European Journal of Medicinal Chemistry最新文献

{"title":"Design, synthesis, and structure-activity relationship of 5,7- dimethylbenzo[d]thiazoles as novel Kv7.2/7.3 activators with antiepileptic effects","authors":"Denggao Zhang ,&nbsp;Wei Xiang ,&nbsp;Jie Liu ,&nbsp;Wei Li ,&nbsp;Zhen Qiao ,&nbsp;KeWei Wang ,&nbsp;Liming Shao","doi":"10.1016/j.ejmech.2025.117660","DOIUrl":"10.1016/j.ejmech.2025.117660","url":null,"abstract":"<div><div>The activation of neuronal Kv7 channels has emerged as an important therapeutic strategy for epilepsy due to their role in regulating neuronal excitability. Retigabine (RTG), a Kv7.2/7.3 channel activator, was previously approved for epilepsy treatment but was withdrawn in 2017 because of its side effects of ophthalmological and dermatological pigmentation. Despite this setback, Kv7.2/7.3 channel remains a promising target for the development of antiepileptic drugs (AEDs). Previous studies have attributed the toxic metabolic quinone/azaquinone diimines and associated blue discoloration of RTG to its electron-rich tri-amine aromatic scaffold. A common strategy to mitigate this toxicity involves removing the <em>ortho-</em>aniline moiety of RTG. In this study, we designed and synthesized a series of compounds based on dimethylbenzene heterocyclic scaffolds as Kv7.2/7.3 activators. Among them, compound <strong>2c</strong> demonstrated improved efficacy in Rb⁺ efflux assays and exhibited comparable activity in whole-cell patch clamp recordings on Kv7.2/7.3 channels. Moreover, compound <strong>2c</strong> was effective in both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (<em>sc-</em>PTZ) mouse models, with ED₅₀ values of 4.02 mg/kg and 43.17 mg/kg, respectively. The LD₅₀ value of <strong>2c</strong> in acute toxicity experiments was 340.35 mg/kg (95 % CI: 293.68–394.45) in mice. Additionally, <strong>2c</strong> exhibited locomotor impairment with at TD₅₀ of 48.93 mg/kg in an open field test and 49.25 mg/kg in a rotarod test. Compound <strong>2c</strong> also demonstrated reasonable pharmacokinetic (PK) properties and blood-brain barrier (BBB) penetration, along with good photostability. Site-directed mutagenesis, combined with molecular docking, confirmed that <strong>2c</strong> interacted with key residues (W236, F305, and L299) in the Kv7.2 channel. Our findings suggest that compound <strong>2c</strong> is a promising lead compound with a novel scaffold as a Kv7.2/7.3 activator for the management of epilepsy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117660"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858230","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":"Structural optimization and pharmacological evaluation of diphenyl amine esters as anti-hepatocellular carcinoma agents by targeting TAR RNA-binding protein 2","authors":"Ruihan Zhang ,&nbsp;Zhao Wu ,&nbsp;Hairong Wang ,&nbsp;Minghui Ji ,&nbsp;Tianze Shen ,&nbsp;Linhan Yang ,&nbsp;Yiming Li ,&nbsp;Jialing Yu ,&nbsp;Yinqiao Huang ,&nbsp;Lingyu Li ,&nbsp;Zihan Xu ,&nbsp;Yuwen Sheng ,&nbsp;Xiaoli Li ,&nbsp;Fei Wang ,&nbsp;Weilie Xiao","doi":"10.1016/j.ejmech.2025.117676","DOIUrl":"10.1016/j.ejmech.2025.117676","url":null,"abstract":"<div><div>Hepatocellular Carcinoma (HCC), a leading cause of cancer-related death in the world, urgently requires novel therapeutic strategies and drug targets. The TRBP-Dicer complex plays a critical role in miRNA biosynthesis, which can be regulated by small molecules to exert anti-cancer effects. This study presented the structural modification of the natural product (−)-Gomisin M1(GM), resulting in the synthesis of 37 derivatives with a diphenyl amine ester scaffold. Several of these derivatives exhibited enhanced modulation of miRNA biogenesis compared to GM. Notably, derivative <strong>13j</strong> displayed improved binding affinity to TRBP and greater efficacy in modulating miRNA biosynthesis, as well as anti-HCC activity <em>in vitro</em> and <em>in vivo</em>. Further investigation revealed that <strong>13j</strong> induced apoptosis and pyroptosis while inhibiting the epithelial-to-mesenchymal transition process in HCC cells. In terms of druggability, <strong>13j</strong> possesses favorable drug-likeness and a promising safety profile. These findings provide a promising scaffold with potent activity and low toxicity, offering a foundation for the development of miRNA-based therapeutic strategies for HCC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117676"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862706","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 the first-in-class FABP/PPAR multiple modulator for the treatment of metabolic dysfunction-associated steatohepatitis","authors":"Ya Chen ,&nbsp;Zibin Liao ,&nbsp;Jianming Mao ,&nbsp;Wenxin Wang ,&nbsp;Yuxia Liu ,&nbsp;Wei Dai ,&nbsp;Zheng Wen ,&nbsp;Sishi Liu ,&nbsp;Yayi Chen ,&nbsp;Yiming Ma ,&nbsp;Xiaoying Wang ,&nbsp;Zheng Li","doi":"10.1016/j.ejmech.2025.117635","DOIUrl":"10.1016/j.ejmech.2025.117635","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic syndrome, and the development of new drugs is urgently needed. Fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid absorption, metabolism and inflammation. Considering the synergistic effect of FABP and PPAR in the regulation of MASH pathophysiology, the development of FABP/PPAR multiple modulators might be a promising anti-MASH strategy. Herein, the first-in-class FABP/PPAR multiple modulators were designed by hybrid resveratrol and PPARs agonist Elafibranor. Among them, the compound <strong>27</strong> was identified as the optimal FABP/PPAR multiple modulator (FABP1 IC₅₀ = 0.65 μM, FABP4 IC₅₀ = 1.08 μM, PPARα EC₅₀ = 9.19 μM, PPARγ EC₅₀ = 2.20 μM, PPARδ EC₅₀ = 1.58 μM). Further MST assay confirmed the direct interaction of compound <strong>27</strong> and FABP1, providing a robust validation of its target specificity. In MASH mice, compound <strong>27</strong> exhibited a better therapeutic effect than clinical candidate obeticholic acid in ameliorating multiple pathological features of MASH. This study reported the successful discovery of the first-in-class FABP/PPAR multiple modulators, which provided preliminary evidence that such multi-target agents have broad medical prospects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117635"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858203","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 hydrazide-based PI3K/HDAC dual inhibitors with enhanced pro-apoptotic activity in lymphoma cells","authors":"Baogeng Hou ,&nbsp;Geng Jia ,&nbsp;Zhongqiang Li ,&nbsp;Yuqi Jiang ,&nbsp;Yuxin Chen ,&nbsp;Xiaoyang Li","doi":"10.1016/j.ejmech.2025.117658","DOIUrl":"10.1016/j.ejmech.2025.117658","url":null,"abstract":"<div><div>PI3K and HDAC are concurrently upregulated in a variety of cancers, and simultaneous inhibition of PI3K and HDAC may synergistically inhibit tumor proliferation and induce apoptosis, providing a rationale for the study of dual-target PI3K/HDAC inhibitors. In this study, we rationally designed and synthesized a series of novel PI3K/HDAC dual-target inhibitors by combining the morpholino-triazine pharmacophore of PI3K inhibitor ZSTK474 with the hydrazide moiety of HDAC1-3 selective inhibitor <strong>11h</strong>. Representative compound <strong>31f</strong> possessed both PI3K (IC₅₀ = 2.5–80.5 nM for PI3Kα, β, γ, and δ) and HDAC1-3 inhibitory activities (IC₅₀ = 1.9–75.5 nM for HDAC1-3). <strong>31f</strong> showed potent antiproliferative activity against a variety of tumor cell lines. Meanwhile, we designed and synthesized tool molecule <strong>39a</strong>, a HDAC inhibitor structurally similar to <strong>31f</strong>. In the mantle cell lymphoma Jeko-1 cell line, <strong>31f</strong> showed significantly greater efficacy than the single inhibitors in inducing apoptosis. In conclusion, this study provided insights into the development of novel hydrazide-based dual HDAC/PI3K inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117658"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858204","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":"Marine natural products as potential anti-Pseudomonas aeruginosa agents: challenges and advances","authors":"Liu-Xia Lv ,&nbsp;Jun-Na Yin ,&nbsp;Yi-Lin Sun ,&nbsp;Mei-Yan Wei ,&nbsp;Wen-Qing Jiang ,&nbsp;Yu-Cheng Gu ,&nbsp;Xiao-Ping Yang ,&nbsp;Chang-Lun Shao","doi":"10.1016/j.ejmech.2025.117670","DOIUrl":"10.1016/j.ejmech.2025.117670","url":null,"abstract":"<div><div>Antimicrobial resistance (AMR) has become a pressing need to address in the major global public health challenges, posing a serious threat to human health. <em>Pseudomonas aeruginosa</em> (PA) is one of the most concerning Gram-negative pathogens and is typically treated with broad-spectrum antibiotics. PA exhibits resistance to multiple antibiotics, multifactorial virulence, and dynamic hyperadaptation, which results in a particularly formidable challenge in eliminating PA from patients. The problem of drug resistance is becoming increasingly serious, and the development of new antibiotics is extremely lagging behind, resulting in no drug with a new structure and mechanism being approved for the treatment of infections caused by drug-resistant Gram-negative bacteria over the past half-century. Consequently, the development of new antibiotics is of utmost urgency and importance. Marine natural products (MNPs) have become an important source for developing new antibiotics due to their unique properties. So far, 44 potential molecules with significant anti-PA activity have been isolated from marine organisms, of which 19 have been reported as quorum-sensing system inhibitors (QSIs) with potential for further development. In this review, we provide a comprehensive summary of the current status of drug resistance, pathogenic mechanisms, and resistance mechanisms associated with PA infections. We also highlight the challenges and opportunities presented by MNPs in the development of anti-PA drugs, and offer recommendations to accelerate the antibiotic development process, thereby providing valuable insights for the study and exploitation of novel antibiotics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117670"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858209","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 advances in developing bioorthogonally activatable photosensitizers for photodynamic therapy","authors":"Shuyi Ning ,&nbsp;Yuanyuan Yao ,&nbsp;Xinchi Feng ,&nbsp;Yulin Tian","doi":"10.1016/j.ejmech.2025.117672","DOIUrl":"10.1016/j.ejmech.2025.117672","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) is a promising and powerful cancer therapeutic modality, which can generate cytotoxic reactive oxygen species (ROS) from light-irradiated photosensitizers (PSs) to eradicate tumors. To overcome the drawbacks of currently used PSs, researchers have leveraged the advantages of bioorthogonal reactions to design diverse bioorthogonally activatable photosensitizers with excellent tumor selectivity, high ROS generation controllability, and low adverse effect for effective antitumor photodynamic therapy. In this review, we comprehensively summarize and highlight the recent advances in the development of bioorthogonally activatable photosensitizers, including the structure types, designing strategies, activation patterns, photophysical properties, ROS generation efficiency, <em>in vitro</em> and <em>in vivo</em> activities, biological applications, and limitations. We also provide directions and perspectives to address the therapeutic challenges of bioorthogonally activatable photosensitizers for promoting clinical applications. We believe that the principles summarized here will offer useful references for further development of next-generation advanced intelligent photosensitizers and related strategies to realize precise and efficient tumor treatment in the future.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117672"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858210","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":"Synthetic flavonoid dimers: Synthesis strategies and biological activities","authors":"Rui Pereira ,&nbsp;Daniela Ribeiro ,&nbsp;Vera L.M. Silva ,&nbsp;Eduarda Fernandes","doi":"10.1016/j.ejmech.2025.117669","DOIUrl":"10.1016/j.ejmech.2025.117669","url":null,"abstract":"<div><div>The continuous search for novel and safer drug candidates remains imperative to address ever-evolving health challenges. Nature has long served as a source of inspiration for drug discovery, particularly through bioactive compounds such as flavonoids. Among them, flavonoid dimers, first identified nearly a century ago, have shown promising biological activities that often surpass those of their monomeric counterparts while showing minimal side effects. Nonetheless, these compounds suffer from limitations such as low bioavailability and moderate potency. To mitigate these challenges, researchers have developed synthetic strategies to obtain them, expand their structural diversity, and optimize their properties. The design of completely unnatural flavonoid dimers offers new opportunities for drug discovery.</div><div>In contrast to previous review articles, this review explores the potential of synthetic flavonoid dimers. It provides an overview of the main synthetic methodologies to obtain them, illustrating how the evolution of the synthetic protocols has also driven the development of novel unnatural compounds. It then focuses on highlighting the bioactivities reported for synthetic flavonoid dimers, in particular anti-inflammatory, anticancer, and antimicrobial. Finally, this review highlights a specific subclass of synthetic flavonoid dimers that emerged in the last decade but remains underexplored, proposing its classification as fused <em>bis-flavonoids</em>. The aim is to drawattention to their potential importance by giving them a unique nomenclature from other subclasses and highlighting their biological activities.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117669"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853229","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 a CYP2E1 inhibitor and its therapeutic potential in severe acute pancreatitis","authors":"Jinhuan Qiu ,&nbsp;Jiakun Lu ,&nbsp;Xiaodi Wang ,&nbsp;Yajie Zhang ,&nbsp;Mengxian Guo ,&nbsp;Fan Guo ,&nbsp;Haiwei Xu ,&nbsp;Hailing Qiao","doi":"10.1016/j.ejmech.2025.117666","DOIUrl":"10.1016/j.ejmech.2025.117666","url":null,"abstract":"<div><div>Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the cytochrome P450 family, playing a crucial role in metabolizing a wide range of endogenous and exogenous compounds. It is also pivotal in the onset and progression of inflammation. Despite the demonstrated anti-inflammatory effects of existing CYP2E1 inhibitors in various animal models, their clinical application remains limited due to poor selectivity, high toxicity, degradation susceptibility, and limited <em>in vivo</em> solubility. Through virtual screening, synthesis, and optimization, we identified compound <strong>10</strong> as a favorable selective and potent CYP2E1 inhibitor, with a <em>K</em>_d of 7.02 μM, an IC₅₀ of 1.64 μM, and a <em>K</em>_i of 0.897 μM. Notably, treatment with <strong>10</strong> significantly reduced mortality, inflammation, and oxidative stress in mouse models of severe acute pancreatitis (SAP) induced by Caerulein combined with lipopolysaccharide (LPS) or <span>l</span>-Arginine. <strong>10</strong> significantly promoted the expression of Nrf2 in pancreatic tissues of the two SAP models; <em>in vitro</em> studies revealed that inactivation of Nrf2 signaling and increase of reactive oxygen species (ROS) were reversed by <strong>10</strong> in Caerulein-treated AR42J cells. Overall, our study identified a selective and potent small molecule CYP2E1 inhibitor <strong>10</strong>, which may not only serve as a candidate compound for the treatment of SAP but also lay the groundwork for future drug development of anti-inflammatory agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117666"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858206","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":"Study of the antileishmanial activity of novel guanidine and hybrid acridine – guanidine compounds","authors":"Luana Ribeiro dos Anjos ,&nbsp;Julyanne Maria Saraiva de Souza ,&nbsp;Airton Lucas Souza dos Santos ,&nbsp;Anna Fabisikova ,&nbsp;Michael Klemm-Abraham ,&nbsp;Martin Zehl ,&nbsp;Klinger Antonio da Franca Rodrigues ,&nbsp;Eduardo Rene Perez Gonzalez","doi":"10.1016/j.ejmech.2025.117651","DOIUrl":"10.1016/j.ejmech.2025.117651","url":null,"abstract":"<div><div>The inadequacies of the currently available treatment options for leishmaniasis, a highly prevalent but neglected tropical disease caused by protozoan parasites, urge the discovery and development of novel, safe, and efficacious antileishmanial drugs. In continuation of our work on <em>N</em>, <em>N</em>′, <em>N</em>″-trisubstituted guanidines, which have shown promising results, we present in this study a series of new derivatives with further improved activity against the species <em>Leishmania</em> (<em>Leishmania) amazonensis</em>, <em>Leishmania</em> (<em>Leishmania</em>) <em>infantum</em> and <em>Leishmania</em> (<em>Viannia</em>) <em>braziliensis</em>. This enhancement was achieved by replacing the benzoyl group as one of the three guanidine substituents of the starting structures with an acridinyl group, which consistently decreased the IC₅₀ values against the promastigote form of <em>L.</em> (<em>V.) braziliensis</em> by a factor of 5.7–37. The three most active acridinylguanidines all showed submicromolar IC₅₀ values against the promastigote forms of all three tested parasite species and a selectivity index &gt;200 compared to RAW 264.7 macrophages. Similar results were obtained against <em>L.</em> (<em>V.) braziliensis</em> axenic and intramacrophage amastigotes, with ACRL-G5 showing an EC₅₀ of 0.53 μM against both and a selectivity index of 347. ACRL-G5 was also shown to increase the levels of TNF-α and nitric oxide and to decrease the concentration of IL-10 in the supernatant of <em>L.</em> (<em>V.) braziliensis</em>-infected macrophages. All three tested acridinylguanidines strongly increased the membrane permeability of <em>L. braziliensis</em> promastigotes at concentrations above the IC₅₀.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117651"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858205","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, total synthesis, and biological evaluation of tyrcinnamins as antibacterial agents and tyrosinase activators","authors":"Di Mao ,&nbsp;Baoyue Wei ,&nbsp;Chao Liu ,&nbsp;Bing Zhang ,&nbsp;Zhiwei Zhang ,&nbsp;Yuhan Zhang ,&nbsp;Zhuang Li ,&nbsp;Boxiang Ding ,&nbsp;Hai Ye ,&nbsp;Jingjing Wang ,&nbsp;Lijuan Sun ,&nbsp;Yanan Gai ,&nbsp;Pengwei Yu ,&nbsp;Hideaki Kakeya ,&nbsp;Shan Lu","doi":"10.1016/j.ejmech.2025.117665","DOIUrl":"10.1016/j.ejmech.2025.117665","url":null,"abstract":"<div><div>Microorganisms serve as critical resources for the discovery of new antibacterial drug leads. Herein, we report the screening, isolation, and identification of tyrcinnamin (<strong>1</strong>) from the endophytic <em>Streptomyces</em> sp. JS-B1. The total synthesis, biological evaluation, and structural-activity relationship study of tyrcinnamin and its synthetic derivatives led to the discovery of <strong>7a</strong>, a promising lead compound with significant antibacterial activity, notable tyrosinase activation activity, and an excellent safety profile. The analysis of molecular docking of <strong>7a</strong> with mushroom tyrosinase reveals that <strong>7a</strong> may competitively occupy the binding site of <span>l</span>-DOPA on the surface of tyrosinase without interfering with the substrate binding at the active center, thereby reducing the ineffective occupancy of <span>l</span>-DOPA on the tyrosinase surface and improving the binding efficiency of <span>l</span>-DOPA at the active center. The structure of <strong>7a</strong> represents a new chemical scaffold for the development of new antibiotics and tyrosinase activators, making valuable contributions to both drug discovery and cosmetics development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117665"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858207","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}