European Journal of Medicinal Chemistry最新文献

{"title":"Medicinal chemistry approaches to the discovery and development of p300/CBP inhibitors for cancer therapy","authors":"Huan Wang ,&nbsp;Dandan Song ,&nbsp;Miao Miao ,&nbsp;Simeng Wu ,&nbsp;Jiao Wang ,&nbsp;Zhe Huang ,&nbsp;Hao Ding","doi":"10.1016/j.ejmech.2025.117959","DOIUrl":"10.1016/j.ejmech.2025.117959","url":null,"abstract":"<div><div>p300 and CBP (CREB-binding protein) are homologous histone acetyltransferases (HATs) that function as transcriptional co-activators, playing pivotal roles in regulating gene expression through acetylation of histones and transcription factors. Their dysregulation has been implicated in various cancers, making them attractive targets for therapeutic intervention. Significant advancements have been made in the discovery and development of small-molecule inhibitors targeting p300/CBP. These efforts have led to the identification of potent and selective inhibitors, such as A-485, which specifically targets the HAT domain, demonstrating notable antitumor activity in preclinical models. Structure-based drug design and high-throughput screening have facilitated the optimization of these inhibitors, enhancing their selectivity and pharmacokinetic properties. Additionally, the development of covalent inhibitors and PROTACs (proteolysis-targeting chimeras) has expanded the arsenal against p300/CBP, offering novel mechanisms to modulate their activity. With several inhibitors progressing into clinical trials, the therapeutic potential of targeting p300/CBP in oncology is becoming increasingly evident. This review examines p300/CBP inhibitors reported from 2019, focusing on the medicinal chemistry optimization strategies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117959"},"PeriodicalIF":6.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594851","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":"Reducing burst release and enhancing sustained release in SAIB-based implants: The role of polyphenol-modification","authors":"Xue Wang ,&nbsp;Zao Ji ,&nbsp;Di Wu ,&nbsp;Tengfei Zhou ,&nbsp;Yongjun Wang ,&nbsp;Lu Liu ,&nbsp;Guangqi Yan","doi":"10.1016/j.ejmech.2025.117958","DOIUrl":"10.1016/j.ejmech.2025.117958","url":null,"abstract":"<div><div>Sucrose acetate isobutyrate (SAIB)-based in situ forming implants (SADS) are promising for long-acting drug delivery but suffer from undesirable burst release. Here, we propose a molecular-level strategy to mitigate burst release by covalently modifying the antipsychotic drug aripiprazole (ARP) with polyphenols—specifically 4-hydroxybenzoic acid (HBA), protocatechuic acid (PCA), and gallic acid (GA). These moieties form strong hydrogen bonds with SAIB, enhancing drug–matrix interactions. Among them, ARP-GA exhibited the best performance, showing a significant reduction in burst release (8.99 ± 2.10 %) compared to unmodified ARP (22.84 ± 1.03 %) and sustained release over 30 days in vitro. In vivo pharmacokinetics in rats confirmed prolonged circulation with a 2.5-fold increase in AUC (1466.59 ± 139.35 vs. 592.66 ± 157.68 ng/mL•d), extended T_max (6.40 ± 2.97 vs. 0.29 ± 0.42 days), and lower C_max/C_S (2.32 vs. 3.41), indicating improved release control. Rheological and porosity analysis supported the enhanced drug retention mechanism via hydrogen bonding. This approach also proved effective for six additional drugs, suggesting broad applicability. These findings demonstrate that polyphenol modification of APIs offers a carrier-compatible, drug-centric solution for burst release regulation. Overall, this strategy significantly enhances the safety and efficacy of SAIB-based long-acting injectable systems.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117958"},"PeriodicalIF":6.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587021","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, asymmetric synthesis and biological evaluation of new bisbenzylisoquinoline-orexin receptor antagonists for insomnia treatment","authors":"Jing Fang ,&nbsp;Yang Wang ,&nbsp;Jia He ,&nbsp;Chengyu Ge ,&nbsp;Yindi Zhang ,&nbsp;Yufeng Liu ,&nbsp;Yueping Jiang ,&nbsp;Shao Liu","doi":"10.1016/j.ejmech.2025.117957","DOIUrl":"10.1016/j.ejmech.2025.117957","url":null,"abstract":"<div><div>The development of new orexin receptor (OXR) antagonists represents a crucial avenue for addressing the urgent need for safe and effective anti-insomnia drugs in clinical practice. Our group discovered neferine, a bisbenzylisoquinoline alkaloid isolated from <em>Nelumbinis Plumula</em>, exhibited a predicted binding affinity for OXR through virtual screening. Herein, we report the asymmetric synthesis of neferine and its isomers using a novel CuBr•Me₂S/picolinic acid-catalyzed arylation method. Biological assay results indicated that (<em>R,S</em>)-neferine demonstrated superior OXR antagonistic activity than suvorexant, with good binding affinities of KD (OX₁R) 0.68 and (OX₂R) 0.81 nM. In vivo pharmacodynamic studies showed that (<em>R,S</em>)-neferine reduced spontaneous activities in mice more effectively than daridorexant and significantly improved sleep in insomnia mice. Furthermore, (<em>R,S</em>)-neferine can restore the significant downregulation of PER1 and PER2, along with the upregulation of BMAL1 caused by insomnia, and decrease the expression of OX₁R and OX₂R, thereby improving core circadian rhythm disorders. (<em>R,S</em>)-neferine carried outstanding pharmacokinetic (F = 63.7 %) and safety profiles (LD50 &gt; 500 mg/kg), no mortality or histopathological changes were observed during the acute toxicity test. Overall, this work highlights the therapeutic potential of the OXR antagonist (<em>R,S</em>)-neferine, providing candidates and viable drug development strategies for the treatment of insomnia.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117957"},"PeriodicalIF":6.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587020","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":"trans-A2B-Corroles containing an oxime moiety: Novel photosensitizers for photodynamic therapy of lung cancer","authors":"João Braz ,&nbsp;Catarina Mestre ,&nbsp;Bruna D.P. Costa ,&nbsp;Susana M.M. Lopes ,&nbsp;Ana Clara B. Rodrigues ,&nbsp;Ana Cristina Gonçalves ,&nbsp;Maria F. Botelho ,&nbsp;J.Sérgio Seixas de Melo ,&nbsp;Mafalda Laranjo ,&nbsp;Marta Pineiro ,&nbsp;Teresa M.V.D. Pinho e Melo","doi":"10.1016/j.ejmech.2025.117946","DOIUrl":"10.1016/j.ejmech.2025.117946","url":null,"abstract":"<div><div>A series of fourteen <em>trans</em>-A₂B-corroles containing an oxime moiety were synthesized based on the reactivity of nitrosoalkenes towards dipyrromethanes, to evaluate their potential as a safe therapeutic option for photodynamic therapy (PDT) of lung cancer (LC). These macrocycles exhibited photophysical and acid-base properties suitable for use as photosensitizers (PS) in biological systems. Structure-photodynamic activity relationships were established by evaluating the photodynamic effects of the compounds on human lung cancer cell lines (A549 and H1299). The strong photodynamic activity observed demonstrated that the oxime group plays a crucial role in enhancing biological activity. In fact, the model corrole without an oxime moiety (5,10,15-triphenylcorrole) showed no photodynamic activity against any of the studied LC cell lines (IC₅₀ &gt; 10 μM), whereas all fourteen oxime-functionalized corroles exhibited significantly lower IC₅₀ values. Among them, triazole-oxime derivatives displayed the highest activity, followed by phenyl-oxime and methyl-oxime corroles. The lead photosensitizers, with IC₅₀ values below 50 nM and no cytotoxicity <em>per se</em>, outperformed Temoporfin, the active compound in Foscan®, a clinically approved PS. This highlights oxime-functionalized <em>trans</em>-A₂B-corroles as promising candidates for photodynamic therapy of LC. The <em>in vivo</em> efficacy of one oxime-corrole based PDT was also evaluated using the chick embryo chorioallantoic membrane model demonstrating its potential as an effective photosensitizer <em>in vivo</em>.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 117946"},"PeriodicalIF":6.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587025","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":"HSQC-guided discovery and structural optimization of antiadipogenic indole diterpenoids from endophytic fungus Penicillium janthinellum H-6","authors":"Lei Li ,&nbsp;Xin-Ying Zhu ,&nbsp;Jun-Yu Zhu ,&nbsp;Qing-Ya Cui ,&nbsp;Yu-Wei Lin ,&nbsp;Qing-Ren Lu ,&nbsp;Shu-Qi Wu ,&nbsp;Yi-Fan Fu ,&nbsp;Qi-Lang Zhou ,&nbsp;Tao Yuan ,&nbsp;Zhang-Hua Sun ,&nbsp;Dong Huang ,&nbsp;Fang-Yu Yuan ,&nbsp;Sheng Yin ,&nbsp;Gui-Hua Tang","doi":"10.1016/j.ejmech.2025.117956","DOIUrl":"10.1016/j.ejmech.2025.117956","url":null,"abstract":"<div><div>Chemical investigation of <em>Penicillium janthinellum</em> H-6 using HSQC-guided small molecule accurate recognition technology (SMART) led to the isolation of nine new indole diterpenoids (IDTs), penijanidines D−L (<strong>1</strong>−<strong>9)</strong>, along with four known analogues (<strong>10</strong>−<strong>13</strong>). Architecturally, compound <strong>1</strong> represents an unusual imine-containing IDT, while compounds <strong>2</strong> and <strong>3</strong> are rare 1(2),2(18)-di-<em>seco</em>-IDT derivatives. Their structures including absolute configuration were determined by spectroscopic analysis and computational method. Meanwhile, structure optimization of the primary penijbirine (<strong>15</strong>) was conducted to obtain 22 new IDT derivatives (<strong>21</strong>−<strong>42</strong>). Systematic evaluation of the antiadipogenic effects of 42 IDTs, including 13 isolated ones (<strong>1</strong>−<strong>13</strong>), seven previously reported ones (<strong>14</strong>−<strong>20</strong>), and 22 semi-synthetic derivatives (<strong>21</strong>−<strong>42</strong>), in 3T3-L1 adipocytes identified the structurally optimized derivative <strong>38</strong> as the most potent molecular for triglyceride-lowering activity, exhibiting an EC₅₀ value of 0.25 ± 0.05 μM. Preliminary structure-activity relationship (SAR) analysis highlighted critical pharmacophoric features governing the lipid-lowering efficacy of these compounds. Mechanism studies revealed that <strong>38</strong> suppressed adipogenesis and lipogenesis via activating the AMPK signaling pathway, evidenced by significantly increased phosphorylation of AMPK (p-AMPK). Surface plasmon resonance (SPR) assays further confirmed that compound <strong>38</strong> directly bond to the AMPK protein with an affinity of <em>K</em>_D = 12.4 μM. This study not only expands the chemical diversity of bioactive IDTs but also identifies <strong>38</strong> as a novel AMPK-targeting lead compound for potential anti-obesity drug development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117956"},"PeriodicalIF":6.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587024","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":"CHI3L1-targeted small molecules as glioblastoma therapies: Virtual screening-based discovery, biophysical validation, pharmacokinetic profiling, and evaluation in glioblastoma spheroids","authors":"Hossam Nada,&nbsp;Longfei Zhang,&nbsp;Baljit Kaur,&nbsp;Moustafa T. Gabr","doi":"10.1016/j.ejmech.2025.117960","DOIUrl":"10.1016/j.ejmech.2025.117960","url":null,"abstract":"<div><div>Glioblastoma (GBM) remains the most aggressive primary brain malignancy with a 10 % three-year survival rate. Chitinase-3-like protein 1 (CHI3L1) has emerged as a critical factor in the progression of GBM progression, invasion, and treatment resistance. However, small molecule inhibitors targeting CHI3L1 are largely unexplored. Microscale thermophoresis (MST) investigation of the direct binding potential of reported CHI3L1 modulators (<strong>K284</strong>, <strong>G721</strong>–<strong>0282</strong>, <strong>CHI3L1-IN-1</strong>) revealed modest to undetectable direct CHI3L1 binding affinity. Herein, pharmacophore-based virtual screening of in-house library resulted in the discovery of <strong>G28</strong> as the most potent small molecule CHI3L1 binder reported to date. The CHI3L1 binding affinity of <strong>G28</strong> was validated using MST and surface plasmon resonance (SPR). To evaluate the GBM-modulatory potential of <strong>G28</strong>, we conducted comprehensive pharmacokinetic and 3D spheroid studies alongside established CHI3L1 modulators. <strong>G28</strong> demonstrated outstanding bioavailability and low toxicity, addressing key limitations faced by previous CHI3L1-targeted strategies. Notably, in 3D GBM spheroid models, <strong>G28</strong> significantly outperformed reported CHI3L1 small molecule modulators, showing the most pronounced dose-dependent reductions in spheroid weight, migration, and viability. These findings position <strong>G28</strong> as the most promising CHI3L1-targeted small molecule to date and a compelling candidate for GBM therapeutic development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117960"},"PeriodicalIF":6.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587022","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":"Structure-based design of benzofuran library as P. aeruginosa quorum sensing inhibitors: Synthesis, biological evaluation and molecular docking study","authors":"Noha G. Mohamed ,&nbsp;Wesam S. Qayed ,&nbsp;Mahmoud M. Sheha ,&nbsp;Farghaly A. Omar ,&nbsp;Wael A.H. Hegazy ,&nbsp;Shaimaa I. Nazeih","doi":"10.1016/j.ejmech.2025.117950","DOIUrl":"10.1016/j.ejmech.2025.117950","url":null,"abstract":"<div><div>Two series of benzofuran-based thiosemicarbazides <strong>7, 8(a</strong>–<strong>l)</strong> are evaluated as <em>P. aeruginosa</em> quorum sensing inhibitors (<em>QSIs</em>). The studied compounds resulted in reduction of violacein production of <em>C. violaceum,</em> at ¼ <em>MIC</em>, up to 26.04–67.36 %, relative to the reference drug azithromycin (54 %). <em>In vitro</em> evaluation of QS and antivirulence activities, at the same concentration, against <em>P. aeruginosa, showed</em> promising inhibitory effect of biofilms formation, bacterial motility and virulence factors production (pyocyanin, and rhamnolipids). Compounds <strong>7a</strong>, <strong>7d</strong>, and <strong>7k</strong> inhibit biofilm formation up to 57.31 %, 67.54 %, 78.38 %, respectively, in addition to &gt;50 % inhibition of hemolysin production. On the other hand, compounds <strong>8a, 8d, 8f</strong> and <strong>8k</strong> of the bromobenzofuran series showed, 55.66 %, 50.67 %, 73.34 %, 79.93 %, reduction in biofilm formation, respectively. Compounds <strong>8d</strong> and <strong>8f</strong> exhibit &gt;50 % reduction of hemolysin and protease. <em>In vivo</em> study on mice groups infected with <em>P. aeruginosa,</em> previously treated with compounds <strong>7k</strong> or <strong>8f,</strong> revealed 50 % survival protection, accompanied by decrease in bacterial loads in kidney and liver tissues up to 50 % relative to the untreated group. Moreover, cytotoxicity study on human lung cell line (WI-38), demonstrates the safety of 7k and 8f (CC₅₀ = 96.75 ± 3.02 and 142.4 ± 4.44, respectively). Molecular docking study into <em>PqsR</em>^<em>LBD</em>, (PDB: <span><span>6b8a</span><svg><path></path></svg></span>), showed promising interactions with the essential amino acids in the binding pockets. MD analysis revealed that compounds <strong>8f</strong> and <strong>7k</strong>, exhibit superior binding characteristics compared to the native inhibitor. Through a blend of structural snugness, dynamic stabilization, and energetically favorable interactions, <strong>8f</strong> stands out as a particularly promising scaffold for the development of next-generation <em>PqsR</em> inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117950"},"PeriodicalIF":6.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587026","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":"The roles of fused-cyclopropanes in medicinal chemistry: Insights from the past decade","authors":"Dongsheng Li","doi":"10.1016/j.ejmech.2025.117951","DOIUrl":"10.1016/j.ejmech.2025.117951","url":null,"abstract":"<div><div>Fused-cyclopropane rings have become increasingly prevalent in modern drug discovery and medicinal chemistry campaigns as they can provide inherent three-dimensionality, structural novelty, and unique physicochemical properties. This review presents an overview of examples from the primary medicinal chemistry literature over the past decade to illustrate diverse applications of fused-cyclopropane ring motifs, including (a) enhanced metabolic stability, (b) improved target binding potency, (c) novel chemotype generation, (d) reduced off-target effects, (e) increased membrane/blood-brain barrier (BBB) permeability, (f) improved hydrolytic stability, (g) mitigated toxicity liability, (h) enhanced chemical stability, and (i) improved aqueous solubility.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117951"},"PeriodicalIF":6.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587023","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 novel covalent PI3Kδ inhibitors bearing alaninamide moiety by lysine-targeted covalent strategy","authors":"Bo Yuan ,&nbsp;Mengyan Ma ,&nbsp;Yujie Wu,&nbsp;Jiaxin Liu,&nbsp;Mengyao Chen,&nbsp;Ying Lai,&nbsp;San-Qi Zhang,&nbsp;Minhang Xin","doi":"10.1016/j.ejmech.2025.117948","DOIUrl":"10.1016/j.ejmech.2025.117948","url":null,"abstract":"<div><div>PI3Kδ is involved in a wide range of cellular processes, including cell growth, proliferation and differentiation, making it as one of the most valuable targets for the treatment of hematologic tumors. Herein, we developed a series of novel covalent PI3Kδ inhibitors bearing alaninamide moiety by lysine-targeted covalent strategic design. The optimal compound <strong>M7</strong>, containing the phenolic ester warhead, demonstrated excellent <em>in vitro</em> strong bioactivity and selectivity for PI3Kδ. Furthermore, <strong>M7</strong> exhibited potently antiproliferative activity against SU-DHL-6 and Pfeiffer cells. <strong>M7</strong> significantly reduced p-AKT levels, arrested the cell cycle and induced cell apoptosis. Wash-out experiments demonstrated that <strong>M7</strong> sustained the inhibitory effect on SU-DHL-6 cells and inhibited p-AKT expression consistently. Protein mass spectrometry confirmed the covalent binding of <strong>M7</strong> to K779 of PI3Kδ through amide bonding formation. This study expanded the scope of lysine-targeted covalent design and provided a strong foundation for the development of novel, potent covalent PI3Kδ inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117948"},"PeriodicalIF":6.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578174","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":"Targeting voltage-gated proton channel HV1: Optimised 5-phenyl-2-aminoimidazoles with anticancer potential","authors":"Martina Piga ,&nbsp;Geraldo Jorge Domingos ,&nbsp;Adam Feher ,&nbsp;Ferenc Papp ,&nbsp;Kavya C. Bangera ,&nbsp;Zoltan Varga ,&nbsp;Florina Zakany ,&nbsp;Tamas Kovacs ,&nbsp;Jaka Dernovšek ,&nbsp;Tihomir Tomašič ,&nbsp;Nace Zidar","doi":"10.1016/j.ejmech.2025.117936","DOIUrl":"10.1016/j.ejmech.2025.117936","url":null,"abstract":"<div><div>The voltage-gated proton channel (H_V1) has been linked to the development of tumours, neuroinflammatory diseases, immune disorders and infertility, making H_V1 inhibitors promising candidates for therapeutic development. In this study, we designed and synthesized an optimised series of 5-phenyl-2-aminoimidazole-based H_V1 inhibitors, with the most potent compounds exhibiting low micromolar IC₅₀ values. Structural analysis highlighted the importance of an unsubstituted 2-aminoimidazole core and flexible linkers for optimal ligand-channel binding, driven by hydrogen bonding and hydrophobic interactions. Antiproliferative assays showed that the most potent H_V1 inhibitors had IC₅₀ values in the low micromolar range, with greater efficacy against THP-1 cells (human monocytic leukaemia), which express H_V1 at high levels, compared to MCF-7 cells (human breast cancer) with lower H_V1 expression. The type II compounds exhibited superior drug-like properties, including improved solubility, plasma protein binding and permeability compared to previous 5-phenyl-2-aminoimidazole-based H_V1 inhibitors, as well as robust metabolic stability. However, selectivity over the K_V1.3 and Na_V1.5 channels remained limited. This work advances the development of H_V1 inhibitors. It provides valuable chemical tools to study the role of H_V1 in disease pathogenesis and lays the foundation for new therapeutic strategies targeting H_V1-mediated signalling pathways.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117936"},"PeriodicalIF":6.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578177","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}