Bioorganic Chemistry最新文献

{"title":"Integrating synthesis, pharmacological evaluation, and molecular dynamics simulation of novel 8-substituted theophylline hybrids as potential PDE-4B inhibitors, bronchodilators and antibacterial","authors":"Taha F.S. Ali ,&nbsp;Marina A.O. Yani ,&nbsp;Ibrahim M. Salem ,&nbsp;Hend Mamdoh ,&nbsp;Mohamed F. Radwan ,&nbsp;Tarek S. Ibrahim ,&nbsp;Eman A.M. Beshr ,&nbsp;Alaa M. Hayallah","doi":"10.1016/j.bioorg.2026.109591","DOIUrl":"10.1016/j.bioorg.2026.109591","url":null,"abstract":"<div><div>Methylxanthines, particularly theophylline, have long served as effective bronchodilators for severe asthma. Emerging evidence links bacterial infection to asthma pathogenesis, motivating the search for multifunctional therapeutic agents. In this study, a series of 8-substituted 1,3-dimethylxanthines bearing aryl and heteroaryl groups were synthesized and structurally characterized by NMR, elemental analysis, and HR-ESI-MS. Most compounds exhibited significant bronchodilator activity in an acetylcholine-induced guinea pig model, surpassing theophylline. The compounds demonstrated potent <em>in vitro</em> PDE-4B inhibition relevant to asthma-related inflammation. Several derivatives also showed antibacterial activity against susceptible Gram-positive and Gram-negative strains in asthmatic patients. Molecular docking and 200 ns molecular dynamics simulations revealed strong and stable binding of the most active compounds, <strong>14d</strong> and <strong>17</strong> <strong>k</strong>, within the PDE-4B active site, correlating with their <em>in vivo</em> efficacy. Notably, <strong>17</strong> <strong>k</strong> displayed superior oral pharmacokinetic properties, high lipophilicity, moderate solubility, and optimal molecular size, comparable to theophylline and roflumilast (standard PDE-4B inhibitor). These findings identify <strong>17</strong> <strong>k</strong> as a promising lead for the development of orally active dual-acting agents for asthma management.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109591"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136937","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":"Methylated homoisoflavonoids liriopeins A–D as apoptosis inducers and macrophage-activating anticancer agents: Synthesis and biological evaluation","authors":"Sangil Kwon ,&nbsp;Minkyu Ji ,&nbsp;Woonseong Shin ,&nbsp;Chaelin Lee ,&nbsp;Yonghee Jung ,&nbsp;Ju-Hee Kang ,&nbsp;Jungro Lee ,&nbsp;Ran Hui Kim ,&nbsp;Seongwon Yu ,&nbsp;Seung Hyun Oh ,&nbsp;Munhyung Bae ,&nbsp;Inmoo Rhee ,&nbsp;Seung-Yong Seo","doi":"10.1016/j.bioorg.2026.109605","DOIUrl":"10.1016/j.bioorg.2026.109605","url":null,"abstract":"<div><div>Homoisoflavonoids, a unique subclass of flavonoids with an additional C3 carbon, exhibit diverse pharmacological activities. Herein, we report the first total synthesis and stereochemical elucidation of liriopeins A–D, naturally occurring homoisoflavonoids bearing methyl substituents on their A ring. Using regioselective aromatic halogenation and late-stage Suzuki–Miyaura methylation, we achieved straightforward access to the four compounds and resolved their enantiomers by chiral-phase HPLC. The absolute configuration of the natural liriopeins was unambiguously determined to be the (<em>R</em>)-form, representing the first structural confirmation of these natural products. In contrast, the synthetic (<em>S</em>)-enantiomer of liriopein C exhibited the markedly stronger cytotoxicity against non-small-cell lung cancer cells, with sub-micromolar IC₅₀ values. Mechanistic studies revealed the induction of apoptosis, as confirmed by Annexin V/7-AAD staining and poly (ADP-ribose) polymerase cleavage. In addition to its direct cytotoxicity, liriopein C treatment enhanced macrophage-mediated tumor cell clearance in vivo, significantly increasing the uptake of cancer cells by F4/80⁺CD11b⁺ peritoneal macrophages. These findings demonstrate that liriopeins possess dual antitumor and immunomodulatory activity, highlighting their potential as natural product-inspired leads for cancer immunochemotherapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109605"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136942","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":"Advances in mechanisms, combined therapeutic strategies and dual-target inhibitors for synergistic antitumor effects of HDAC and PD-1/PD-L1 pathway","authors":"Zhan-Hui Jin ,&nbsp;Jun-Jie Xu ,&nbsp;Jin-Ying Liu ,&nbsp;Ya-Lan Wang ,&nbsp;Hui Liu ,&nbsp;Yu-Qing Zhao ,&nbsp;Yamei Li ,&nbsp;Xiaoting Li ,&nbsp;Qing-Kun Shen","doi":"10.1016/j.bioorg.2026.109541","DOIUrl":"10.1016/j.bioorg.2026.109541","url":null,"abstract":"<div><div>Histone deacetylase (HDAC) inhibitors exert anti-tumor effects by modulating epigenetic states, cell cycle progression, and immune responses. This includes reactivating tumor suppressor genes, interfering with DNA damage repair processes, and enhancing anti-tumor immune responses. Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors function by blocking the interaction between PD-1 and its ligand PD-L1, thereby restoring and augmenting T cell-mediated anti-tumor immunity. Studies have demonstrated that HDAC inhibitors can upregulate PD-L1 expression, potentially enhancing the efficacy of immune checkpoint inhibitors and improving therapeutic outcomes by modulating the tumor microenvironment. This review article systematically explores the mechanisms of interaction between HDAC and PD-1/PD-L1 in cancer therapy; recent advances in combination treatment strategies; and the current landscape of dual-target inhibitors from a drug design perspective. It provides a detailed discussion on the challenges and future directions associated with the combined application of HDAC inhibition and cancer immunotherapy, as well as the development of dual-function small molecules.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109541"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136925","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":"Strategic engineering of imidazopyridine-benzoxazole hybrids targeting microtubule dynamics: comprehensive inhibition of the metastatic cascade","authors":"Burak Kuzu ,&nbsp;Mustafa Cakir ,&nbsp;Eda Acikgoz","doi":"10.1016/j.bioorg.2026.109615","DOIUrl":"10.1016/j.bioorg.2026.109615","url":null,"abstract":"<div><div>A series of twenty novel imidazopyridine–benzoxazole hybrid (<strong>Imp1–20</strong>) derivatives was designed and synthesized, and their antiproliferative activities were evaluated against MDA-MB-231 breast and DLD-1 colorectal cancer cell lines. Among them, <strong>Imp-18</strong> and <strong>Imp-20</strong> emerged as the most potent candidates, with low micromolar to nanomolar IC₅₀ values and significant reductions in cancer cell adhesion and colony formation. Flow cytometry analyses demonstrated that both compounds induced apoptosis and promoted cell-cycle arrest, reflected by Sub-G1 accumulation and perturbations in G1/G0 and G2/M phases. Immunofluorescence imaging of β-tubulin confirmed that <strong>Imp-18</strong> and <strong>Imp-20</strong> compromise microtubule integrity, with <strong>Imp-18</strong> displaying stronger tubulin-disrupting activity than nocodazole. The resulting microtubule destabilization was consistent with mitotic arrest and activation of apoptotic signaling pathways. Additionally, both compounds markedly inhibited cancer cell migration, indicating an ability to impair metastatic behavior. Overall, these findings identify <strong>Imp-18</strong> and <strong>Imp-20</strong> as promising microtubule-targeting agents with robust anticancer potential, providing a strong basis for further mechanistic studies and structural optimization within the framework of medicinal and bioorganic chemistry.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109615"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136928","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":"An immunomodulatory ochratoxin analogue from marine Aspergillus sp. potentiates macrophage defense against Edwardsiella tarda via AIFM1-mediated necroptosis inhibition","authors":"Yan-Jun Liu ,&nbsp;Kai-feng Chen ,&nbsp;Ran Wang ,&nbsp;Jing Yu ,&nbsp;Zi-long Chen ,&nbsp;Guan-Jun Yang ,&nbsp;Li-Jian Ding ,&nbsp;Jiong Chen","doi":"10.1016/j.bioorg.2026.109610","DOIUrl":"10.1016/j.bioorg.2026.109610","url":null,"abstract":"<div><div><em>Edwardsiella tarda</em> is an intracellular pathogen capable of surviving within macrophages, evading immune surveillance, and inducing apoptosis and necrosis, leading to systemic infections in both aquatic animals and humans. Unlike traditional ochratoxins—mycotoxins known for nephrotoxic, hepatotoxic, and immunotoxic effects—we identified a novel hydroxy-containing ochratoxin derivative, ochratoxin E (<strong>1</strong>), along with three known ochratoxins (<strong>2</strong>–<strong>4</strong>), from the marine fungus <em>Aspergillus</em> sp. NBU1109. The structure and absolute configuration of compound <strong>1</strong> were elucidated using HRESIMS, NMR, ECD calculations, and single-crystal X-ray diffraction. Crucially, compound <strong>1</strong> showed no cytotoxicity in human LX-2 or murine RAW 264.7 cells, in contrast to the toxic effects of compounds <strong>2</strong>–<strong>4</strong>. Functionally, compound <strong>1</strong> enhanced macrophage phagocytosis and bactericidal activity agains<em>t E. tarda</em>, and suppressed apoptosis and necrosis. Mechanistically, drug-affinity responsive target stability (DARTS), molecular docking, and cellular thermal shift assays (CETSA) confirmed that compound <strong>1</strong> directly binds AIFM1. This interaction blocked the AIFM1–RIP3 association, reduced RIP3 nuclear translocation, and inhibited apoptotic–necroptotic signaling. These results delineate a unique, non-toxic ochratoxin derivative that targets the AIFM1/RIP3 axis to bolster macrophage defense, highlighting its promise as a lead compound for anti-<em>E. tarda</em> therapy development.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109610"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140508","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":"Unlocking the catalytic potential of transaminase: A two-decade evolution toward green and scalable biocatalysis","authors":"Priyanka Mundhe ,&nbsp;Pooja Sahu ,&nbsp;Anitta Martin,&nbsp;P. Madhumitha,&nbsp;Meenu Kumari,&nbsp;Priyanka Bajaj","doi":"10.1016/j.bioorg.2026.109545","DOIUrl":"10.1016/j.bioorg.2026.109545","url":null,"abstract":"<div><div>Over the past two decades, transaminases or aminotransferases have been involved in the chemoenzymatic synthesis of active pharmaceutical ingredients by highly efficient and straightforward catalysis of prochiral ketones to chiral amines. These enzymes are promising targets used in the pharmaceutical sector since they are relatively easy to clone and express from a variety of bacteria and other species, where they play key catalytic roles in amino acid metabolic pathways. Also, their high thermal and solvent stability makes them very suitable candidates for use in industry. These enzymes are selected based on their substrate specificity and catalytic efficiency, and are further evolved into industrial enzymes using protein engineering and enzyme recyclability methods. Their key catalytic role in APIs and pharmaceutical-relevant molecules synthesis involves asymmetric synthesis, kinetic resolution, and deracemization. Although these enzymes are now regularly used in industry for the synthesis of Sitagliptin, Mexiletine, Dolutegravir, etc., there is still scope for improvement involving challenges such as equilibrium thermodynamics, co-product removal, limited substrate tolerance, and scope. This review focuses on the detailed use of these enzymes in the pharmaceutical industry over the past 20 years and comprehensive approaches encompassing protein and equilibrium engineering, immobilization, continuous-flow biocatalysis, smart donors, and multi-enzymatic cascades, which have been and are being used for their evolution into the pharmaceutical industry.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109545"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130410","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":"Investigating the epigenetic modulating potential of gallic acid during ethanol-induced toxicity: In silico and in vitro approaches","authors":"Rubin Nishanth Armstrong ,&nbsp;Krithika Narayanan ,&nbsp;Maheshvare Natesan ,&nbsp;Suresh Senthilkumar ,&nbsp;Shalini Rajakumar ,&nbsp;Sakthi Sree Karthikeyan ,&nbsp;Yamunarani Alagudurai ,&nbsp;Devipriya Nagarajan ,&nbsp;Rekha Arcot ,&nbsp;Naiyf S. Alharbi ,&nbsp;Muthu Thiruvengadam","doi":"10.1016/j.bioorg.2026.109576","DOIUrl":"10.1016/j.bioorg.2026.109576","url":null,"abstract":"<div><div>Alcohol-related disorders contribute significantly to morbidity, mortality, and economic burdens worldwide. Excessive alcohol consumption affects almost all organs, particularly liver, intestine, and kidney, by generating excessive free radicals during metabolism, which disrupts cellular epigenetic homeostasis and contributes to the disease onset. One of the effective therapeutic strategy for alcohol-induced toxicity involves the use of immunosuppressants and corticosteroids, but with numerous side effects. The exploration of cost-effective, low-toxicity natural products for alcohol-associated liver disease is of growing interest. Moreover, the mechanistic relationship between oxidative stress-induced epigenetic dysregulation and ethanol-induced toxicity remains unexplored. Based on the above concepts, we investigated the effect of gallic acid (GA), a phytochemical known for its potent antioxidant activity against ethanol-induced hepatotoxicity. WRL 68 cells were treated with ethanol and GA under two different conditions: acute (24 h) and chronic (14 d). GA (30 μM) protected cells from oxidative stress by maintaining the levels of SOD, CAT, GSH, and TBARS in the ethanol-treated group. Under acute exposure to ethanol, GA significantly downregulated miR_21_5p, miR_17_5p, HAT, and HDM, and upregulated miR_199a_5p, miR_129_5p, miR_26b_5p, HDACs, and HMTs expression. GA preserved DNA integrity and prevented the cells from undergoing apoptosis by suppressing the expression of apoptotic genes (<em>Cas 3, Cas 9</em>, and <em>Bax</em>). During chronic exposure to ethanol, GA restored cellular homeostasis by maintaining the epigenetic balance of the cells and attenuated EMT progression in WRL 68 cells. Based on our findings, we suggest that GA can act as an antioxidant and protect cells from epigenetic dyshomeostasis during ethanol exposure. However, extensive analyses, such as protein expression profiling and ChIP assays, are required to understand the mechanistic insights of GA in maintaining the epigenetic balance of cells under ethanol toxicity.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109576"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136939","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":"Integrative computational and experimental approaches to Hydnocarpus wightianus phytochemicals: Targeting breast Cancer through systems biology, molecular dynamics simulations, and in vitro validation in MDA-MB-231 cells","authors":"Nachammai Kathiresan ,&nbsp;Prajisha Jayaprakash ,&nbsp;Ponnuchamy Kumar ,&nbsp;Kulanthaivel Langeswaran","doi":"10.1016/j.bioorg.2026.109621","DOIUrl":"10.1016/j.bioorg.2026.109621","url":null,"abstract":"<div><div>Breast cancer causes a huge burden on healthcare systems, and it is crucial to identify new drugs from nature sources with better efficacy and safety profile. By employing an integrated computational and experimental strategy, the current study focuses on discovering phytochemicals from <em>Hydnocarpus wightianus</em> as anti-breast cancer agents, with the major concern of mechanistic understanding and molecular stability. Initially, <em>H. wightianus</em> phytochemicals were subjected to drug-likeness screening and their possible molecular targets were predicted using SwissTargetPrediction. Breast cancer associated genes were collected from GeneCards and OMIM databases. Compound–target and protein–protein interaction networks were constructed and analyzed using Cytoscape, CytoHubba, and MCODE to find out the important hub genes and functional modules. Further, Gene Ontology and KEGG pathway enrichment analyses were performed to confirm the biological relevance. Identified potential genes were docked and top leads were analyzed using ADMET profiling, and molecular dynamics simulations. Molecular Electrostatic Potential mapping and Density Functional Theory calculations were employed to reveal the electronic distribution and chemical reactivity of the predominant <em>H. wightianus</em> compound. MDA-MB-231 breast cancer cells were used for experimental validation. <em>In vitro</em> studies showed that cell death caused by the drug increased in relation to its concentration, mitochondria lost their potential, and cells were undergoing apoptotic ones as confirmed by Rhodamine 123, Hoechst, and AO/EtBr staining. The combination of network pharmacology, molecular dynamics, and DFT-based electronic analysis, along with experimental validation, ranks <em>H. wightianus</em> bioactive compounds as promising therapeutic candidates for future preclinical and clinical trials in the fight against breast cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109621"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155577","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":"Tracking ferroptosis in stroke models via an ESIPT-based near-infrared fluorescent probe for real-time monitoring of mitochondrial GSH dynamics","authors":"Weibo Wang ,&nbsp;Yichen Xu ,&nbsp;Yingying Lu ,&nbsp;Jiao Zhao ,&nbsp;Pengcheng Wang","doi":"10.1016/j.bioorg.2026.109597","DOIUrl":"10.1016/j.bioorg.2026.109597","url":null,"abstract":"<div><div>Ischemic stroke arises from vascular occlusion that triggers oxygen-glucose deprivation in neurons and glial cells, subsequently leading to metabolic collapse, excitotoxicity, and ultimately neuronal dysfunction and cell death. Ferroptosis, a form of regulated cell death characterized by iron accumulation and excess reactive oxygen species (ROS), is a key process in the pathological progression of ischemic stroke. Yet, current approaches for the investigation and treatment of ferroptosis in ischemia are limited by sensitivity of detection, spatial resolution to examine affected cells and tissues, and capacity for real-time monitoring. To address such challenges, we have developed a novel mitochondria-targeted fluorescent probe, <strong>XZTU-red-GSH</strong>, based on an excited-state intramolecular proton transfer (ESIPT) mechanism, such that the probe exhibits prominent, near-infrared emission at 720 nm and a large stokes shift of 315 nm, markedly enhancing fluorescence sensitivity and signal-to-noise ratio. Structurally, <strong>XZTU-red-GSH</strong> incorporates an <em>N</em>-methylpyridinium moiety for mitochondria targeting <em>via</em> electrostatic interactions, a 2,4-dinitrobenzenesulfonyl group as a selective response unit for glutathione (GSH), and a triethylene glycol monomethyl ether fragment to optimize the lipophilicity-hydrophilicity balance for optimizing blood-brain barrier permeability. In both oxygen-glucose deprivation/reperfusion (OGD/R) cellular models and middle cerebral artery occlusion (MCAO) animal models, the probe enabled <em>in situ</em> visualization of dynamic mitochondrial glutathione (mGSH) depletion during ferroptosis. Furthermore, our experiments with this probe demonstrated that the ferroptosis inhibitor Ferrostatin-1 (Fer-1) mitigates neuronal injury by preserving mGSH homeostasis. Taken together, our results indicate that <strong>XZTU-red-GSH</strong> is a novel tool to explore the dynamic features ferroptosis and ischemic stroke</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109597"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123035","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 elfamycin-class inhibitors combating carbapenem-resistant Acinetobacter baumannii from the Antarctic-derived Streptomyces sp. A3-7","authors":"Yueting Zhang ,&nbsp;Jie Shan ,&nbsp;Junjie Liu ,&nbsp;Nengfei Wang ,&nbsp;Seoung Rak Lee ,&nbsp;Huayue Li","doi":"10.1016/j.bioorg.2026.109606","DOIUrl":"10.1016/j.bioorg.2026.109606","url":null,"abstract":"<div><div>Carbapenem-resistant <em>Acinetobacter baumannii</em> (CRAB) poses a critical global health threat. An activity-guided screen of eight Antarctic <em>Streptomyces</em> strains identified the active isolate <em>Streptomyces</em> sp. A3-7, from which four new elfamycin-class polyketides (<strong>1</strong>–<strong>4</strong>) and one known analogue (<strong>5</strong>) were obtained. The structures of these compounds were elucidated through extensive MS and NMR spectroscopic analysis, and their biosynthesis is directed by the <em>krn</em> gene cluster. Anti-CRAB evaluation revealed that <strong>5</strong> was the most potent, with an MIC of 0.4 μg/mL, whereas <strong>1</strong> was inactive up to 50 μg/mL, indicating that the tetrahydrofuran ring in the kirromycin-type scaffold (<strong>1</strong>) significantly reduces anti-<em>A. baumannii</em> activity, whereas the linear “open” ethylene glycol scaffold of the kirrothricin-type analogues (<strong>2</strong>–<strong>5</strong>) provides a more effective antibacterial framework. A gradual decrease in potency was observed for <strong>2</strong>–<strong>4</strong> (MICs 1.6–12.5 μg/mL), suggesting the pyridone ring is a key functional group for activity within the kirrothricin series. Notably, all compounds demonstrated low cytotoxicity toward normal hepatocytes AC2F (CC₅₀ &gt; 20 μM). This promising safety profile, combined with their potent activity, highlights the potential of kirrothricin-type compounds as promising drug candidates for combating CRAB.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109606"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163216","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}