European Journal of Medicinal Chemistry最新文献_第3页

Design, synthesis, and in vitro/in vivo evaluation of novel diphenyl-1,2,4-triazine-3-yl-thioacetamide-chalcone hybrids as potent α-glucosidase inhibitors targeting type 2 diabetes. 新型二苯基-1,2,4-三嗪-3-基硫代乙酰胺-查尔酮复合物作为2型糖尿病有效α-葡萄糖苷酶抑制剂的设计、合成和体外/体内评价

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-28 DOI: 10.1016/j.ejmech.2026.119271

Elika Salehi Ghalehsefid, Mohammad Halimi, Hassan Mohammadi, S Morteza F Farnia, Shahab Kermaninia, Navid Dastyafteh, Somayeh Mojtabavi, Jahan B Ghasemi, Mina Saeedi, Bagher Larijani, Maryam Mohammadi-Khanaposhtani, Mohammad Mahdavi

{"title":"Design, synthesis, and in vitro/in vivo evaluation of novel diphenyl-1,2,4-triazine-3-yl-thioacetamide-chalcone hybrids as potent α-glucosidase inhibitors targeting type 2 diabetes.","authors":"Elika Salehi Ghalehsefid, Mohammad Halimi, Hassan Mohammadi, S Morteza F Farnia, Shahab Kermaninia, Navid Dastyafteh, Somayeh Mojtabavi, Jahan B Ghasemi, Mina Saeedi, Bagher Larijani, Maryam Mohammadi-Khanaposhtani, Mohammad Mahdavi","doi":"10.1016/j.ejmech.2026.119271","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119271","url":null,"abstract":"A novel series of 5,6-diphenyl-1,2,4-triazine-3-yl-thioacetamide-chalcone hybrids (9a-n) was designed, synthesized, and evaluated for their antidiabetic potential. All derivatives exhibited potent in vitro α-glucosidase inhibitory activity (IC50 = 0.2-112 μM) compared with acarbose (IC50 = 750.0 μM). The most potent compound, 9b (IC50 = 0.2 μM), acted as a competitive inhibitor with a Ki value of 200 nM and demonstrated significant glucose-lowering activity in a zebrafish model. In addition, compound 9b effectively inhibited bovine serum albumin (BSA) glycation relative to aminoguanidine. Molecular docking and molecular dynamics revealed stable binding of compound 9b within the α-glucosidase active site, with a binding energy of -9.2 kcal/mol, compared with -4.04 kcal/mol for acarbose. According to the in silico ADMET analysis, compound 9b showed oral bioavailability comparable to acarbose, together with improved drug-like properties. Overall, these findings identify compound 9b as a promising lead α-glucosidase inhibitor with potent in vitro and in vivo antihyperglycemic activity, warranting further investigation for the treatment of type 2 diabetes.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119271"},"PeriodicalIF":6.7,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872504","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 β-carboline derivatives as potent STAT3 dual phosphorylation inhibitor for hepatocellular carcinoma treatment. 发现β-碳碱衍生物作为肝细胞癌治疗中有效的STAT3双磷酸化抑制剂。

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-27 DOI: 10.1016/j.ejmech.2026.119276

Ziqing Jian, Lanyi Wei, Meilin Ren, Zhike Zhou, Zhiyao Zhu, Jianhua Wei, Rizhen Huang, Yanli Xu, Ye Zhang, Yanyan Chen

{"title":"Discovery of β-carboline derivatives as potent STAT3 dual phosphorylation inhibitor for hepatocellular carcinoma treatment.","authors":"Ziqing Jian, Lanyi Wei, Meilin Ren, Zhike Zhou, Zhiyao Zhu, Jianhua Wei, Rizhen Huang, Yanli Xu, Ye Zhang, Yanyan Chen","doi":"10.1016/j.ejmech.2026.119276","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119276","url":null,"abstract":"Hepatocellular carcinoma (HCC) remains a significant clinical challenge, and targeting the dual phosphorylation of signal transducer and activator of transcription 3 (STAT3) has emerged as a promising strategy for HCC treatment. In this study, 25 novel β-carboline-benzo[b]thiophene 1,1-dioxide hybrids were designed and synthesized via structural modification of the β-carboline scaffold. Among them, compound 18 exhibited the most potent antiproliferative activity against Huh-7 cells in vitro, with an IC50 value of 1.30 ± 0.05 μM, and significantly suppressed colony formation and cell migration. Mechanistic investigations demonstrated that compound 18 directly bound to STAT3 protein with a KD value of 5.63 μM, as determined by surface plasmon resonance (SPR), and markedly inhibited its phosphorylation at both Tyr705 and Ser727 residues, consequently blocking its nuclear translocation. In addition, compound 18 impaired mitochondrial function by reducing ATP production and elevating reactive oxygen species (ROS) levels. In a Huh-7 xenograft mouse model, compound 18 administered at 7.5 mg/kg achieved a tumor inhibition rate of 55.08%. Collectively, these results indicate compound 18 as a promising STAT3 dual phosphorylation inhibitor for HCC treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119276"},"PeriodicalIF":6.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862893","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 pharmacological evaluation of terrein derivatives targeting hepatocellular carcinoma. 针对肝细胞癌的terrein衍生物的设计、合成和药理学评价。

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-27 DOI: 10.1016/j.ejmech.2026.119260

Wenxing Li, Guohui Yi, Dan Huang, Yang Hui, Wenhao Chen

{"title":"Design, synthesis, and pharmacological evaluation of terrein derivatives targeting hepatocellular carcinoma.","authors":"Wenxing Li, Guohui Yi, Dan Huang, Yang Hui, Wenhao Chen","doi":"10.1016/j.ejmech.2026.119260","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119260","url":null,"abstract":"Hepatocellular carcinoma is a malignant tumor that ranks sixth in incidence and third in mortality globally. In this study, based on the principles of chemical splicing and prodrug synthesis strategies, a total of 26 new derivatives, including 17 cinnamic acid derivatives, 8 quinoline derivatives, and 1 triazole derivative, were designed and synthesized using terrein (1), isolated from the endophytic fungus Aspergillus terreus of Sphagneticola trilobata as the parent compound. Among these, the IC50 values for the proliferation-inhibitory effects of the cinnamic acid derivative 1i and the quinoline derivative 2a on liver cancer cells Hep G2 were 0.8 and 4.6 μM, respectively, which were 120 and 21-fold stronger than those of 1. In addition, 1i and 2a exhibited proliferation inhibition rates against Hep G2 cells were observed to be lower by factors of 14.4 and 9.65, respectively, compared to those against AML-12 cells, demonstrating that moderate selectivity and a certain therapeutic window are exhibited by these compounds. Molecular mechanism studies have shown that both 1i and 2a could induce apoptosis in Hep G2 cells by inhibiting the PI3K/Akt signaling pathway, arresting the cell cycle, and suppressing cell proliferation and migration. The difference is that 1i arrested the cell cycle in the S phase, while 2a arrested it in the G0/G1 phase. Further transcriptomic analysis, combined with molecular docking and isothermal titration calorimetry results, indicated that the likely target of 1i was NCF2, while the target of 2a was WNT9A. In vivo studies further confirmed that 1i demonstrated superior anti-tumor activity and safety compared to positive control Sorafenib. Overall, the findings of this study indicate that derivatives 1i and 2a are highly promising candidate drugs for the treatment of hepatocellular carcinoma.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119260"},"PeriodicalIF":6.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872520","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 Pyrazolo[3,4-d]pyrimidine-6-amine Derivatives as Potent Polo-like Kinase 2 Inhibitors 新型吡唑[3,4-d]嘧啶-6-胺衍生物作为有效的polo样激酶2抑制剂的发现

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-27 DOI: 10.1016/j.ejmech.2026.119269

Seoyeong Yang, Su Hyun Ji, Soomin Kim, Kang-Gon Lee, Sieun Park, Donghwa Shin, Hwan Won Chung, Dongkyun Han, Misook Ham, Jiyoung Moon, Jung In Pyo, Da-Kyoung Koh, Hyebin Lee, Jeongmin Moon, Jaehoon Sim, Jinha Yu, Chan Seong Cheong, Chiman Song, Seo-Jung Han

{"title":"Discovery of Novel Pyrazolo[3,4-d]pyrimidine-6-amine Derivatives as Potent Polo-like Kinase 2 Inhibitors","authors":"Seoyeong Yang, Su Hyun Ji, Soomin Kim, Kang-Gon Lee, Sieun Park, Donghwa Shin, Hwan Won Chung, Dongkyun Han, Misook Ham, Jiyoung Moon, Jung In Pyo, Da-Kyoung Koh, Hyebin Lee, Jeongmin Moon, Jaehoon Sim, Jinha Yu, Chan Seong Cheong, Chiman Song, Seo-Jung Han","doi":"10.1016/j.ejmech.2026.119269","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119269","url":null,"abstract":"Polo-like kinase 2 (PLK2), a serine/threonine kinase involved in cell cycle regulation, has emerged as a promising therapeutic target in cancer due to its role in tumor cell proliferation and survival. In this study, we report the design and synthesis of novel PLK2 inhibitors, featuring pyrazolo[3,4-<ce:italic>d</ce:italic>]pyrimidine derivatives. Among them, compounds <ce:bold>8</ce:bold> and <ce:bold>11</ce:bold> exhibited potent PLK2 inhibitory activity, with IC<ce:inf loc=\"post\">50</ce:inf> values of 0.36 μM and 0.78 μM, respectively (ON1231320, IC<ce:inf loc=\"post\">50</ce:inf> = 0.10 μM). In colorectal cancer cell lines SW480 and HT29, compounds <ce:bold>8</ce:bold> and <ce:bold>11</ce:bold> suppressed cell proliferation in a dose-dependent manner, induced apoptosis, caused cell cycle arrest, and inhibited anchorage-independent growth. Notably, compound <ce:bold>11</ce:bold> showed significant <ce:italic>in vivo</ce:italic> tumor growth efficacy in a xenograft mouse model (TGI = 69.37%), markedly superior to ON1231320 (TGI = 8.36%) with favorable pharmacokinetic parameters. These findings establish pyrazolo[3,4-<ce:italic>d</ce:italic>]pyrimidine derivatives as promising PLK2 inhibitors with strong therapeutic potential for colorectal cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885577","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 new short template-designed peptide with good antitumor potential by an alternative modification of threonine and its phosphorylation 通过苏氨酸的替代修饰及其磷酸化而设计的具有良好抗肿瘤潜力的新型短模板肽

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-26 DOI: 10.1016/j.ejmech.2026.119272

Linfeng Liu, Fengzhan Wu, Yuxia Wang, Ruixuan Mao, Jingjing Wang, Jie Liu, Sanhu Gou, Chao Zhong, Hui Liu, Li Xie, Yun Zhang, Jingman Ni

{"title":"A new short template-designed peptide with good antitumor potential by an alternative modification of threonine and its phosphorylation","authors":"Linfeng Liu, Fengzhan Wu, Yuxia Wang, Ruixuan Mao, Jingjing Wang, Jie Liu, Sanhu Gou, Chao Zhong, Hui Liu, Li Xie, Yun Zhang, Jingman Ni","doi":"10.1016/j.ejmech.2026.119272","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119272","url":null,"abstract":"Anticancer peptides (ACPs) are widely considered a promising antitumor alternative due to their unique action mechanism. A new type of ACPs with short sequence, excellent antitumor activity, low toxicity and good stability is urgently needed. In this work, a series of new short ACPs were designed and synthesized based on the novel short template (KLLK)<ce:inf loc=\"post\">3</ce:inf>W by altering its hydrophobicity, net charge, and amino acid structure. By analyzing the structure-bioactivity relationship, the results showed that P1 with one Trp in the C-terminal showed stronger antitumor activity and relatively greater cell selectivity than the other P series peptides. After the further structural optimization, the T derivatives, particularly 2pT with pThr substitution at the amphipathic interface 2nd site showed desirable antitumor activity while maintaining significantly decreased hemolytic activity (an 8.5-fold reduction) and an improved serum half-life (a 2.4-fold increase) compared with P1. Mechanistic studies revealed the multiple action modes involving potent membrane disruption and intramolecular effects, demonstrating remarkable potential in combination with PTX. Moreover, the in vivo studies confirmed that 2pT had excellent antitumor efficacy comparable to that of P1, exhibiting substantial superiority over the control groups (2T and PTX). Taken together, this study offers the valuable insights into developing promising short ACPs with good potential for tumor treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853276","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

Structure-Based Virtual Screening Leads to the Discovery of a 4,5-Dihydropyrazole Derivative as the First Dual Inhibitor of West Nile Virus NS3 Helicase and Protease 基于结构的虚拟筛选导致发现4,5-二氢吡唑衍生物作为西尼罗病毒NS3解旋酶和蛋白酶的第一个双重抑制剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-26 DOI: 10.1016/j.ejmech.2026.119273

Antonio Lupia, Roberta Emmolo, Giulia Atzeni, Erica Sanna, Salvatore Nieddu, Alessia Onali, Laura Demuru, Annalaura Paulis, Simona Distinto, Angela Corona, Francesca Esposito, Rita Meleddu, Filippo Cottiglia, Sharon D. Bryant, Elias Maccioni, Enzo Tramontano

引用次数: 0

Soluble guanylate cyclase stimulators and activators: Chemistry, biology, and therapeutic advances. 可溶性鸟苷酸环化酶刺激剂和激活剂：化学、生物学和治疗进展。

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-26 DOI: 10.1016/j.ejmech.2026.119257

Zeping Zuo, Haoran Yang, Qipu Feng, Junpeng Ran, Mao Chen

{"title":"Soluble guanylate cyclase stimulators and activators: Chemistry, biology, and therapeutic advances.","authors":"Zeping Zuo, Haoran Yang, Qipu Feng, Junpeng Ran, Mao Chen","doi":"10.1016/j.ejmech.2026.119257","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119257","url":null,"abstract":"The discovery of soluble guanylate cyclase (sGC) stimulators and activators has provided invaluable tools for elucidating nitric oxide (NO)-sGC signaling and has opened up novel therapeutic opportunities for cardiovascular diseases and beyond. In recent years, sGC modulators have garnered widespread attention as promising agents for diseases such as pulmonary hypertension, heart failure, chronic kidney disease, and diabetic retinopathy-with sGC stimulators and sGC activators emerging as key research focuses in this field. Although first-in-class sGC stimulators (e.g., riociguat, vericiguat) and activators (e.g., cinaciguat) have advanced into clinical use or development, most subsequent candidates continue to be refined to optimize efficacy, safety, and target selectivity. This review provides a comprehensive and systematic exploration of sGC stimulators and sGC activators in the context of disease therapy. Specifically, these small molecules are classified and elaborated based on their mechanisms of action, structural characteristics, and development trajectories; for each category, the binding modes, structural features, and pharmacological activities of representative compounds are analyzed in detail, while their inherent advantages and limitations are critically evaluated. Collectively, this review offers valuable insights and guidance for the future research and development of safer, more effective, and more precisely targeted sGC modulators.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119257"},"PeriodicalIF":6.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872491","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

N-Terminal Polarity Reversal of Cysteine-Terminated Peptides: A Strategy to Develop Potent Metallo-β-Lactamase Inhibitors with In vivo Efficacy 半胱氨酸末端肽的n端极性反转：开发体内有效的金属β-内酰胺酶抑制剂的策略

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-25 DOI: 10.1016/j.ejmech.2026.119261

Jiameng Yu, Ziying Chen, Bing Zhang, Tao Zhang, Bo Ji, Rui Li, Jianwen Feng, Mengmiao Zhang, Shaoshen Guo, Lifen Gao, Mutu Huang, Zhihui Jiang

{"title":"N-Terminal Polarity Reversal of Cysteine-Terminated Peptides: A Strategy to Develop Potent Metallo-β-Lactamase Inhibitors with In vivo Efficacy","authors":"Jiameng Yu, Ziying Chen, Bing Zhang, Tao Zhang, Bo Ji, Rui Li, Jianwen Feng, Mengmiao Zhang, Shaoshen Guo, Lifen Gao, Mutu Huang, Zhihui Jiang","doi":"10.1016/j.ejmech.2026.119261","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119261","url":null,"abstract":"The emergence of metallo-β-lactamase (MBL)-producing pathogens poses a critical threat to the efficacy of β-lactam antibiotics, with no clinically approved inhibitors currently available. Here, we report a rational design strategy for potent MBL inhibitors based on a “polarity reversal” of the N-terminus of cysteine-terminated peptides. A series of N-terminally protected di- and tripeptides were synthesized and evaluated. Two lead compounds, Fmoc-FFC and Fmoc-MC, emerged as potent, competitive inhibitors of clinically relevant MBLs, including NDM-1, VIM-2, and IMP-1, with K<ce:inf loc=\"post\">i</ce:inf> values in the low micromolar range. These compounds demonstrated remarkable synergistic activity with meropenem, restoring its potency against MBL-producing <ce:italic>E. coli</ce:italic> by up to 1024-fold. Both inhibitors exhibited excellent biocompatibility with minimal cytotoxicity and hemolytic activity. Crucially, in a murine systemic infection model, co-administration of Fmoc-FFC with meropenem achieved a 100% survival rate, compared to 0% for monotherapy. This work validates the N-terminal polarity reversal as a powerful strategy for developing MBL inhibitors and presents Fmoc-FFC as a promising lead candidate for combating infections caused by multi-drug resistant superbugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"40 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853277","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 Quinoline-Based Hybrid Anticancer Agents (2025-Present): Synthetic Strategies, SAR and Mechanistic Insights 基于喹啉的杂化抗癌药物的最新进展（2025年至今）：合成策略、SAR和机制见解

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-24 DOI: 10.1016/j.ejmech.2026.119263

Sanjeev Kumar Patel

{"title":"Recent Advances in Quinoline-Based Hybrid Anticancer Agents (2025-Present): Synthetic Strategies, SAR and Mechanistic Insights","authors":"Sanjeev Kumar Patel","doi":"10.1016/j.ejmech.2026.119263","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119263","url":null,"abstract":"This review highlights the recent emerging therapeutic potential of quinoline-based scaffolds in anticancer drug discovery. A systematic and integrative review methodology was adopted, emphasising recent literature on synthetic strategies, structure-activity relationship (SAR) trends, mechanistic insights and in vitro/in vivo evaluations of quinoline derivatives. Modern synthetic approaches have enabled the efficient construction of structurally diverse quinoline hybrids with enhanced pharmacological profiles. Biological investigations reveal that several quinoline hybrids exhibit potent anticancer activity in low micromolar to submicromolar ranges. Additionally, exceeding the efficacy of standard drugs while demonstrating enhanced selectivity towards cancer cells. Mechanistically, these compounds act through multi-target modulation, induction of apoptosis, mitochondrial dysfunction and cell cycle arrest. SAR analyses indicated that strategic substitutions on the quinoline core and hybridisation with bioactive compounds enhance target binding and efficacy. Furthermore, in silico approaches, including molecular docking and ADME profiling, provide critical support for experimental findings and facilitate rational lead optimisation. Despite promising outcomes, challenges related to drug resistance, toxicity and pharmacokinetics persist. These limitations may be addressed through continuous advancement in the design and optimisation of anticancer-active molecular frameworks. Overall, quinoline hybrids represent a versatile and promising scaffold for the development of next-generation anticancer agents.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853278","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 piperazine-based multi-site occupying coronavirus M^pro inhibitors with potent and broad-spectrum antiviral activity. 基于哌嗪的多位点占位冠状病毒Mpro抑制剂的发现，具有有效的广谱抗病毒活性。

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-08-22 DOI: 10.1016/j.ejmech.2026.119248

Bing Ye, Myoung Kyu Lee, Letian Song, Yeon Seo Jeon, Mei Wang, Xianghan Bai, Shenghua Gao, Meehyein Kim, Peng Zhan, Xinyong Liu

{"title":"Discovery of piperazine-based multi-site occupying coronavirus Mpro inhibitors with potent and broad-spectrum antiviral activity.","authors":"Bing Ye, Myoung Kyu Lee, Letian Song, Yeon Seo Jeon, Mei Wang, Xianghan Bai, Shenghua Gao, Meehyein Kim, Peng Zhan, Xinyong Liu","doi":"10.1016/j.ejmech.2026.119248","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119248","url":null,"abstract":"The continuous evolution of SARS-CoV-2 and the emergence of drug-resistant variants underscore the urgent need for broad-spectrum antiviral agents targeting conserved viral proteins. The main protease (Mpro) represents a promising target due to its essential role in coronavirus replication. In this study, we report the discovery and optimization of a novel series of piperazine-based Mpro inhibitors using a multi-site binding strategy guided by analysis of conserved residues within the coronavirus Mpro active sites. Starting from the noncovalent lead GC-14, systematic optimization of substituents occupying the S1', S1, S2, and S4 subsites of Mpro led to the development of the noncovalent inhibitor GY-e2, which showed improved inhibitory efficacy against both SARS-CoV-2 and SARS-CoV Mpro. To further enhance its antiviral efficacy in cellular models, reactive warheads targeting C145 were incorporated into the scaffold to generate covalent inhibitors. This strategy yielded the isomeric compounds Y-U0-R and Y-U0-S, which displayed potent Mpro inhibition and markedly enhanced antiviral activity in SARS-CoV-2-infected Calu-3 cells. Moreover, both compounds exhibited broad-spectrum antiviral activity against other human coronaviruses, and notably remained effective against the two major Nirmatrelvir-resistant strains evaluated in this study. Mechanistic studies further confirmed kinetically stable binding and time-dependent inhibition of Y-U0-R, supporting the rationale of covalent inhibitor design. These findings highlight the utility of structure-based design for the development of promising broad-spectrum anti-coronavirus agents.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119248"},"PeriodicalIF":6.7,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872517","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