Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Design, synthesis and preliminary evaluation of mosquitoicidal activity of arecoline derivatives targeting muscarinic acetylcholine receptors","authors":"Hongyue Bu ,&nbsp;Qi-Long Wu ,&nbsp;Cun-Chen Wang ,&nbsp;Qiaolu Guo ,&nbsp;Shengqun Deng ,&nbsp;Yiji Li ,&nbsp;Shuojin Wang","doi":"10.1016/j.bmcl.2026.130548","DOIUrl":"10.1016/j.bmcl.2026.130548","url":null,"abstract":"<div><div>To develop novel mosquito control agents, we designed and synthesized a series of derivatives based on the natural alkaloid arecoline as a lead compound, targeting muscarinic acetylcholine receptors (mAChRs). Using computer-aided drug design and docking techniques focused on mAChRs, we designed piperidine derivatives and screened for synthetically accessible candidates. The compounds were synthesized, structurally characterized, and evaluated for activity via a Fluo-4 calcium fluorescence assay using Chinese Hamster Ovary-K1 (CHO-K1) cells expressing the muscarinic acetylcholine receptor M1. Most compounds showed potent mAChRs agonist activity, with Half Maximal Effective Concentration (EC₅₀) values below 10 μM. In subsequent insecticidal activity tests, these piperidine derivatives exhibited strong larvicidal effects against <em>Aedes aegypti</em>. The Median Lethal Concentration (LC₅₀) values for compounds <strong>1a</strong>, <strong>2a</strong>, <strong>3a</strong>, <strong>4a</strong>, <strong>13a</strong>, <strong>22a</strong>, <strong>2b</strong>, and <strong>9b</strong> were 58.4, 29.6, 11.4, 21.7, 42.0, 61.7, 125.9, and 81.6 mg/L, respectively. Notably, compound 13a maintained high insecticidal activity even against pyrethroid-resistant mosquitoes, indicating a mode of action different from conventional neurotoxic insecticides. These results demonstrate that mAChR-targeting derivatives derived from betel alkaloids represent a promising strategy for developing new mosquito control agents and offer a novel approach to combating insecticide resistance.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130548"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monaprenylindole A, a prenylated indole derivative from marine-derived Streptomyces sp., accelerates wound healing through the enhancement of keratinocyte motility via the modulation of cytoskeletal remodeling and growth factor pathways","authors":"Eun-Young Lee ,&nbsp;Mücahit Varlı ,&nbsp;Hiyoung Kim ,&nbsp;Soyeong Kim ,&nbsp;Seongeun Kang ,&nbsp;Jungwook Chin ,&nbsp;Hongchan An ,&nbsp;Hangun Kim ,&nbsp;Sang-Jip Nam","doi":"10.1016/j.bmcl.2026.130539","DOIUrl":"10.1016/j.bmcl.2026.130539","url":null,"abstract":"<div><div>Wounds pose significant healthcare challenges, prompting the need for novel therapeutics with pro-regenerative potential. Natural products from marine-derived actinomycetes are a promising source of small bioactive molecules. The first total syntheses of monaprenylindole A (<strong>1</strong>) and its analog (<strong>2</strong>) were accomplished. Here, we report the isolation, structural characterization, synthesis, and pharmacological evaluation of monaprenylindole A (<strong>1</strong>) and its analog, 6-isoprenylindole-3-carboxylic acid (<strong>2</strong>), for their wound healing potential. Compounds <strong>1</strong> and <strong>2</strong> were isolated from a marine-derived <em>Streptomyces</em> sp. and structurally characterized using mass spectrometry (MS), ultraviolet (UV), and nuclear magnetic resonance (NMR) analyses. Firstly, we analyzed the predicted favorable pharmacokinetics and safety of the compounds for their underlying translational potential. Furthermore, pharmacological network analysis identified multiple wound healing-related gene targets that were modulated by these molecules, suggesting a multi-target mechanism. In vitro assays showed that all compounds enhanced keratinocyte invasion, with compound <strong>1</strong> demonstrating the strongest effects by upregulating genes involved in cell motility. Furthermore, compound <strong>1</strong> promoted the upregulation of key motility-related genes, suggesting that this compound promotes wound healing through activating transcriptional programs involved in adhesion, cytoskeletal remodeling, growth factors, and spheroid formation, indicating a shift toward regenerative epithelial behavior. Finally, topical treatment with <strong>1</strong> significantly accelerated wound closure in a murine model. These results highlight the potential of monaprenylindole A as promising multi-target therapeutics for skin repair.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130539"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel imidazolium salts bearing 2-oxindoles scaffold as potent acetylcholinesterase inhibitors for Alzheimer's disease: Design, synthesis, in vitro and in silico studies","authors":"Le Quoc Tien ,&nbsp;Hien Thi Thanh Phung ,&nbsp;Huy-Hoang Do ,&nbsp;Tiep N. Khac ,&nbsp;Pham Thi Ngoc Minh ,&nbsp;Vu Ngoc Hai Linh ,&nbsp;Nguyen Quoc Thang ,&nbsp;Shuai Wang ,&nbsp;Phuong-Thao Tran","doi":"10.1016/j.bmcl.2026.130560","DOIUrl":"10.1016/j.bmcl.2026.130560","url":null,"abstract":"<div><div>In this study, a series of thirty-five novel imidazolium salts bearing a 2-oxindoles were designed and synthesized as potent acetylcholinesterase (AChE) inhibitors for Alzheimer's disease. Structural diversity was introduced through substituent variation on both the oxindole and phenyl rings to investigate structure–activity relationships. All compounds were evaluated in vitro by the modified Ellman assay, revealing several highly potent inhibitors in the nanomolar to subnanomolar range. The most active compound, <strong>32</strong>, exhibited an IC₅₀ of 0.17 nM, surpassing galantamine and donepezil. Enzyme kinetic study indicated that all compounds act as mixed-type AChE inhibitors. Machine learning–based binding affinity predictions (ΔG_ML = −10.30 to −8.18 kcal/mol) correlated well with experimental activity. Molecular docking against AChE (PDB ID: <span><span>4EY6</span><svg><path></path></svg></span> and <span><span>7E3H</span><svg><path></path></svg></span>) revealed that compounds bearing electron-withdrawing substituents exhibited superior binding scores and favorable interactions with key catalytic residues and aromatic residues. Molecular dynamics (200 ns) simulations demonstrated that compound <strong>32</strong> maintained a highly stable conformation within the AChE active site, with consistent hydrogen bonding and low root-mean-square deviation (RMSD) fluctuations. In addition, MM-PBSA binding free energy analysis (ΔG_total = −33.42 kcal/mol) further confirmed its strong and stable interactions compared with galantamine (−17.82 kcal/mol) and donepezil (−21.20 kcal/mol). Furthermore, in silico ADME predictions suggested favorable oral absorption and potential blood-brain barrier permeability for compound <strong>32</strong>, while maintaining an acceptable safety profile compared to galantamine and donepezil. These promising findings highlight the potential of oxindole–imidazolium hybrids as effective AChE inhibitors and warrant further investigation for the development of novel anti-Alzheimer agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130560"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of triazolopyrimidinone- and imidazotriazinone-based tankyrase inhibitors: Identification of Basroparib (STP1002) as a clinical candidate","authors":"Hwan Jung Lim ,&nbsp;Uk-Il Kim ,&nbsp;Kwang Rok Kim ,&nbsp;Jun Mi Lee ,&nbsp;Kyeong-Yong Park ,&nbsp;Hyung Tae Bang ,&nbsp;Jihye Yoon ,&nbsp;Eunsol Jo ,&nbsp;Kyungjin Kim ,&nbsp;Jung-Nyoung Heo","doi":"10.1016/j.bmcl.2026.130549","DOIUrl":"10.1016/j.bmcl.2026.130549","url":null,"abstract":"<div><div>We report the design, synthesis, and characterization of a novel series of triazolopyrimidinone and imidazotriazinone derivatives as potent and selective TNKS1/2 inhibitors. These compounds bind to the nicotinamide pocket of TNKS and exhibit strong enzymatic inhibition and cellular Wnt/β-catenin pathway suppression, with minimal off-target activity against other PARP family members. Among them, <strong>11b</strong> (STP1002, Basroparib) demonstrated the most favorable profile, with sub-nanomolar IC₅₀ values for TNKS1/2, high selectivity, and excellent physicochemical and ADME properties. These findings support the further development of STP1002 as a promising therapeutic candidate for Wnt-driven cancers, with potential applications as both a monotherapy and in combination with other targeted agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130549"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric oxide and α-glucosidase inhibitors from Ludwigia adscendens: An integrated in vitro and in silico study","authors":"Thi Bich Hanh Dam ,&nbsp;Truong Nhan Ngu ,&nbsp;Phu Chi Hieu Truong ,&nbsp;Hong Khuyen Thi Pham ,&nbsp;Thi Thu Le Vu ,&nbsp;Tien Lam Do ,&nbsp;Hai Nam Vu ,&nbsp;Phuong Dai Nguyen Nguyen ,&nbsp;Thi Thuy Loan Le ,&nbsp;Thi Thuy Do ,&nbsp;Phi Hung Nguyen ,&nbsp;Minh Quan Pham ,&nbsp;Le Minh Hoang ,&nbsp;Tien Khi Nguyen ,&nbsp;Dao Cuong To","doi":"10.1016/j.bmcl.2026.130556","DOIUrl":"10.1016/j.bmcl.2026.130556","url":null,"abstract":"<div><div><em>Ludwigia adscendens</em> (Onagraceae) has been traditionally used for the treatment of inflammatory and metabolic disorders; however, the bioactive constituents responsible for these effects remain insufficiently characterized. In this study, twelve secondary metabolites (<strong>1</strong>−<strong>12</strong>), including triterpenoids, flavonoids, and phenolic acids, were isolated from L. <em>adscendens</em> and evaluated for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and <em>α</em>-glucosidase activity <em>in vitro</em>. Among the tested compounds, sulfuretin (<strong>8</strong>) exhibited the most potent NO inhibitory activity (IC₅₀ = 12.3 ± 0.56 μM), while uvaol (<strong>3</strong>) and ursolic aldehyde (<strong>4</strong>) showed strong <em>α</em>-glucosidase inhibition (IC₅₀ = 5.6 ± 0.7 and 4.2 ± 0.3 μM, respectively), surpassing acarbose. Molecular docking studies against inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and oligo-1,6-glucosidase supported the experimental findings, revealing favorable binding affinities and key interactions consistent with the observed structure–activity relationships. <em>In silico</em> ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis predicted acceptable drug-likeness and low acute toxicity for the active compounds. Collectively, these results identify sulfuretin as a promising dual anti-inflammatory and antidiabetic scaffold, while triterpenoid derivatives emerge as potent and selective <em>α</em>-glucosidase inhibitors, providing a rational basis for further medicinal chemistry optimization.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130556"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives and its potential applications in atherosclerosis","authors":"Xia Chen ,&nbsp;Ruilin Zhang ,&nbsp;Zhaolong He ,&nbsp;Xin Qian ,&nbsp;Chuxin Yao ,&nbsp;Xiaoyu Xiong ,&nbsp;Fangke Weng ,&nbsp;Shiqiang Xu ,&nbsp;Ya Wu ,&nbsp;Zihui Li","doi":"10.1016/j.bmcl.2026.130554","DOIUrl":"10.1016/j.bmcl.2026.130554","url":null,"abstract":"<div><div>In the search for novel anti-atherosclerotic agents, we herein report the design, synthesis, and evaluation of a series of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives (<strong>5a</strong>–<strong>5n</strong>). Cytotoxicity assessment in RAW 264.7 cells indicated minimal toxicity for most compounds under experimental conditions. Notably, compound <strong>5j</strong> exhibited superior anti-inflammatory activity, significantly attenuating intracellular reactive oxygen species (ROS) while maintaining exceptional cytocompatibility (&gt;100% cell viability at 1.25–20 μM) and demonstrating the most potent suppression of lipid accumulation. Mechanistic studies revealed that compound <strong>5j</strong> synergistically modulates two key pathways: downregulation of pro-inflammatory cytokines (TNF-<em>α</em>, IL-1<em>β</em>, IL-6) and restoration of cholesterol homeostasis via upregulation of ABCG1, leading to enhanced cholesterol efflux and 69.9% inhibition of foam cell formation at 3.25 μM (<em>p</em> &lt; 0.001). SwissADME predictions indicated that compound <strong>5j</strong> possesses favorable membrane permeability, high gastrointestinal absorption, and potential oral bioavailability. These findings establish compound <strong>5j</strong> as a potential lead for developing atherosclerosis therapies through coordinated modulation of inflammation and lipid metabolism.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130554"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiolabeled probes for tumor hypoxia imaging","authors":"Shuo Li,&nbsp;Taiwei Chu","doi":"10.1016/j.bmcl.2026.130565","DOIUrl":"10.1016/j.bmcl.2026.130565","url":null,"abstract":"<div><div>The hypoxic microenvironment within tumors serves as a pivotal factor that propels malignant progression and fosters resistance to both radiotherapy and chemotherapy. Therefore, non-invasive hypoxia imaging using radionuclides is crucial for establishing personalized treatment plans. This review summarizes research progress on various radiolabeled hypoxia imaging probes. It focuses on bioreductive nitroimidazole derivatives, metal complexes, novel molecules targeting hypoxia-induced proteins (such as CA IX), and dual-targeting probes. The review elucidates the relationship between probe structural design and <em>in vivo</em> imaging performance. The development of probes has transitioned from an initial emphasis on high lipophilicity and uptake (e.g., [¹⁸F]FMISO) to a novel phase centered on hydrophilic modifications, including glycosylation and PEGylation. These modifications optimize pharmacokinetics and improve the signal-to-noise ratio. This review details the impact of various strategies on probe uptake in tumor and non-target tissues. These strategies encompass the nitroimidazole positional isomer effect, particularly highlighting the benefits of the 2-position, along with multivalent implementations. They also include the precise regulation of linker types and lengths, the selection of radionuclide chelators, and molecular charge adjustment. Furthermore, a comparative analysis elucidates the pivotal function of “fine-tuning the redox potential” in augmenting specificity. Modifying probes by incorporating electron-donating groups moderately decreases their reduction potential. This strategy effectively reduces non-specific background signals and achieves an optimal redox potential window. Finally, this review provides a concise summary of the existing challenges associated with hypoxia-targeting probes and puts forth innovative concepts for their future development. Ideal probe design should aim for the precise synergy of “appropriate pharmacokinetics”, “optimal redox potential”, and dual-targeting or multi-targeting strategies. These methodologies furnish a theoretical foundation and design concepts for the forthcoming generation of tumor hypoxia imaging agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130565"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological profile of a novel 4-C-branched pyrrolidine-containing iminosugar","authors":"Monika Tvrdoňová ,&nbsp;Yuliia Zuzak ,&nbsp;Martina Bago Pilátová ,&nbsp;Dávid Jáger ,&nbsp;Roman Mezencev ,&nbsp;Miroslava Martinková","doi":"10.1016/j.bmcl.2026.130557","DOIUrl":"10.1016/j.bmcl.2026.130557","url":null,"abstract":"<div><div>A novel 4-<em>C</em>-branched sugar mimetic based on a 1,4-dideoxy-1,4-imino-<span>d</span>-lyxitol (DIL) scaffold was designed and synthesised. Its construction features an early-stage introduction of the side chain <em>via</em> an OCM reaction followed by an alkylative cyclisation, providing the desired heterocyclic system. The subsequent interconversion of functional groups accompanied by the selective deprotection protocol allowed the tetrahydrofuran ring to be cleaved. Cell viability experiments revealed a cytotoxic effect of the target compound comparable to that of cisplatin on the A2058 and MCF-7 cancer cell lines. Moreover, 4-<em>C</em>-tridecyl-DIL proved to be moderately active against Jurkat and HeLa cells (IC₅₀ = 20.58 μM and 22.7 μM, respectively). In addition, docking studies identified the binding modes of this novel pyrrolidine-based iminosugar to human β-glucocerebrosidase.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130557"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of furo[2,3-b]isoquinoline derivatives as novel Pks13 inhibitors with reduced hERG inhibition","authors":"Jiangfeng Tian ,&nbsp;Renyu Zhang ,&nbsp;Zhiyang Xing ,&nbsp;Yuanyuan Liu ,&nbsp;Weijie Lin ,&nbsp;Xupeng Huang ,&nbsp;Zihe Rao ,&nbsp;Wei Peng ,&nbsp;Yuying Fang","doi":"10.1016/j.bmcl.2026.130561","DOIUrl":"10.1016/j.bmcl.2026.130561","url":null,"abstract":"<div><div>Pks13 is a promising target for tuberculosis (TB) treatment, offering a new pathway for anti-TB drug development. Although benzofuran derivatives such as <strong>TAM16</strong> have demonstrated significant efficacy in vitro and in vivo, their development was discontinued due to concerns about hERG inhibition. Herein, we designed and synthesized a series of novel furo[2,3-<em>b</em>]isoquinoline derivatives using ring fusion and basicity-reduction strategies. Through SAR studies, compound <strong>B23</strong> was identified as a potent Pks13 inhibitor (IC₅₀ = 1.12 μM) with significantly reduced hERG inhibition (IC₅₀ &gt; 10 μM). The markedly improved hERG selectivity not only validates our structural strategy for mitigating cardiotoxicity risks, but also provides a solid foundation for further development of Pks13-TE inhibitors that combine potent anti-TB activity with an improved safety profile.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130561"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternariol from the endophytic fungus Alternaria sp. S4 acts as a membrane-targeting bactericidal agent against Staphylococcus aureus","authors":"Yanlin He ,&nbsp;Yuwan Zhang ,&nbsp;Wei Wang ,&nbsp;Chaoyong Cui ,&nbsp;Qianyun Hao ,&nbsp;Hongguan Xie ,&nbsp;Rui Yang","doi":"10.1016/j.bmcl.2025.130513","DOIUrl":"10.1016/j.bmcl.2025.130513","url":null,"abstract":"<div><div>The endophytic fungus <em>Alternaria</em> sp. S4, derived from <em>Ruta graveolens</em>, shows significant antimicrobial potential, but its active components and mode of action require clarification. Through bioassay-guided fractionation, alternariol (<strong>1</strong>) and alternariol-5-<em>O</em>-methyl ether (<strong>2</strong>) were isolated from the ethyl acetate fraction of <em>Alternaria</em> sp. S4 and characterized spectroscopically. Compound <strong>1</strong> exhibited potent bactericidal activity against <em>Staphylococcus aureus</em> (MIC = 4 μg/mL, MBC = 16 μg/mL), whereas compound <strong>2</strong> was inactive. Time-growth assays confirmed concentration-dependent bacterial eradication, with 2× MIC of compound <strong>1</strong> achieving complete growth inhibition. Mechanistic investigations revealed that compound <strong>1</strong> targets the bacterial membrane, inducing depolarization, compromising permeability (evidenced by ion leakage and release of intracellular constituents), and causing ultrastructural damage visualized via SEM. Furthermore, compound <strong>1</strong> prevented biofilm formation via bacterial eradication and disrupted preformed biofilms. Checkerboard assays indicated additive effects when combined with conventional antibiotics. Notably, compound <strong>1</strong> displayed no hemolytic activity even at 1024 μg/mL, highlighting its membrane selectivity. This work identifies alternariol as a promising membrane-targeting bactericidal agent from an endophytic source, capable of preventing biofilm establishment, with potential for combinatorial therapy against <em>S. aureus</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130513"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}