European Journal of Medicinal Chemistry最新文献

Design, Synthesis, and Biological Evaluation of Novel Macrocyclic Derivatives as Potent ATP-Citrate Lyase Inhibitors

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-27 DOI: 10.1016/j.ejmech.2025.117684

Yongjun Zang, Maoying Shi, Luyang Tai, Yuanyang Hu, Yu Wang, Runan Zheng, Zhiqi Feng, Haoliang Yuan, Xiaoan Wen, Liang Dai

引用次数: 0

Refinement of imidazo[2,1-a]pyrimidines in pursuit of potential drug candidates against group 2 influenza A viruses

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-26 DOI: 10.1016/j.ejmech.2025.117679

Malaika D. Argade, Varada Anirudhan, Sean P. Bradley, Łukasz Tomorowicz, Ryan Bott, Boopathi Sownthirarajan, Christian A. Zielinski, John P. Sloan, Dejan S. Nikolic, Arsen M. Gaisin, Terry W. Moore, Balaji Manicassamy, Norton P. Peet, Lijun Rong, Irina N. Gaisina

{"title":"Refinement of imidazo[2,1-a]pyrimidines in pursuit of potential drug candidates against group 2 influenza A viruses","authors":"Malaika D. Argade, Varada Anirudhan, Sean P. Bradley, Łukasz Tomorowicz, Ryan Bott, Boopathi Sownthirarajan, Christian A. Zielinski, John P. Sloan, Dejan S. Nikolic, Arsen M. Gaisin, Terry W. Moore, Balaji Manicassamy, Norton P. Peet, Lijun Rong, Irina N. Gaisina","doi":"10.1016/j.ejmech.2025.117679","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117679","url":null,"abstract":"We discovered a series of imidazo[1,2-a]pyrimidines as potent, group 2 selective inhibitors of influenza A viruses (IAVs) that target the hemagglutinin-mediated viral entry process. Preliminary hit-to-lead optimization efforts afforded promising IAV inhibitors with improved activity against infectious H7N7 and H3N2 viruses. We now report a more comprehensive cycle of structure-activity relationship studies and optimization of metabolic stability, and overall druglike properties of this series of imidazo[1,2-a]pyrimidines, which allowed in the identification of two lead compounds that show promise as preclinical candidates. Compounds 10 and 12 inhibited pseudotyped H7N1 with EC50 values of 0.09 and 0.47 μM, respectively. They were among the most potent compounds in the viral replication assay when tested against infectious H3N2 IAV, and they also demonstrated remarkable activity against avian influenza viruses; these data designated these imidazo[1,2-a]pyrimidines as potent broad-spectrum group 2 IAV inhibitors. Compounds 10 and 12 exhibit dissimilar but desirable DMPK profiles, and therefore they offer different options for specific and effective patient treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876295","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

Exploring the Correlation of Linker Structure and Antimicrobial Activities of Pyridinium-Based Cationic Biocides: Aromatic versus Aliphatic Architectures

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-26 DOI: 10.1016/j.ejmech.2025.117673

Nikita A. Frolov, Mary A. Seferyan, Elena V. Detusheva, Evgeniya A. Saverina, Elizabeth Son, Radmir N. Akchurin, Alena S. Kartseva, Victoria V. Firstova, Anatoly N. Vereshchagin

{"title":"Exploring the Correlation of Linker Structure and Antimicrobial Activities of Pyridinium-Based Cationic Biocides: Aromatic versus Aliphatic Architectures","authors":"Nikita A. Frolov, Mary A. Seferyan, Elena V. Detusheva, Evgeniya A. Saverina, Elizabeth Son, Radmir N. Akchurin, Alena S. Kartseva, Victoria V. Firstova, Anatoly N. Vereshchagin","doi":"10.1016/j.ejmech.2025.117673","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117673","url":null,"abstract":"Cationic biocides, particularly quaternary ammonium compounds (QACs), play a vital role in controlling microbial infections across various industries, healthcare facilities and households. As their widespread use increased drastically in the last few years due to COVID-19, there is growing concern about the development of resistance among microorganisms exposed to cationic biocides. It is crucial to recognize this threat in advance and respond by modifying and replacing the old generation of commercial biocides. Reported here is the pyridinium-based bis-QACs tuning via combination of two simple synthesis approaches to achieve novel biocide’s architectures with mixed linkers. The obtained compounds were subjected to a broad bioactivity assay against a panel of 26 microbial pathogens, including multi-resistant bacterial ESKAPEE strains, fungi and biofilms. Novel hit-compounds showed improved antibacterial and antibiofilm action, rapid bacterial eradication within 15-30 min of exposure and 4.5-fold lower hemotoxicity, as well as lower potential for the development of bacterial resistance compared to commercial lead antiseptic octenidine. Highlighted findings and insights will serve as a good basis for further studies of bis-QACs as highly effective biocides.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1187 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876293","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 novel CDK4/6 and BRD4 dual inhibitors for treatment of KRAS-mutant NSCLC

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-26 DOI: 10.1016/j.ejmech.2025.117685

Xiaojie Tong, Tong Shen, Song Li, Liqiang Wu

{"title":"Design, synthesis, and biological evaluation of novel CDK4/6 and BRD4 dual inhibitors for treatment of KRAS-mutant NSCLC","authors":"Xiaojie Tong, Tong Shen, Song Li, Liqiang Wu","doi":"10.1016/j.ejmech.2025.117685","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117685","url":null,"abstract":"CDK4/6 is the candidate therapeutic target for KRAS-mutant NSCLC. However, its frequent primary and acquired resistance limits its potential clinical application. Recently it had been shown that BRD4 up-regulation induced conferred resistance of KRAS-mutant NSCLC cells to CDK4/6 inhibitor, and BRD4 inhibitor synergized with CDK4/6 inhibitor induced senescence in KRAS-mutant NSCLC tumors and cells, meanwhile, the combined therapy extended survival of the KRAS-mutant NSCLC mouse model. Thus, a series of CDK4/6 and BRD4 dual inhibitors were prepared to target KRAS-mutant NSCLC, Among these compounds, PJ2 exhibited potent antiproliferative effects against KRAS-mutant NSCLC cells NCI-H358 (IC50 = 0.34 ± 0.01 μM) and A549 (IC50 = 0.31 ± 0.04 μM), and had excellent inhibitory effects on CDK4, CDK6, BRD4(BD1) and BRD4(BD2), and IC50 values were 168.75 ± 46.32 nM, 292.45 ± 11.67 nM, 23.17 ± 3.61 nM and 3.12 ± 0.15 nM, respectively. Mechanism research indicated that PJ2 induced cell cycle arrest, senescence and apoptosis through ROS-mediated DNA damage. Furthermore, PJ2 could effectively suppress the migration and invasion of NCI-H358. These results proved that developing potent CDK4/6 and BRD4 dual inhibitors was a promising strategy for the KRAS-mutant NSCLC therpy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"76 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876296","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

Virtual Screening and Fragment Growth Strategy for Developing Near-Infrared Fluorescent Probes to Detect Aβ in Alzheimer’s Disease Model

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-25 DOI: 10.1016/j.ejmech.2025.117695

Guanyu Xu, Can Zhou, Geng Su, Zeyin Liang, Jianyu Wu, Tiantian Tang, Yuemin Bian, Jian Cai, Yi Zou, Jian Yang

{"title":"Virtual Screening and Fragment Growth Strategy for Developing Near-Infrared Fluorescent Probes to Detect Aβ in Alzheimer’s Disease Model","authors":"Guanyu Xu, Can Zhou, Geng Su, Zeyin Liang, Jianyu Wu, Tiantian Tang, Yuemin Bian, Jian Cai, Yi Zou, Jian Yang","doi":"10.1016/j.ejmech.2025.117695","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117695","url":null,"abstract":"Amyloid fibrils are well-established biomarkers of Alzheimer's disease (AD), and the development of novel near-infrared fluorescent (NIRF) probes for early detection of β-amyloid can help differentiate AD from other neurodegenerative conditions. In this study, we report the discovery of an effective NIRF probe, probe 6-4, through a combined approach of virtual screening and fragment growth. Probe 6-4 binds strongly to Aβ oligomers and aggregates, showing robust fluorescent properties with an emission maximum near 650 nm when bound to Aβ aggregates and oligomers. It exhibits high sensitivity, with a nearly 100-fold increase in fluorescence intensity, and strong affinity (Kd = 9.4 nM for oligomers and 12.5 nM for aggregates). In vivo and ex-vivo NIRF imaging studies further demonstrated that probe 6-4 can distinguish AD transgenic model mice from wild-type controls. Overall, probe 6-4 proves to be a potent and efficient tool for detecting Aβ aggregates and oligomers in the brain, validating the effectiveness of combining virtual screening and fragment growth in developing NIRF probes for AD research.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876300","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

Annual review of EGFR inhibitors in 2024

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-25 DOI: 10.1016/j.ejmech.2025.117677

Chao Gao, Wanning Wang, Tong Liu, Xingyu Li, Yongbo Yu, Jianhui Wu

引用次数: 0

Harnessing the Bishomolithocholic Acid Scaffold for Selective Sialyltransferase Inhibition: A Targeted Approach to Suppress Breast Cancer Metastasis

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-24 DOI: 10.1016/j.ejmech.2025.117674

Ser John Lynon P. Perez, Zih-Fan Hsu, Tzu-Ting Chang, Chia-Ling Chen, Wen-Shan Li

{"title":"Harnessing the Bishomolithocholic Acid Scaffold for Selective Sialyltransferase Inhibition: A Targeted Approach to Suppress Breast Cancer Metastasis","authors":"Ser John Lynon P. Perez, Zih-Fan Hsu, Tzu-Ting Chang, Chia-Ling Chen, Wen-Shan Li","doi":"10.1016/j.ejmech.2025.117674","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117674","url":null,"abstract":"ST6GAL1 plays a crucial role in the progression of triple-negative breast cancer (TNBC), highlighting its potential as a therapeutic target for this aggressive cancer subtype. Due to the high metastatic potential of TNBC and the limitations of current therapies, selective and potent ST6GAL1 inhibitors are urgently needed. In this study, a scaffold-hopping approach from lithocholic acid to bishomolithocholic acid successfully led to the discovery of novel ST6GAL1 inhibitors, SPP-037 and HZF01, with enhanced biological activity and selectivity. Both compounds significantly inhibited MDA-MB-231 cell migration, HUVEC tube formation, tumor growth, and metastasis in vitro and in vivo. Molecular docking studies revealed key interactions between the ST inhibitors and ST6GAL1, supporting their enhanced selectivity and binding affinity. Additionally, SPP-037 and HZF01 were found to block integrin α2,6-sialylation, disrupting integrin activation and downstream signaling pathways involving the phosphorylation of focal adhesion kinase (FAK) and paxillin, which are critical for cell migration. These results underscore the potential of targeting ST6GAL1 to suppress tumor progression and metastasis, offering a promising avenue for treating aggressive breast cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"73 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872487","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

Molecular and supramolecular routes to enhance Gadolinium-based contrast agents relaxivity: How far are we from the theoretical optimal value?

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-24 DOI: 10.1016/j.ejmech.2025.117668

Lorenzo Palagi , Dario Livio Longo , Éva Tóth , Carlo C. Quattrocchi , Aart J. van der Molen , Silvio Aime , Eliana Gianolio

{"title":"Molecular and supramolecular routes to enhance Gadolinium-based contrast agents relaxivity: How far are we from the theoretical optimal value?","authors":"Lorenzo Palagi , Dario Livio Longo , Éva Tóth , Carlo C. Quattrocchi , Aart J. van der Molen , Silvio Aime , Eliana Gianolio","doi":"10.1016/j.ejmech.2025.117668","DOIUrl":"10.1016/j.ejmech.2025.117668","url":null,"abstract":"<div><div>Gadolinium Based Contrast Agents (GBCAs) are routinely used in the clinical practice to enhance the diagnostic potential of MRI. Their contrast enhancing capabilities rely on their ability to increase the relaxation rate of tissue water protons. This property is expressed by the relaxivity, whose value is determined by structural, electronic and dynamic characteristics of the GBCA. Based on extensive experimental work over the past four decades and the well-established theory of paramagnetic relaxation, it is usually possible to correlate observed relaxivity values to specific molecular properties. Key determinants include the number of water molecules and/or exchangeable protons in the first and second coordination spheres, their distance from the paramagnetic Gd3+ ion, the ion's electronic relaxation time, molecular reorientation time, and the exchange rate of the coordinated water molecules. Understanding the key factors that affect relaxivity has enabled the design of systems with optimized structural and dynamic properties. However, some examples demonstrate exceptional relaxivity which cannot be fully explained by the established theory. In particular, GBCAs within confined environments show significant promise for developing high-relaxivity agents. Overall, one may state that nowadays it is possible to attain highly efficient GBCAs thanks to the in-depth understanding of the structural and dynamic determinants of their relaxivity, together with the optimization of their in vivo stability and biodistribution/excretion properties. This knowledge is crucial for the rational design of the next generation of MRI CAs. The domain of Molecular Imaging will also largely benefit from these efforts.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117668"},"PeriodicalIF":6.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872210","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, biophysical and biological evaluation of original condensed pyrrolopyrimidine and pyrrolopyridine ligands as anti-SARS-CoV-2 agents targeting G4

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-23 DOI: 10.1016/j.ejmech.2025.117655

Jean Guillon, Solène Savrimoutou, Nicolas Da Rocha, Albenque-Rubio Sandra, Olivier Helynck, Cyrielle Durand, Jeanne Chiaravalli, Noël Pinaud, Luisa Ronga, Stéphane Moreau, Simon Chirold, Tshering Zangmo, Melika Arab, Lindita Lari, Jean-Louis Mergny, Munier-Lehmann Hélène, Marc Lavigne

{"title":"Design, synthesis, biophysical and biological evaluation of original condensed pyrrolopyrimidine and pyrrolopyridine ligands as anti-SARS-CoV-2 agents targeting G4","authors":"Jean Guillon, Solène Savrimoutou, Nicolas Da Rocha, Albenque-Rubio Sandra, Olivier Helynck, Cyrielle Durand, Jeanne Chiaravalli, Noël Pinaud, Luisa Ronga, Stéphane Moreau, Simon Chirold, Tshering Zangmo, Melika Arab, Lindita Lari, Jean-Louis Mergny, Munier-Lehmann Hélène, Marc Lavigne","doi":"10.1016/j.ejmech.2025.117655","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117655","url":null,"abstract":"The design and synthesis of novel bis[(substituted-aminomethyl)phenyl]phenyl pyrrolopyrimidines, pyrrolopyridines, pyrazolopyrimidines, imidazopyrimidines, and tris[(substituted-aminomethyl)phenyl]phenyl pyrrolopyrimidines are reported here. These original G-quadruplex (G4) ligands have been then subjected to a screening on SARS-CoV-2 using a competition HTRF assay by targeting the SUD-NM/TRF2 RNA G4 interaction. The more promising derivatives have been evaluated in vitro to determine their potential antiviral effect on two different cell lines infected by two SARS-CoV-2 strains. This study revealed a clear correlation between their antiviral property and their efficacy to prevent the SUD/G4 interaction. This correlation supports the choice of SUD/RNA G4 complexes formed during SARS-CoV-2 infection as new antiviral targets.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862741","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

Aromatic group-induced self-assembly of short antimicrobial peptides: unveiling exceptionally potent antimicrobial efficacy 芳香基团诱导的短抗菌肽自组装：揭示异常强大的抗菌功效

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-04-23 DOI: 10.1016/j.ejmech.2025.117659

Yao Liu , Tingting Yang , Beibei Li , Yu Wang , Xu Ouyang , Zufang Ba , Yuhuan Zhao , Zhongwei Yu , Bingqian Ren , Pengyi Yan , Xueting Liu , Liru Yuan , Qingyang Xu , Chao Zhong , Hui Liu , Yun Zhang , Sanhu Gou , Jingman Ni

{"title":"Aromatic group-induced self-assembly of short antimicrobial peptides: unveiling exceptionally potent antimicrobial efficacy","authors":"Yao Liu , Tingting Yang , Beibei Li , Yu Wang , Xu Ouyang , Zufang Ba , Yuhuan Zhao , Zhongwei Yu , Bingqian Ren , Pengyi Yan , Xueting Liu , Liru Yuan , Qingyang Xu , Chao Zhong , Hui Liu , Yun Zhang , Sanhu Gou , Jingman Ni","doi":"10.1016/j.ejmech.2025.117659","DOIUrl":"10.1016/j.ejmech.2025.117659","url":null,"abstract":"<div><div>Self-assembled antimicrobial peptides (AMPs) have superior antimicrobial properties from their supramolecular nanostructures. A systematic study is needed to determine which AMPs can generate more significant self-assembled structures for antimicrobial activity. In this study, thirty-six self-assembled AMPs were systematically designed by combining six hexapeptide sequences with five aromatic groups, exploring the contributions of different sequences and groups to self-assembly and antimicrobial properties. Most peptides had broad-spectrum antimicrobial and self-assembly capabilities. Moderate self-assembly can endow these new AMPs with excellent antimicrobial properties. Candidate peptides Nap-f5f6 and Npx-f5f6 had outstanding antimicrobial activity, low toxicity, and high selectivity. This may be due to their self-assembly into nanofibers and nanospheres via π-π stacking provided by C- and N-terminal aromatic groups. Their membrane-disrupting bactericidal mechanism gives a rapid effect and prevents antibiotic resistance. Also, in infected mouse skin wounds, Nap-f5f6 and Npx-f5f6 had low toxicity, reduced bacterial load, and accelerated wound healing.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117659"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866588","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