myeloid leukemia cells","authors":"Marion Polomski, Marie Brachet-Botineau, Benjamin Victoir, Cécile Croix, Fabrice Gouilleux, Gildas Prié","doi":"10.1016/j.ejmech.2024.117211","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117211","url":null,"abstract":"Signal Transdcer and Activator of Transcription 5A and 5B (STAT5A/5B) are key effectors of tyrosine kinase oncogenes in myeloid leukemias. It is now clearly evidenced that inhibition of STAT5A/5B not only blocks the growth and survival of myeloid leukemia cells but also overcomes the resistance of leukemic cells to chemotherapy. Previous screening experiments allowed us to identify 17f as a lead compound with promising antileukemic activity that blocks the phosphorylation and transcriptional activity of STAT5A/5B in myeloid leukemia cells addicted to these proteins. In light of these findings, we initiated further pharmacomodulations of 17f to develop new derivatives with enhanced antileukemic activity. Our screening assays identified 14a, an aminopyrimidine derivative of 17f, as a new lead compound that: 1) blocks the growth and survival of myeloid leukemia cells at sub-micromolar concentrations, 2) targets the phosphorylation of STAT5 but also the expression of STAT5B and 3) relieves the resistance of Chronic and Acute Myeloid leukemia cells to conventional chemotherapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"335 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888942","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

Innovative design and potential applications of covalent strategy in drug discovery 共价策略在药物发现中的创新设计和潜在应用

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-26 DOI: 10.1016/j.ejmech.2024.117202

Tianyong Tang, Jiaxiang Luo, Dan Zhang, Yang Lu, Wen Liao, Jifa Zhang

{"title":"Innovative design and potential applications of covalent strategy in drug discovery","authors":"Tianyong Tang, Jiaxiang Luo, Dan Zhang, Yang Lu, Wen Liao, Jifa Zhang","doi":"10.1016/j.ejmech.2024.117202","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117202","url":null,"abstract":"Covalent inhibitors provide persistent inhibition while maintaining excellent selectivity and efficacy by creating stable covalent connections with specific amino acids in target proteins. This technique enables the precise inhibition of previously undruggable targets, lowering the frequency of administration and potentially bypassing drug resistance. Because of these advantages, covalent inhibitors have tremendous potential in treating cancer, inflammation, and infectious illnesses, making them extremely important in modern pharmacological research. Covalent inhibitors targeting EGFR, BTK, and KRAS (G12X), which overcome drug resistance and off-target, non-\"medicinal\" difficulties, as well as covalent inhibitors targeting SARS-CoV-2 Mpro, have paved the way for the development of new antiviral medicines. Furthermore, the use of covalent methods in drug discovery procedures, such as covalent PROTACs, covalent molecular gels, covalent probes, CoLDR, and Dual-targeted covalent inhibitors, preserves these tactics' inherent features while incorporating the advantages of covalent inhibitors. This synthesis opens up new therapeutic opportunities. This review comprehensively examines the use of covalent techniques in drug discovery, emphasizing their transformational potential for future drug development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"70 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886829","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

Identification of a Selective Pyruvate Dehydrogenase Kinase 1 (PDHK1) Chemical Probe by Virtual Screening 选择性丙酮酸脱氢酶激酶1 （PDHK1）化学探针的虚拟筛选鉴定

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-26 DOI: 10.1016/j.ejmech.2024.117210

Mason A. Baber, Mya D. Gough, Larisa Yeomans, Kyle Giesler, Kendall Muzzarelli, Chih-Jung Chen, Zahra Assar, Peter L. Toogood

{"title":"Identification of a Selective Pyruvate Dehydrogenase Kinase 1 (PDHK1) Chemical Probe by Virtual Screening","authors":"Mason A. Baber, Mya D. Gough, Larisa Yeomans, Kyle Giesler, Kendall Muzzarelli, Chih-Jung Chen, Zahra Assar, Peter L. Toogood","doi":"10.1016/j.ejmech.2024.117210","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117210","url":null,"abstract":"PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth in vitro and in vivo, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound 7 as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound 10. Structure-activity studies based on 10 identified 17 as a low μM inhibitor of PDHK1 (IC50 = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound 17 inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify 17 as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886827","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

A review of kappa opioid receptor antagonists and their clinical trial landscape 阿片受体拮抗剂及其临床研究进展综述

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-25 DOI: 10.1016/j.ejmech.2024.117205

Maloba M.M. Lobe, Saroj Verma, Vaishali M. Patil, Malliga R. Iyer

引用次数: 0

Corosolic acid and its derivatives targeting MCCC1 against insulin resistance and their hypoglycemic effect on type 2 diabetic mice 靶向MCCC1的科罗索酸及其衍生物对2型糖尿病小鼠胰岛素抵抗的影响及其降糖作用

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-25 DOI: 10.1016/j.ejmech.2024.117184

Guiyan Huang, Yu Lin, Jianping Zhao, Junlei Zhang, Yuexin Du, Mingyue Xiao, Heng Li, Zhong Chen, Naixin Kang, Ikhlas A. Khan, Yanli Liu, Bin Huang, Qiongming Xu

{"title":"Corosolic acid and its derivatives targeting MCCC1 against insulin resistance and their hypoglycemic effect on type 2 diabetic mice","authors":"Guiyan Huang, Yu Lin, Jianping Zhao, Junlei Zhang, Yuexin Du, Mingyue Xiao, Heng Li, Zhong Chen, Naixin Kang, Ikhlas A. Khan, Yanli Liu, Bin Huang, Qiongming Xu","doi":"10.1016/j.ejmech.2024.117184","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117184","url":null,"abstract":"Corosolic acid (CA), a natural triterpenoid, exhibits various biological activities and is often called a plant-derived insulin due to its significant hypoglycemic effects, making it especially beneficial for individuals with diabetes or high blood glucose levels. However, CA has notable in vitro toxicity, low water solubility, and poor pharmacokinetic properties. To address these limitations, a series of CA derivatives were synthesized, resulting in the identification of derivative H26, which demonstrates a significantly enhanced hypoglycemic effect, reduced toxicity, and improved pharmacokinetic characteristics compared to CA. To identify the target protein of CA and investigate its therapeutic potential, a chemical probe derived from natural products, called CA-biotin, was designed and synthesized. By employing an avidin-biotin affinity binding system, we distinguished the differential protein bands between CA-biotin and biotin. This quantitative proteomic analysis revealed, for the first time, that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) directly binds to CA. The interaction between H26 and MCCC1 was examined in vitro. The research on the mechanisms by which CA and H26 address Type 2 diabetes mellitus (T2DM) concentrated on the insulin resistance signaling pathway, specifically targeting MCCC1. The results indicated that H26 shows significant promise as a potential hypoglycemic agent, while MCCC1 may serve as a valuable target for addressing insulin resistance. This presents a promising opportunity for developing new medications aimed at improving the health of patients with type 2 diabetes mellitus (T2DM) or hyperglycemia.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"123 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884494","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

Design, Synthesis and Biological Evaluation of Galantamine Analogues for Cognitive Improvement in Alzheimer's Disease 加兰他明类似物对阿尔茨海默病认知改善的设计、合成和生物学评价

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-12-24 DOI: 10.1016/j.ejmech.2024.117198

Mengzhen Li, Chao Ma, Yao Li, Hanxun Wang, Xiaomeng Xiu, Xueqi Zhao, Peng Liu, Huali Yang, Maosheng Cheng

{"title":"Design, Synthesis and Biological Evaluation of Galantamine Analogues for Cognitive Improvement in Alzheimer's Disease","authors":"Mengzhen Li, Chao Ma, Yao Li, Hanxun Wang, Xiaomeng Xiu, Xueqi Zhao, Peng Liu, Huali Yang, Maosheng Cheng","doi":"10.1016/j.ejmech.2024.117198","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117198","url":null,"abstract":"Galantamine plays a crucial role in the management of brain disorders. In this study, a series of galantamine analogues were designed, synthesized and evaluated as potential therapeutic agents for Alzheimer's disease (AD). Compound C2, a dual inhibitor of cholinesterase, was obtained by introducing a benzylpyridine ring to the hydroxyl group of galantamine. Compared to galantamine (hAChE, IC50 = 1529 ± 6 nM), C2 exhibited excellent inhibitory activities against hAChE (IC50 = 513.90 ± 9.60 nM) and hBuChE (IC50 = 357.77 ± 10.24 nM). Further studies revealed that C2 possessed significant abilities to protect PC12 cells from H2O2-induced apoptosis and reactive oxygen species (ROS) production. The acute toxicity test in vivo indicated that C2 exhibited a remarkable safety profile. Whether in the acute memory impairment induced by the Aβ1-42 model or in the amnesia induced by the scopolamine model, oral administration of C2 demonstrated superior improvement on cognition and spatial memory. In summary, both in vitro and in vivo results suggest that C2 deserves to be further explored as an anti-AD agent.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884498","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