Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Design, synthesis, antifungal activity, and molecular docking studies of benzothiazole, S-benzyl-2,4-isodithiobiuret, and thiourea derivatives of 1-hepta-O-benzoyl-β-d-maltose nanoparticles","authors":"Shankesh C. Zyate ,&nbsp;Nikita V. Awajare ,&nbsp;Sanjay S. Gaikwad ,&nbsp;Kunal Raut ,&nbsp;Vikas Jha ,&nbsp;Amardeep R. Jadhao ,&nbsp;Poonam T. Agrawal","doi":"10.1016/j.bmcl.2025.130499","DOIUrl":"10.1016/j.bmcl.2025.130499","url":null,"abstract":"<div><div>The surge in fungal infection-related mortality worldwide is being caused by drug resistance to well-established antifungals such azole derivatives (bifonazole, fluconazole, miconazole, and clotrimazole). Finding novel molecules that are structurally different to these could be a useful tactic to get over medication resistance that is currently on the market. In an effort to develop highly potent non-resistance antifungal agents, we reported a series of compounds with benzothiazole, S-benzyl-2,4-isodithiobiuret and thiourea derivatives of 1-hepta-O-benzoyl-β-<span>d</span>-maltose NPs and their antifungal activity against the most infectious fungal strain <em>Candida albicans</em>. Numerous analogues among the synthesized compounds have shown potent antifungal activity. All the synthesized compounds were tested in vitro for determining their anticandidal activity. Almost all the compounds were found to be highly potent than established antifungal drugs (MIC ¼ 0.25–0.125 mg mL⁻¹) against <em>Candida albicans</em> strain. An in silico molecular docking study was also performed to comprehend the mode of action of the active compounds towards prospective target 1EA1 binding protein.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130499"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712700","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 evaluation of novel oxanthrene scaffold-derived oxazolidinone antibiotics with potent antitubercular activity and low cellular toxicity","authors":"Kelsey R. Latterell ,&nbsp;Evan Keil ,&nbsp;Benjamin R. Kraemer ,&nbsp;Joe B. Huisken ,&nbsp;Ben A. Thomas ,&nbsp;Noah Daniels ,&nbsp;Amit Kaushik ,&nbsp;Maria Lillian Olson ,&nbsp;Pamela Meléndez Noriega ,&nbsp;Maria Alejandra Pizarro Daniels ,&nbsp;Daron E. Janzen ,&nbsp;Gyanu Lamichhane ,&nbsp;Monica Campo ,&nbsp;J. Thomas Ippoliti","doi":"10.1016/j.bmcl.2025.130505","DOIUrl":"10.1016/j.bmcl.2025.130505","url":null,"abstract":"<div><div>Oxazolidinones are a class of antibiotics used to treat bacterial infections in humans and are a component of the treatment regimen for multidrug-resistant tuberculosis. However, current clinically used examples of the class display poor safety profiles, and improved, next-generation drugs are urgently needed. Here we report the synthesis of two novel oxazolidinones: T504 and its regioisomer T542. Alongside the previously reported compound T145, we evaluate their inhibitory activity against the causative agent of tuberculosis, <em>Mycobacterium tuberculosis</em>. We also explore their antimycobacterial activity in a human monocyte-derived macrophage model of infection. Both T145 and T504 demonstrate potent activity and low cellular toxicity in human macrophages. The investigation reveals vast discrepancies in activities between the two regioisomers (T504 and T542), offering insights into the structure-activity relationship of substitutions on the oxanthrene scaffold.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130505"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761787","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 and optimization of 2,3-Dihydroindole derivatives as STING receptor allosteric agonists","authors":"Ying Liu ,&nbsp;Jing Wu ,&nbsp;Ni Gao ,&nbsp;Lin Zheng ,&nbsp;Wenbo Zhang ,&nbsp;Fabao Zhao ,&nbsp;Bairu Meng ,&nbsp;Xinyong Liu ,&nbsp;Lanyu Liu ,&nbsp;Huajun Zhao ,&nbsp;Dongwei Kang","doi":"10.1016/j.bmcl.2025.130508","DOIUrl":"10.1016/j.bmcl.2025.130508","url":null,"abstract":"<div><div>STING allosteric agonists targeting the cryptic pocket in the transmembrane domain (TMD) could overcome the limitations of membrane permeability and oligomerization instability that are inherent to conventional cGAMP mimetics. Although compounds such as C53 and NVS-STG2 have been reported as TMD-targeting agonists, their therapeutic potential is restricted by insufficient potency. In this work, compound <strong>LA24</strong> was identified as a novel potent STING allosteric agonist through structure-based multilevel virtual screening combined with rational optimization. It exhibited an EC₅₀ value of 0.82 μM, being superior to that of the reference C53 (EC₅₀ = 2.80 μM). Molecular modeling studies revealed that <strong>LA24</strong> exhibited enhanced STING agonistic activity by forming hydrogen bonds with key transmembrane domain residues G114 and Y106, as well as π–π stacking interactions with H50. These findings suggested that <strong>LA24</strong> holds promise as a novel lead compound for the development of STING-targeted immunomodulatory therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130508"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145779668","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 novel imidazo[4,5-b]pyridine derivatives as noncovalent reversible Bruton’s tyrosine kinase inhibitors","authors":"Yeojeong Kim ,&nbsp;Jingyang Sun ,&nbsp;Kyoungyim Lee ,&nbsp;Soobin Kim ,&nbsp;Danbi Lee ,&nbsp;Bomi Park ,&nbsp;Yeji Lee ,&nbsp;Inah Hwang ,&nbsp;Jae-Sang Ryu","doi":"10.1016/j.bmcl.2025.130497","DOIUrl":"10.1016/j.bmcl.2025.130497","url":null,"abstract":"<div><div>Bruton's tyrosine kinase (BTK) has emerged as a validated therapeutic target for B-cell malignancies and autoimmune disorders, and covalent BTK inhibitors have demonstrated remarkable clinical efficacy. However, because of concerns regarding their off-target effects and safety profiles, there is research interest in developing noncovalent, reversible inhibitors. Herein, we report the design, synthesis, and biochemical evaluation of novel imidazo[4,5-<em>b</em>]pyridine derivatives as noncovalent BTK inhibitors. Through a concise three-step synthetic route, we prepared 16 structurally diverse analogs (<strong>6a</strong>–<strong>p</strong>) bearing various substituents on the imidazole scaffold. The results of biochemical evaluation showed that <strong>6b</strong>, <strong>6o</strong>, and <strong>6p</strong> are the most potent inhibitors, with IC₅₀ values of 1.14, 1.54, and 2.46 μM, respectively. The results of structure–activity relationship studies revealed that 2,4-dihydroxyphenyl substitution on the A-ring and extended functionalities (morpholinomethyl or 4-acetamido group) on the B-ring significantly enhanced the inhibition of BTK. The results of molecular docking studies elucidated key binding interactions and showed that the hydroxyl groups form hydrogen bonds with the Thr474 gatekeeper residue and the Met477 hinge region residue, whereas B-ring substituents extend toward the DFG motif. The preliminary kinase selectivity profiling of <strong>6b</strong> against 39 kinases demonstrated promising selectivity, with significant inhibition observed primarily for BTK and c-Src. Although these compounds show moderate potency compared with clinically approved BTK inhibitors, their noncovalent, reversible nature offers potential advantages with regard to selectivity, toxicity, and pharmacological effects. Moreover, these compounds represent valuable starting points for further optimization toward developing novel therapeutics for B-cell malignancies and autoimmune disorders with potentially improved safety profiles for long-term treatment.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130497"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699419","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":"Iridium and rhenium complexes in photodynamic and sonodynamic therapy: mechanistic insights and therapeutic potential","authors":"Sreejani Ghosh ,&nbsp;Rinku Chakrabarty ,&nbsp;Priyankar Paira","doi":"10.1016/j.bmcl.2025.130479","DOIUrl":"10.1016/j.bmcl.2025.130479","url":null,"abstract":"<div><div>Cancer maintains to be a major worldwide health epidemic, and despite breakthroughs in targeted agents, immunotherapy, chemotherapy, and surgery, considerable limitations persist. These comprise therapeutic resistance, dose-limiting toxicities, late diagnosis, and microenvironmental barriers, including hypoxia and poor perfusion. The spatiotemporally regulated, locally activated cytotoxicity that photodynamic therapy (PDT) and sonodynamic therapy (SDT) provide has made them appealing substitutes. They may also be used in conjunction with immunotherapy and imaging. SDT uses ultrasound to allow for deeper penetration and partial oxygen independence, whereas PDT uses light to activate photosensitisers. Both approaches produce radical intermediates and reactive oxygen species (ROS), which harm vital biomolecules and activate several pathways leading to programmed cell death, hence decreasing the probability of resistance. However, SDT necessitates the optimisation of acoustic parameters and verified clinical protocols, while PDT is limited by oxygen reliance and poor light penetration. Transition metal complexes, especially those of iridium (III) and rhenium (I), offer special benefits for PDT and SDT because of their intrinsic luminescence, effective triplet-state creation, high spin–orbit coupling, and variable photophysical characteristics. Their translational potential is being advanced by rational design tactics such as theranostic pairing, red/NIR and two-photon activation, nanocarrier integration, and Type I biasing for hypoxia tolerance. With continuous attempts to standardise dosimetry and sensitiser design, SDT is still in the early phases of evaluation, whereas PDT is clinically established. This study highlights Ir and Re complexes as adaptable next-generation sensitisers that could broaden the therapeutic reach of externally activated cancer medicines by synthesising molecular insights, representative chemical classes, and translational obstacles.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130479"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627295","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":"Design, synthesis, and antibacterial activity evaluation of tryptanthrin derivatives","authors":"Bing-Yuan Yan ,&nbsp;Ran-Qi Feng ,&nbsp;Chen Qu ,&nbsp;Xu-Wen Li","doi":"10.1016/j.bmcl.2025.130503","DOIUrl":"10.1016/j.bmcl.2025.130503","url":null,"abstract":"<div><div>A series of tryptanthrin derivatives were designed, synthesized and evaluated for their antibacterial activity against the marine pathogen <em>Vibrio parahaemolyticus</em>. The bioactivity assessment revealed that compounds <strong>7h</strong> and <strong>8c</strong> exhibited potent antibacterial effects against <em>V. parahaemolyticus</em> without cytotoxicity toward mammalian cells. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents on the phenyl ring played a crucial role in enhancing antibacterial activity. Furthermore, compounds <strong>7h</strong> and <strong>8c</strong> demonstrated strong antibiofilm activity at concentrations of 8 μg/mL and 6 μg/mL, respectively, effectively inhibiting both biofilm formation and maturation in <em>V. parahaemolyticus.</em> These results demonstrate that compounds <strong>7h</strong> and <strong>8c</strong> exhibited efficacy against drug-resistant <em>Vibrio</em> strains, providing insight into the application of tryptanthrin derivatives as potential antibacterial agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130503"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740264","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":"Multifaceted roles of HDAC7 in disease and the evolving chemical toolkit for its modulation","authors":"Wenwen Nie ,&nbsp;Baoli Ding ,&nbsp;Xiaotong Chen ,&nbsp;Li Jiang ,&nbsp;Qiaojun He ,&nbsp;Ji Cao ,&nbsp;Cheng-Liang Zhu","doi":"10.1016/j.bmcl.2025.130510","DOIUrl":"10.1016/j.bmcl.2025.130510","url":null,"abstract":"<div><div>Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs catalytically inefficient and underscores their versatile roles beyond intrinsic deacetylation. Structurally, HDAC7 is distinguished from its paralogs by its lack of the conserved N-terminal glutamine-rich domain. This combination of functional duality and a unique structural context enables HDAC7 to regulate a vast array of cellular processes. Consequently, its dysregulation is implicated in numerous pathologies, including cancer and autoimmune disorders, establishing it as a compelling therapeutic target. However, effectively and selectively targeting HDAC7 is complicated by its context-dependent biological modes of actions and the high structural homology it shares with other class IIa isoforms. This review first provides a current overview of the multifaceted roles of HDAC7 in human diseases and discusses how its contributions are dictated by the complex interplay between its catalytic and diverse scaffolding functions. We then summarize the recent medicinal chemistry efforts, from the class-selective deacetylase inhibitors to the recently emerged targeted protein degraders that not only achieve superior isoform selectivity but also modulate HDAC7's deacetylase-independent functions. By bridging the functional complexity of HDAC7 with the latest advances in chemical biology tools, we aim to provide a timely summary of the current status of HDAC7 as a druggable target and offer a perspective on strategies guiding the development of next-generation modulators.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130510"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797624","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":"Chemiluminescent probes for imaging cysteine cathepsin activity","authors":"Jiyun Zhu ,&nbsp;Sara Gutkin ,&nbsp;Shiyu Chen ,&nbsp;Shih-Po Su ,&nbsp;Hai Phan ,&nbsp;Doron Shabat ,&nbsp;Matthew Bogyo","doi":"10.1016/j.bmcl.2025.130480","DOIUrl":"10.1016/j.bmcl.2025.130480","url":null,"abstract":"<div><div>The cysteine cathepsins are a family of proteases that are widely expressed in diverse cell types. However, because their activity is highly upregulated at sites of inflammation, they are ideal targets for imaging a range of disease pathologies including cancer, atherosclerosis, fibrosis and others. While significant advances have been made in generation of activatable ‘smart’ probes for cathepsin activity, virtually all of these agents use fluorescent reporters which require a laser light source to induce a signal from the probe. We describe here the development and application of chemiluminescent probes for imaging cysteine cathepsin activity in cells and tissues. These probes provide rapid signal generation with low background in cells and tissues without the need for a light source. We demonstrate that a cathepsin probe containing an optimal peptide sequence can be used topically to detect activity in tumor tissues, demonstrating the potential value of this approach for real-time diagnosis of cancer as well as other conditions involving inflammation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130480"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581582","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":"Bicyclic peptide-based CPPTACs for extracellular and cell membrane protein degradation","authors":"Jinyu Bai ,&nbsp;Huaihuai Shi ,&nbsp;Jitun Chen ,&nbsp;Hui Tian ,&nbsp;Jiaxin Liang ,&nbsp;Bichun Chen ,&nbsp;Jiazhong Li ,&nbsp;Lijing Fang","doi":"10.1016/j.bmcl.2025.130496","DOIUrl":"10.1016/j.bmcl.2025.130496","url":null,"abstract":"<div><div>Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130496"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719941","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":"Design, synthesis and biological evaluation of coumarin-based HDAC6 inhibitors for the treatment of ulcerative colitis","authors":"Xiang Qiu ,&nbsp;Lingling Dong ,&nbsp;Hongzhen Shu ,&nbsp;Guangxing Yu ,&nbsp;Yuling Tong ,&nbsp;Hengfan Ni ,&nbsp;Shunjie Zhang","doi":"10.1016/j.bmcl.2025.130500","DOIUrl":"10.1016/j.bmcl.2025.130500","url":null,"abstract":"<div><div>Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound <strong>24</strong> emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC₅₀ value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound <strong>24</strong> efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC₅₀ value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound <strong>24</strong> effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound <strong>24</strong> was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130500"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740259","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}