European Journal of Medicinal Chemistry最新文献

{"title":"α-Ketoamides-based covalent inhibitors in drug discovery: Current status and synthetic methods","authors":"Ho Ying Huang,&nbsp;Nicolas Moitessier","doi":"10.1016/j.ejmech.2026.118558","DOIUrl":"10.1016/j.ejmech.2026.118558","url":null,"abstract":"<div><div>The α-ketoamide moiety is abundant in natural products and has been incorporated by medicinal chemists into novel potential drug candidates. A variety of synthetic methods for preparing this privileged functional group have been disclosed. In this review, we will provide insights into the chemical reactivity of α-ketoamides, their successful incorporation into potent covalent inhibitors and an overview of the synthetic methodologies that are actively used in the discovery of small molecule α-ketoamide covalent inhibitors. Finally, this perspective aims to help medicinal chemists in overcoming synthetic challenges when introducing α-ketoamide groups into more efficient hit/lead molecules, and to highlight the popularity of α-ketoamide in drug design and development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118558"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903002","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}

{"title":"Improved quantitative structure-activity relationship (QSAR) models to predict the activity of hydroxamic acids as HDAC inhibitors against malaria parasites","authors":"Wisam A. Dawood ,&nbsp;Jacinta R. Macdonald ,&nbsp;Tina S. Skinner-Adams ,&nbsp;Eva Hesping ,&nbsp;Alain-Dominique J.P. Gorse ,&nbsp;Katherine T. Andrews","doi":"10.1016/j.ejmech.2025.118525","DOIUrl":"10.1016/j.ejmech.2025.118525","url":null,"abstract":"<div><div>There are ∼600,000 malaria-related deaths annually, predominantly due to <em>Plasmodium falciparum</em> infections. Malaria parasite drug resistance is driving the search for new antimalarials with novel modes of action to current options. Histone deacetylases (HDACs) modulate protein lysine acetylation, regulating a range of cellular processes and are prospective new antimalarial drug targets. To accelerate HDAC inhibitor discovery for malaria, we generated quantitative structure-activity relationship (QSAR) classification models <strong>B1</strong>–<strong>B9</strong> using 572 hydroxamic acid-based structures and their paired <em>P. falciparum</em> 50 % growth inhibition (<em>Pf</em>IC₅₀) values. Tripartite split models <strong>B5</strong>–<strong>B9</strong> demonstrated high accuracy (AUC 0.953–0.984), similar to first-generation tripartite split models <strong>A5</strong>–<strong>A7</strong> (AUC 0.961–0.976). External validation using 106 quisinostat-derived compounds from published sources demonstrated improved accuracy of <strong>B7</strong> and <strong>B8</strong> (&gt;67 %) compared to <strong>A7</strong> (∼5 %), the best first-generation model. Experimental assessment of the <em>in vitro P. falciparum</em> activity of 60 compounds selected from a virtual screen of &gt;36,000 hydroxamic acid-containing structures from the ZINC20 and ChEMBL libraries demonstrated that model <strong>B7</strong> was more accurate (∼81 %) than model <strong>B8</strong> (∼68 %) and <strong>A7</strong> (∼56 %). Moreover, the ability of these QSAR models to triage hydroxamic acid-based compounds with activity against malaria parasites was demonstrated by the identification of three potent antiplasmodial hits (<em>Pf</em>IC₅₀ 8, 14 and 80 nM), two of which were shown to hyperacetylate <em>P. falciparum</em> histone H4 indicating deacetylase inhibition. These data demonstrate the potential of QSAR models to identify HDAC inhibitors for malaria drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118525"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796170","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}

{"title":"Discover of a highly effective covalent inhibitor of CDK6 for triple-negative breast cancer treatment","authors":"Jingting Zeng ,&nbsp;Fucheng Yin ,&nbsp;Yongwei Fan ,&nbsp;Keying Zheng ,&nbsp;Zifeng Zhang ,&nbsp;Liu Liu ,&nbsp;Renxin Jiang ,&nbsp;Na Li ,&nbsp;Fanglan Liu ,&nbsp;Chunhua Xia ,&nbsp;Cheng Wang","doi":"10.1016/j.ejmech.2026.118565","DOIUrl":"10.1016/j.ejmech.2026.118565","url":null,"abstract":"<div><div>CDK4/6 inhibitors are effective in treating HR+/HER2− breast cancer, but they have limitations in treating TNBC and drug-resistant breast cancer. To overcome this challenge, we designed and synthesized a series of novel covalent inhibitors for CDK6 that contain the Palbociclib core pharmacophore. The most promising compound, <strong>C32</strong>, showed good inhibitory activity against CDK6 (IC₅₀ = 0.013 μM) and good inhibitory effects on MDA-MB-231 (IC₅₀ = 0.061 μM), MDA-MB-468 (IC₅₀ = 0.080 μM) and BT-549 (IC₅₀ = 0.044 μM) cells. Compared with that of Palbociclib, the growth inhibitory activities against these two cell types increased by approximately 200-fold. Compound <strong>C32</strong> can effectively inhibit the proliferation and migration of TNBC cells and induce apoptosis and S-phase cell cycle arrest. <strong>C32</strong> can also induce excessive mitochondrial oxidative phosphorylation by remodeling cellular metabolic patterns, leading to the generation of ROS and mitochondrial damage. In vivo experiments further demonstrated that <strong>C32</strong> has a favorable safety profile and pharmacokinetic properties, while exhibiting significant anti-TNBC effects. As a novel CDK6 covalent inhibitor, <strong>C32</strong> is expected to be a candidate compound for the treatment of TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118565"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995831","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}

{"title":"Preclinical evaluation of 68Ga-labeled acetazolamide derivatives as radiotracers targeting carbonic anhydrase IX in clear cell renal cell carcinoma","authors":"Wanjia Liu ,&nbsp;Yimin Chen ,&nbsp;Zehua Li ,&nbsp;Mengchao Cui","doi":"10.1016/j.ejmech.2026.118577","DOIUrl":"10.1016/j.ejmech.2026.118577","url":null,"abstract":"<div><div>Clear-cell renal cell carcinoma (ccRCC) represents the predominant histological subtype of renal carcinoma and accounts for the majority of kidney cancer-related deaths. Conventional [¹⁸F]<strong>FDG</strong> PET frequently fails to detect ccRCC because of its intrinsically low glucose metabolism. Carbonic anhydrase IX (CAIX), a hypoxia-inducible, tumor-specific cell-surface enzyme that is highly expressed in nearly all ccRCCs but absent from healthy kidney tissue, represents an attractive alternative target. Here, we developed a panel of modularly designed ⁶⁸Ga-labeled acetazolamide analogues incorporating varied linkers and chelators. Among these, [⁶⁸Ga]Ga-<strong>14</strong> demonstrated the most favorable overall profile, including high stability and optimized pharmacokinetics. [⁶⁸Ga]Ga-<strong>14</strong> bound recombinant human CAIX with high affinity (IC₅₀ = 61 ± 9.5 nM). In OS-RC-2 xenograft models, it achieved superior tumor uptake (SUV_max = 1.41 ± 0.04) and tumor-to-muscle ratio (9.68) at 1 h post-injection. Despite gradual tumor washout, rapid clearance from non-target tissues increased the tumor-to-muscle ratio to 14.92 at 2 h. CAIX specificity was validated by a blocking study in which excess inhibitor reduced tumor uptake by 95 %. These findings identify [⁶⁸Ga]Ga-<strong>14</strong> as a highly promising CAIX-targeted PET tracer for sensitive detection of ccRCC, with potential for future theranostic applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118577"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949947","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}

{"title":"Discovery of an orally bioavailable pyridone-based BRD4 inhibitor with potent antitumor efficacy in colorectal cancer","authors":"Zhangyun Fang ,&nbsp;Shuai Zhan ,&nbsp;Churu Mao ,&nbsp;Ningjing Zhang ,&nbsp;Xiaofeng Zhao ,&nbsp;Yun Huang ,&nbsp;Wanjing Ding ,&nbsp;Zhongjun Ma","doi":"10.1016/j.ejmech.2026.118573","DOIUrl":"10.1016/j.ejmech.2026.118573","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a major clinical burden with limited durable responses. Given reports implicating Bromodomain-containing protein 4 (BRD4) in CRC proliferation and therapy resistance, more potent BRD4-targeting agents with proven <em>in-vivo</em> activity are needed. Through virtual screening followed by structure-guided chemical modification, we identified <strong>H5</strong> as a BRD4 inhibitor. In biochemical assays, <strong>H5</strong> shows IC₅₀ = 7.9 ± 0.5 nM, outperforming <strong>JQ-1</strong> (IC₅₀ = 33.0 ± 1.0 nM) by 4-fold. Molecular dynamics simulations indicate that <strong>H5</strong> engages BRD4 <em>via</em> hydrogen bonds with Asn140 and Asp88 and a water-mediated bridge to Gln85. In the HCT-116 xenograft mouse model, oral administration of <strong>H5</strong> suppressed tumor growth (TGI = 82 % at 50 mg/kg) and downregulated the BRD4-driven oncoproteins c-MYC and BCL-2. Collectively, <strong>H5</strong> emerges as a highly promising BRD4-targeted candidate for colorectal cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118573"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956880","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}

{"title":"Current landscape and therapeutic prospects of indole hybrids for prostate cancer treatment: A mini-review","authors":"Zhi Xu,&nbsp;Yang Shi,&nbsp;Bowen Pan,&nbsp;Huabin Wang","doi":"10.1016/j.ejmech.2026.118583","DOIUrl":"10.1016/j.ejmech.2026.118583","url":null,"abstract":"<div><div>Prostate cancer ranks second in incidence and fifth in mortality among all cancer types in males. This striking epidemiological profile highlights its status as a major health concern that poses a severe threat to men's lives and health globally. Although traditional chemotherapeutics and targeted therapies for prostate cancer have made considerable progress, critical challenges remain, including high metastatic potential, acquired drug resistance, and unfavorable prognosis in patients with advanced disease, highlighting the imperative to develop novel therapeutic strategies. Indole hybrids, versatile and promising anticancer scaffolds formed by integrating indole moieties with other pharmacophores, exhibit prominent multi-targeted regulatory capabilities in prostate cancer therapy, enabling simultaneous modulation of key oncogenic pathways to address the complex molecular mechanisms of both hormone-sensitive and castration-resistant subtypes. Compared to single-scaffold derivatives, indole hybrids demonstrate enhanced anticancer potency and reduced off-target toxicity <em>via</em> synergistic effects between conjugated moieties, while also showing potential in overcoming drug resistance by circumventing single-target mutation-induced resistance and inhibiting ABC transporters to reverse multidrug resistance. Moreover, their structural flexibility facilitates structural optimization for improved pharmacokinetic properties and tailored efficacy against specific prostate cancer phenotypes, making indole hybrids valuable candidates for developing novel therapeutic agents to meet unmet clinical needs in prostate cancer treatment. This review summarizes the recent advances in indole hybrids with anti-prostate cancer activity from 2021 to date, striving to open new directions for developing novel prostate cancer therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118583"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962236","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}

{"title":"Recent progress of napabucasin as privileged scaffold in the discovery of anticancer agents","authors":"Xiaojuan Yang ,&nbsp;Guoyang Ma","doi":"10.1016/j.ejmech.2026.118559","DOIUrl":"10.1016/j.ejmech.2026.118559","url":null,"abstract":"<div><div>Cancer is a major health issue worldwide, necessitating the development of novel treatments because treating this disease is challenging. Napabucasin, a furan-fused 1,4-naphthoquinone, exhibits significant anticancer activity through various molecular mechanisms and has become a privileged scaffold for developing antitumor therapeutics. In this review, we systematically evaluated recent progress in the use of napabucasin as a privileged scaffold for the discovery of antitumor drugs, focusing on structure-activity relationships (SARs), structural modification strategies, and the illustration of tumor inhibitory pathways from a mechanistic perspective. By conducting multidimensional assessments, we propose feasible directions for developing napabucasins with improved pharmacological properties for cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118559"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895251","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}

{"title":"Computer-Aided optimization of quinazoline-based Aurora kinase inhibitors for enhanced metabolic stability","authors":"Song Chen ,&nbsp;Hongjin Zhai ,&nbsp;Shuhan You,&nbsp;Bin Zhang,&nbsp;Gui Lu","doi":"10.1016/j.ejmech.2025.118548","DOIUrl":"10.1016/j.ejmech.2025.118548","url":null,"abstract":"<div><div>The quinazoline-based Aurora kinase inhibitor <strong>9h</strong>, previously developed by our group, exhibited potent efficacy both <em>in vitro</em> and <em>in vivo</em>. However, its further development was hindered by a short half-life and insufficient metabolic stability. To address these limitations, we employed machine learning-driven <em>in silico</em> models to predict <strong>9h</strong>′s key metabolic sites. Based on these predictions, electronic isosteric substitutions and metabolic blocking strategies were employed to optimize these sites, yielding a series of new quinazoline derivatives. Subsequent liver microsomal stability assays identified compound <strong>4q</strong> as the lead candidate, exhibiting significantly enhanced metabolic stability with a 14-fold and 4.5-fold increase in half-life relative to <strong>9h</strong> in rat and human microsomes, respectively. Pharmacokinetic evaluation in rats revealed <strong>4q</strong> possesses a favorable profile, with an oral half-life of 5.5 h, an intravenous half-life of 4.1 h, and an oral bioavailability of 58 %. Importantly, <strong>4q</strong> maintained potent inhibitory activity <em>in vivo</em>, achieving a tumor growth inhibition rate of 56.7 %, consistent with its robust <em>in vitro</em> efficacy. Molecular docking simulations further elucidated <strong>4q</strong>′s binding mode with Aurora kinase, providing a structural basis for its activity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118548"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895254","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}

{"title":"Fragment-based structure-activity relationship analysis of CK-571 reveals non-interacting groups drive smooth muscle myosin selectivity","authors":"Sharad Kumar Suthar ,&nbsp;Tamás Jernei ,&nbsp;Csilla Kurdi ,&nbsp;Ádam I. Horváth ,&nbsp;Anna Ágnes Rauscher ,&nbsp;Máté Gyimesi ,&nbsp;András Málnási-Csizmadia","doi":"10.1016/j.ejmech.2025.118476","DOIUrl":"10.1016/j.ejmech.2025.118476","url":null,"abstract":"<div><div>Smooth muscle myosin-2 (SMM) is a promising target for treating asthma and COPD, but selective inhibition remains challenging due to the high conservation of myosin-2 isoforms. CK-571 is the first potent and selective SMM inhibitor, despite binding to an allosteric site conserved across isoforms. We performed a fragment-based structure–activity relationship analysis to deconstruct CK-571 and define the role of each segment. The isoquinoline-carbamate and chloro-fluorobenzyl moieties were found to be inactive when isolated. Surprisingly, the presence of a methyl group and a solvent-exposed pair of non-interacting dihydroxyl groups dramatically enhanced potency by up to 100-fold, despite no direct contact with the protein. These findings highlight the critical contribution of non-interacting, flexible groups in optimizing ligand potency and selectivity for conserved targets and establish a framework for the development of improved SMM-targeted therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118476"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785943","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}

{"title":"Rational design of an NLRP3 inhibitor with superior efficacy and safety for gout therapy","authors":"Yichao Kong ,&nbsp;Mengjun Su ,&nbsp;Caihong Jiang ,&nbsp;Haonan Feng ,&nbsp;Yingjie Hu ,&nbsp;Donglai Li ,&nbsp;Zhenyu Mao ,&nbsp;Fengling Liu ,&nbsp;Fuli Zhu ,&nbsp;Yue Guo ,&nbsp;Shuhua Ren ,&nbsp;Man Chi ,&nbsp;Ting Qiu ,&nbsp;Yaxia Yuan ,&nbsp;Weiwei Huang ,&nbsp;Lei Ma ,&nbsp;Xiabin Chen","doi":"10.1016/j.ejmech.2026.118578","DOIUrl":"10.1016/j.ejmech.2026.118578","url":null,"abstract":"<div><div>Gout, driven by urate crystal-induced inflammation, remains a therapeutic challenge due to the limited efficacy and toxicity of current treatments. Targeting the NLRP3 inflammasome, a central driver of gout pathogenesis, offers a promising strategy. While MCC950, a potent NLRP3 inhibitor, demonstrated clinical potential, its discontinuation due to hepatotoxicity underscores the urgent need for safer alternatives. Here, we address these challenges through a rational drug design approach to develop next-generation NLRP3 inhibitors. By leveraging cryo-EM structures and molecular dynamics (MD) simulations of the MCC950-NLRP3 complex, we identified a structurally dynamic region near the furan moiety and an adjacent unoccupied hydrophobic pocket. Systematic structural optimization targeting this pocket enabled the design of <strong>M48</strong>, a derivative that exhibited superior anti-inflammatory activity (IC₅₀ = 11.9 nM), favorable oral bioavailability (89.7 % in rats), and an improved safety profile compared to MCC950. In an MSU-induced mouse gout model, <strong>M48</strong> demonstrates superior anti-inflammatory and analgesic effects compared to indomethacin, with efficacy comparable to colchicine. The design strategy, grounded in computational insights into ligand-protein interactions, demonstrates both scientific rigor and broad applicability for optimizing small-molecule inhibitors. Notably, <strong>M48</strong>'s enhanced efficacy and reduced liver toxicity risk validate the approach's potential for addressing unmet clinical needs in gout and other NLRP3-associated diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118578"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962570","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}