European Journal of Medicinal Chemistry最新文献_第6页

Discovery of potent and orally bioavailable benzothiazole-benzenesulfonamide derivatives as ABCA1 upregulators for the management of dyslipidemia 发现有效的口服苯并噻唑-苯磺酰胺衍生物作为ABCA1上调剂用于管理血脂异常

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-15 DOI: 10.1016/j.ejmech.2026.118582

Wenyan Li , Lijuan Lei , Guosheng Zhang , Yunjin Zhang , Yujie Wang , Yexiang Wu , Ren Sheng , Guijun Yang , Yanni Xu , Hongtao Liu

{"title":"Discovery of potent and orally bioavailable benzothiazole-benzenesulfonamide derivatives as ABCA1 upregulators for the management of dyslipidemia","authors":"Wenyan Li , Lijuan Lei , Guosheng Zhang , Yunjin Zhang , Yujie Wang , Yexiang Wu , Ren Sheng , Guijun Yang , Yanni Xu , Hongtao Liu","doi":"10.1016/j.ejmech.2026.118582","DOIUrl":"10.1016/j.ejmech.2026.118582","url":null,"abstract":"<div><div>ATP-binding cassette transporter A1 (ABCA1), a key regulator of cholesterol efflux and reverse cholesterol transport, represents a promising therapeutic target for atherosclerosis. However, small-molecule ABCA1 upregulators combining high potency and drug-like properties remain scarce. Through rational structure optimization, we designed and synthesized a series of novel benzothiazole-benzenesulfonamide derivatives. These compounds were systematically evaluated by ABCA1 upregulating activity test, followed by mRNA and protein expression analysis of ABCA1, murine macrophages cholesterol efflux experiments, safety assessment, and <em>in vivo</em> efficacy studies in hyperlipidemic golden hamsters and pharmacokinetic (PK) profiling in ICR mice. Several derivatives, particularly compound <strong>85</strong> demonstrated unprecedented ABCA1 upregulating activity (up to 578 %, EC<sub>50</sub> = 0.15 μM). Compounds <strong>25</strong>, <strong>56</strong>, <strong>68</strong>, <strong>85</strong> and <strong>87</strong> significantly induced ABCA1 expression at both mRNA and protein levels, promoted cholesterol efflux in RAW264.7 macrophage cells, and exhibited favorable safety profiles in acute toxicity tests. In hyperlipidemic golden hamsters, these compounds markedly improved plasma lipid profiles—notably increasing HDL-C levels by up to 44 % while effectively reducing TC and TG. Importantly, <strong>85</strong> and <strong>87</strong> displayed exceptional PK properties with oral bioavailability >90 % and systemic exposure significantly superior to conventional lipid-lowering drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118582"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995783","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

Multi-stimuli activated PROTAC prodrug for controlled protein degradation with enhanced therapeutic effects 多重刺激激活PROTAC前药，控制蛋白质降解，增强治疗效果

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-09 DOI: 10.1016/j.ejmech.2026.118571

Tianyang Zhou , Yibo Gao , Bohan Ma, Chi Wang, Shan Xu, Xiaoyu Feng, Bin Wang, Yanlin Jian, Lei Li

{"title":"Multi-stimuli activated PROTAC prodrug for controlled protein degradation with enhanced therapeutic effects","authors":"Tianyang Zhou , Yibo Gao , Bohan Ma, Chi Wang, Shan Xu, Xiaoyu Feng, Bin Wang, Yanlin Jian, Lei Li","doi":"10.1016/j.ejmech.2026.118571","DOIUrl":"10.1016/j.ejmech.2026.118571","url":null,"abstract":"<div><div>Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative strategy for targeted protein degradation, yet their clinical translation is hindered by systemic toxicity and poor tumor selectivity, leading to dose-limiting side effects. To overcome these limitations, we designed a multi-stimuli-responsive prodrug that enables tumor-selective activation of PROTACs in response to elevated reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment. By masking the hydroxyl group of the VHL ligand with a ROS/GSH-cleavable thioether-urea linker, we developed a PROTAC prodrug that responds to <sup>1</sup>O<sub>2</sub>, HOCl, H<sub>2</sub>O<sub>2</sub>, and GSH–key mediators of oxidative stress in tumors. This proof-of-concept was verified by caging BRD4 and AR PROTAC with a methylene blue fluorophore to yield NZ-BRD and NZ-AR. Upon encountering tumor-associated stimuli, these prodrugs underwent efficient activation, releasing functional PROTACs that selectively degraded BRD4 and AR in prostate cancer cells. Intriguingly, the methylene blue liberated during activation served as a self-amplifying photosensitizer, creating a positive feedback loop that boosted <sup>1</sup>O<sub>2</sub> generation and further enhanced prodrug cleavage. The synergistic effect between PROTAC-mediated protein degradation and photodynamic therapy led to superior antitumor efficacy of PROTAC prodrugs <em>in vitro</em> and <em>in vivo.</em> Our work establishes a spatiotemporally controlled drug activation paradigm that combines precision protein degradation with ROS-amplified activation, presenting a promising approach to mitigate the systemic toxicity associated with conventional PROTAC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118571"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920570","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

The mitochondrial gambit: Re-evaluating Antimycin A as a multi-pronged anti-cancer agent 线粒体策略：重新评估抗霉素A作为多管齐下的抗癌药物

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-20 DOI: 10.1016/j.ejmech.2026.118596

Woo Hyun Park

{"title":"The mitochondrial gambit: Re-evaluating Antimycin A as a multi-pronged anti-cancer agent","authors":"Woo Hyun Park","doi":"10.1016/j.ejmech.2026.118596","DOIUrl":"10.1016/j.ejmech.2026.118596","url":null,"abstract":"<div><div>Malignancy's profound dependence on mitochondrial metabolism establishes the organelle as a paramount therapeutic target. This review offers a comprehensive analysis of Antimycin A (AMA), a mitochondrial complex III inhibitor, framing it as a potent, multi-pronged anti-cancer agent. While AMA primarily disrupts oxidative phosphorylation (OXPHOS)—triggering a cascade of adenosine triphosphate (ATP) depletion, massive reactive oxygen species (ROS) surges, and subsequent apoptosis—its therapeutic potential extends significantly to non-canonical functions crucial for countering adaptive resilience. Specifically, AMA acts as a Bcl-2 homology 3 (BH3) mimetic by directly inhibiting B-cell lymphoma-extra large (Bcl-xL) and induces ROS-mediated proteasomal degradation of the c-Myc oncoprotein. Additionally, it effectively targets chemoresistant cancer stem cells (CSCs) by suppressing Wnt/β-catenin signaling. By juxtaposing its powerful anti-neoplastic activities with pharmacological limitations such as systemic toxicity, this paper evaluates ongoing strategies to develop safer, clinically viable analogues. Ultimately, AMA is presented not merely as an experimental tool, but as a pivotal lead compound whose mechanisms illuminate critical vulnerabilities in cancer, providing a strategic blueprint for the future of mitochondria-targeted oncology.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118596"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014763","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

Histone methyltransferases SMYD2: the potential pharmacological target on cancers and aging-related diseases treatment 组蛋白甲基转移酶SMYD2：癌症和衰老相关疾病治疗的潜在药理靶点

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-19 DOI: 10.1016/j.ejmech.2026.118572

Meng Gu , Menglin Zhu , Jianghong Cai , Qian Ding , Wei Hu , Qingwen Hu , Hao Zhang , Xuanzhe Zhu , Yi Zhun Zhu

{"title":"Histone methyltransferases SMYD2: the potential pharmacological target on cancers and aging-related diseases treatment","authors":"Meng Gu , Menglin Zhu , Jianghong Cai , Qian Ding , Wei Hu , Qingwen Hu , Hao Zhang , Xuanzhe Zhu , Yi Zhun Zhu","doi":"10.1016/j.ejmech.2026.118572","DOIUrl":"10.1016/j.ejmech.2026.118572","url":null,"abstract":"<div><div>In epigenetic research, abnormalities in protein methylation modifications are closely related to the development of various diseases. The protein lysine methyltransferase SMYD2 has been extensively studied in cancer and age-related diseases due to its broad substrate specificity. However, SMYD2 as a promising small molecule inhibitor target, the biological functions have not been fully elucidated, and reports on related inhibitors are limited. Here, we will focus on studies about the mechanisms of SMYD2 on the treatment for different cancers and aging-related diseases and clarify the specific SMYD2 inhibitors' effects on different diseases. Moreover, we will also briefly discuss the contradiction points in existing studies, provide novel ideas about further study on SMYD2 structure and inhibitor development and finally, discuss the new aspects in further studies of SMYD2. Hopefully, this review stimulates new ideas in drug development for the treatment of cancer and aging-related diseases, maximizes human life, and benefit society.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118572"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146001182","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 the first dual PD-L1/JAK inhibitor with enhanced in vivo antitumor immunity 发现首个增强体内抗肿瘤免疫的PD-L1/JAK双抑制剂

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-22 DOI: 10.1016/j.ejmech.2026.118605

Zhijie Wang , HaiQi He , Jianwei Xu , Xiaotong Liao , Jun Tan , Chenglong Xu , Jiamin Tan , Lirong Zhang , Qin Wang , Xixiang Yang , Yichang Ren , Guangfa Wang , Yanle Zhi , Jianjun Chen

{"title":"Discovery of the first dual PD-L1/JAK inhibitor with enhanced in vivo antitumor immunity","authors":"Zhijie Wang , HaiQi He , Jianwei Xu , Xiaotong Liao , Jun Tan , Chenglong Xu , Jiamin Tan , Lirong Zhang , Qin Wang , Xixiang Yang , Yichang Ren , Guangfa Wang , Yanle Zhi , Jianjun Chen","doi":"10.1016/j.ejmech.2026.118605","DOIUrl":"10.1016/j.ejmech.2026.118605","url":null,"abstract":"<div><div>Programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors are widely recognized as an effective therapeutic strategy for treating various types of tumors. However, single-target PD-1/PD-L1 inhibitors frequently encounter primary resistance or secondary resistance, posing significant challenges to clinical treatment and creating an urgent need for novel therapeutic approaches. In this study, we designed and synthesized a dual PD-L1/JAK inhibitor <strong>PJ27</strong> for the first time, which showed significant and balanced inhibitory activities against PD-1/PD-L1 (IC<sub>50</sub> = 414 nM) and JAK1 (IC<sub>50</sub> = 786 nM). Besides, <strong>PJ27</strong> exhibited remarkable <em>in vitro</em> immune activation effects. Furthermore, <strong>PJ27</strong> potently and dose-dependently inhibited tumor growth in the LLC lung cancer mouse model without obvious toxicity. Moreover, <strong>PJ27</strong> enhanced the infiltration of CD3<sup>+</sup> CD8<sup>+</sup> and CD3<sup>+</sup> CD4<sup>+</sup> cells into the tumor microenvironment. Additionally, kinase spectrum analysis demonstrated that <strong>PJ27</strong> possessed favorable selectivity towards JAK1. Collectively, <strong>PJ27</strong> represented the first dual PD-L1/JAK inhibitor deserving further research as a tumor immunotherapy agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118605"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021849","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, structure-activity relationship study and molecular modeling of triazolo[4,5-d]pyrimidines targeting an intracellular allosteric binding site of various chemokine receptors 针对多种趋化因子受体胞内变构结合位点的三唑[4,5-d]嘧啶的合成、构效关系研究及分子模拟

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-24 DOI: 10.1016/j.ejmech.2026.118597

Vishnu Kavumkal Omanakuttan , Mathy Froeyen , Sandra Claes , Brent Van Bosstraeten , Katrijn Boon , Dominique Schols , Luc Van Meervelt , Tom Van Loy , Wim Dehaen , Steven De Jonghe

引用次数: 0

Trimethyl Lock-2Cl (TML-2Cl): A self-cyclizing adapter for molecular release in antibody-drug conjugates 三甲基锁- 2cl (TML-2Cl)：抗体-药物偶联物分子释放的自环接头

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-30 DOI: 10.1016/j.ejmech.2026.118640

Xuzhuo Li , Lizhe Bai , Xiaomei Li , Xing Jiang , He Huang , Yunyun Guo , Jiahui Yu , Shiliang Li , Wei Lu , Shulei Zhu

{"title":"Trimethyl Lock-2Cl (TML-2Cl): A self-cyclizing adapter for molecular release in antibody-drug conjugates","authors":"Xuzhuo Li , Lizhe Bai , Xiaomei Li , Xing Jiang , He Huang , Yunyun Guo , Jiahui Yu , Shiliang Li , Wei Lu , Shulei Zhu","doi":"10.1016/j.ejmech.2026.118640","DOIUrl":"10.1016/j.ejmech.2026.118640","url":null,"abstract":"<div><div>The amide bond provides superior stability in chemical structures, enhances selectivity for drug loading, and reduces off-target toxicity during drug delivery. Conventional enzyme-cleavable antibody-drug conjugates (ADCs) typically rely on cathepsin B-sensitive linkers conjugated to self-immolative spacers, such as <em>p</em>-aminobenzyl carbamate (PABC), <em>p</em>-aminobenzyl ether (PABE) spacers or ethylenediamine-derived motifs, to facilitate payload release. In this work, we introduced the trimethyl lock (TML) system as a versatile adapter to expand the scope of applicable payloads. To meet the pKa requirements of 1,6-elimination and subsequent rapid self-cyclization reactions, dichloro-modified trimethyl lock (<strong>TML-2Cl</strong>) was further developed and applied for the first time in drug delivery systems. Using Exatecan as the payload, hydrophilic and cathepsin B-cleavable TML linker–payloads were designed and synthesized. Among these, <strong>L10081</strong> and <strong>L10082</strong>, incorporating the hydrophilic units PSAR-10 or PEG-8, exhibited enhanced capacity for Exatecan release. Furthermore, the ADCs <strong>Her2-L10081</strong> and <strong>Her2-L10082</strong> significantly inhibited tumor growth in an NCI–N87 xenograft mouse model. However, although this adapter <strong>TML-2Cl</strong> exhibits excellent stability, its intrinsic hydrophobicity may limit its suitability for the development of ADCs with high drug-to-antibody ratios (DAR), particularly those incorporating poorly water-soluble payloads.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118640"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089517","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

2-Naphthyl tetrazoles are potent antiproliferative and apoptotic inducers with different tubulin polymerization dynamics inhibitory activity 2-萘基四唑是有效的抗增殖和凋亡诱导剂，具有不同的微管蛋白聚合动力学抑制活性。

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-05 DOI: 10.1016/j.ejmech.2025.118554

Miguel Marín , Laura Gallego-Yerga , Dominik Fachet , Raúl Fuentes-Martín , Silvia González-Pelayo , Simone Reber , Rafael Peláez

{"title":"2-Naphthyl tetrazoles are potent antiproliferative and apoptotic inducers with different tubulin polymerization dynamics inhibitory activity","authors":"Miguel Marín , Laura Gallego-Yerga , Dominik Fachet , Raúl Fuentes-Martín , Silvia González-Pelayo , Simone Reber , Rafael Peláez","doi":"10.1016/j.ejmech.2025.118554","DOIUrl":"10.1016/j.ejmech.2025.118554","url":null,"abstract":"<div><div>Microtubule-targeting agents continue to be a cornerstone of cancer treatment; however, issues like systemic toxicity, poor metabolic stability, and multidrug resistance often restrict their effectiveness. Identifying new molecules that can overcome these limitations is crucial for enhancing therapeutic outcomes. In this work, we present a library of 12 new tubulin-binding compounds, analogues of Combretastatin A-4, incorporating a tetrazole bridge designed to preserve the cisoid disposition required for binding to the colchicine site. These compounds were assayed against a wide range of cancer cell lines, with compounds <strong>23</strong>, <strong>31</strong>, and <strong>32</strong> showing antiproliferative potencies in the low nanomolar range. The mechanism of action was assessed through microscopy experiments, which confirmed disruption of microtubule polymerization in cells. In vitro microtubule polymerization reactions with tubulin isolated from HEK-293 cells showed that compounds with drastically different inhibitory effects on polymerization dynamics elicit similar antiproliferative effects, thus questioning the usual assumption that interference with microtubule dynamics is the fundamental mechanism behind tubulin inhibitors’ actions. Cell cycle and cell death assays revealed atypical behavior for antimitotic agents, showing less mitotic arrest than typically but a significant increase in apoptotic cell populations, thus suggesting that they trigger cell death in an unusual way. In silico conformational and docking studies supported binding at the colchicine site and suggested favourable pharmacokinetic profiles. Together, these results position these compounds as highly promising candidates for development as new antitumor agents, especially <strong>23</strong> for glioblastoma.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118554"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903528","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 Focal Adhesion Kinase (FAK) activators to promote intestinal mucosal healing 发现局灶黏附激酶（FAK）激活剂促进肠黏膜愈合

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-20 DOI: 10.1016/j.ejmech.2026.118606

Ricardo Gallardo-Macias , Qinggang Wang , Ahmed Adham Raafat Elsayed , Guiming Liu , Henry L. Wong , Gunda I. Georg , Marc D. Basson , Vadim J. Gurvich

{"title":"Discovery of Focal Adhesion Kinase (FAK) activators to promote intestinal mucosal healing","authors":"Ricardo Gallardo-Macias , Qinggang Wang , Ahmed Adham Raafat Elsayed , Guiming Liu , Henry L. Wong , Gunda I. Georg , Marc D. Basson , Vadim J. Gurvich","doi":"10.1016/j.ejmech.2026.118606","DOIUrl":"10.1016/j.ejmech.2026.118606","url":null,"abstract":"<div><div>Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) causes injuries in the gastrointestinal mucosa. Proton pump inhibitors are the most common drugs prescribed to decrease upper gastrointestinal side effects caused by NSAIDs. However, they worsen the lower GI injuries caused by NSAIDs and do not directly promote restitution of the epithelial mucosa. Focal adhesion kinase (FAK) is essential in wound healing and epithelial sheet migration, making it an attractive pharmacological target. We have designed, synthesized, and evaluated a series of novel, specific FAK activators that increase FAK phosphorylation at Tyr-397 and promote mucosal healing in a Caco-2 model. We found that novel analogs <strong>10bHCl</strong>, <strong>10kHCl,</strong> and our original lead <strong>5aHCl</strong> are preclinical candidates for further studies towards mucosal wound healing. For lead <strong>5aHCl</strong>, which had previously shown healing in a mouse model, we performed a pharmacokinetic study. There are currently no therapeutics that promote mucosal healing, and no specific FAK activators beyond our work.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118606"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014770","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 and synthesis of dual-activity biphenyl inhibitors against SARS-CoV-2 and bladder cancer 抗SARS-CoV-2和膀胱癌双活性联苯抑制剂的设计与合成

IF 5.9 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-13 DOI: 10.1016/j.ejmech.2026.118581

Lin Lin Shang , Teng Long Hu , Situ Xiong , Songhui Xu , Li Ping Cheng

{"title":"Design and synthesis of dual-activity biphenyl inhibitors against SARS-CoV-2 and bladder cancer","authors":"Lin Lin Shang , Teng Long Hu , Situ Xiong , Songhui Xu , Li Ping Cheng","doi":"10.1016/j.ejmech.2026.118581","DOIUrl":"10.1016/j.ejmech.2026.118581","url":null,"abstract":"<div><div>Targeting the crucial SARS-CoV-2 therapeutic target 3CL<sup>pro</sup>, a natural product MOL007703 was identified from <em>Stellariae Radix</em>. Through systematic optimization, a series of novel biphenyl derivatives were designed to enhance target engagement. Among them, compound L3 shows superior 3CL<sup>pro</sup> inhibition with an IC<sub>50</sub> of 0.15 μM, which is 13.6-fold more potent than the reference drug ebselen (IC<sub>50</sub> = 2.04 μM). L3 also exhibits potent antiviral activity against SARS-CoV-2 (EC<sub>50</sub> = 2.82 μM), comparable to remdesivir (EC<sub>50</sub> = 1.47 μM). Molecular docking revealed that the <em>para</em>-trifluoromethyl-substituted benzene ring occupies the hydrophobic S4 pocket of 3CL<sup>pro</sup>. The electron-withdrawing fluorine atoms promote electrostatic and dipole interactions and act as hydrogen-bond acceptors with residues in the polar S1 pocket, synergistically enhancing inhibitory potency. Furthermore, L3 displays favorable therapeutic potential with low cytotoxicity in HK-2 fibroblasts (CC<sub>50</sub> > 50 μM) and potent concentration-dependent suppression of T24 bladder cancer cell proliferation (IC<sub>50</sub> = 10.99 μM), outperforming the reference drug mitomycin (IC<sub>50</sub> = 16.95 μM). These results highlight fluorinated biphenyl scaffolds as privileged chemotypes for multitarget drug development, enabling concurrent inhibition of viral protease and cancer cell growth. This work provides a rational strategy for repurposing traditional medicine-derived scaffolds into dual-function therapeutics through structural hybridization.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118581"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962569","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