Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"In vitro anti-influenza potential of glyceroglycolipids from cyanobacteria Limnospira fusiformis","authors":"Suresh Chandra V.A.R. Annam ,&nbsp;Ahmed Elbermawi ,&nbsp;Jungmoo Huh ,&nbsp;Jin Zhang ,&nbsp;Zulfiqar Ali ,&nbsp;Ikhlas A. Khan ,&nbsp;Nirmal D. Pugh ,&nbsp;Amar G. Chittiboyina","doi":"10.1016/j.bmcl.2025.130358","DOIUrl":"10.1016/j.bmcl.2025.130358","url":null,"abstract":"<div><div>Previously, a chemical standardization method quantifying six fatty acids was established for <em>Limnospira</em> (formerly <em>Arthrospira</em>) authenticity and quality control. Since glyceroglycolipids constitute a significant source of fatty acids in <em>Limnospira</em>, a targeted phytochemical investigation was performed that resulted in the identification of two novel diacylated glycerol sulfoquinvosides and four known compounds. Notably, <em>in vitro</em> anti-influenza activity of isolated and analogous glyceroglycolipids, specifically two glyceroglycolipids, incorporating γ-linolenic acid and sulfoquinvose units tethered to a glycerol backbone, exhibited the highest anti-influenza activity. These findings suggest that the glyceroglycolipid-enriched fraction from <em>Limnospira</em> holds the potential for direct-acting antiviral properties.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130358"},"PeriodicalIF":2.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774420","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 of a peripherally biased NPSR1 antagonist for neuropeptide S induced inflammation","authors":"Kathleen J. Berger ,&nbsp;Kévin Leguay ,&nbsp;Francois Moreau ,&nbsp;Benny Chan ,&nbsp;Giovanni Martino ,&nbsp;Erica Cho ,&nbsp;Nils Nordstrom ,&nbsp;Sharon Sun ,&nbsp;Elizabeth Franks ,&nbsp;Melissa Kirk ,&nbsp;Joseph Mancini ,&nbsp;Janek Szychowski ,&nbsp;Oliver A. Kent","doi":"10.1016/j.bmcl.2025.130353","DOIUrl":"10.1016/j.bmcl.2025.130353","url":null,"abstract":"<div><div>Neuropeptide S (NPS) is a potent agonist for the GPCR receptor NPSR1, implicated in various physiological and pathological processes, including inflammation. <em>NPSR1</em> gene polymorphisms have been linked to asthma, inflammatory bowel disease, and endometriosis. Activation of NPSR1 triggers signaling through Gαq and Gαs leading to activation of calcium and cAMP respectively, which induces the expression of pro-inflammatory cytokines. Given NPSR1 is widely expressed in the brain and modulates behavioral responses, the development of a non-brain-penetrant NPSR1 antagonist with favorable pharmacokinetics would represent a significant advancement. While promising NPSR1 antagonists like SHA-68R and NPSR-QA1 exist, suboptimal ADME profiles and/or brain penetrance limit pharmacological evaluation of NPSR1 peripheral inhibition. In the present study, a structure-activity relationship analysis of NPSR-QA1 led to the identification of two potent, peripherally restricted NPSR1 antagonists with favorable pharmacokinetic properties. NPSR-QA1 derivatives were screened for NPSR1 antagonism in cell-based calcium and cAMP signaling assays. Two lead compounds were identified that demonstrated sub-nanomolar potency, high solubility, decent unbound clearance, and low brain penetration in mice. In vitro assays using human fibroblasts with enforced expression of <em>NPSR1</em> established that NPS triggered expression of pro-inflammatory markers <em>IL-6</em>, <em>PTGS2</em>, <em>IL-20</em>, and <em>CXCL8</em>, all of which were effectively inhibited by the lead compounds. Further, murine studies with zymosan-induced inflammation showed that NPSR1 antagonism significantly increased resident macrophages in the peritoneum and reduced TNF-α cytokine levels. These findings highlight the potential of NPSR1 antagonism to block inflammation without CNS side effects, advancing the development of NPSR1 antagonists as therapeutic agents for peripheral inflammation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130353"},"PeriodicalIF":2.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768169","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":"Optimization of IRAK1/4/pan-FLT3 kinase inhibitors as treatments for acute myeloid leukemia","authors":"Patrick J. Sutter ,&nbsp;Morgan M. Walker ,&nbsp;Chris J. Finocchio ,&nbsp;Jian-Kang Jiang ,&nbsp;Gregory J. Tawa ,&nbsp;Xiaohu Zhang ,&nbsp;Xin Xu ,&nbsp;Pranav Shah ,&nbsp;Glenn Y. Gomba ,&nbsp;Daniel T. Starczynowski ,&nbsp;Craig J. Thomas ,&nbsp;Scott Hoyt","doi":"10.1016/j.bmcl.2025.130355","DOIUrl":"10.1016/j.bmcl.2025.130355","url":null,"abstract":"<div><div>FLT3 kinase inhibitors have been advanced to the clinic as targeted treatments for acute myeloid leukemia (AML). These inhibitors can produce promising initial responses, but patients often relapse with treatment-resistant disease. A significant factor contributing to relapse involves adaptive signaling through an alternative pathway mediated by IRAK1 and IRAK4 kinases. Compounds that inhibit IRAK1/4 and FLT3 may thus provide superior efficacy relative to compounds that inhibit FLT3 only. We report the optimization of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization efforts have produced key compound <strong>31</strong>, which displays potent inhibition of IRAK1, IRAK4, and FLT3, potent activity in multiple AML tumor cell viability assays, and efficacy superior to that of approved FLT3 inhibitors in multiple mouse xenograft models of AML.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130355"},"PeriodicalIF":2.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774421","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":"Scaffold-leaping optimization of naphthoquinone derivatives as ferroptosis inducer against non-small lung cancer","authors":"Hua Yang ,&nbsp;Xiaoya Wu ,&nbsp;Mengyu Li,&nbsp;Yinuo Wang,&nbsp;Mingmei Guo,&nbsp;Liping Chen,&nbsp;Ruili Ma,&nbsp;Moran Sun","doi":"10.1016/j.bmcl.2025.130360","DOIUrl":"10.1016/j.bmcl.2025.130360","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent programmed cell death pathway, has emerged as a promising therapeutic target for cancer. Herein, a series of naphthoquinone derivatives were designed via scaffold-leaping optimization from lead compound QD394, synthesized and assessed for their anti-proliferation activity against five cancer cell lines, and the structure-activity relationship (SAR) were described. Of these compounds, <strong>I-21</strong> was identified as most active, demonstrating significant anticancer efficacy in vitro (IC₅₀ = 0.76 μM against A549 cell lines). This cytotoxic effect can be counteracted by ferrostatin-1, a ferroptosis inhibitor, indicating that <strong>I-21</strong> may acts as a ferroptosis inducer. Mechanistic studies revealed that <strong>I-21</strong> triggered ferroptosis by depleting glutathione (GSH), elevating reactive oxygen species (ROS) and malondialdehyde (MDA), and downregulating glutathione peroxidase 4(GPX4) expression in A549 cell lines. Furthermore, <strong>I-21</strong> arrested the cell cycle at the G2/M phase and inhibited the migration of A549 cell lines. This study provided the first evidence of naphthoquinone derivatives as ferroptosis inducers, offering a novel leading compound for the non-small cell lung cancer treatment.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130360"},"PeriodicalIF":2.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783123","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 a novel non-toxic analog of clofarabine for the treatment of triple–negative breast cancer","authors":"Omar Moukha-Chafiq,&nbsp;Rebecca Boohaker,&nbsp;Larry D. Bratton,&nbsp;Marina Fosso Yatchang,&nbsp;Anish K. Vadukoot,&nbsp;Sarath Sarngadharan,&nbsp;Corinne Augelli-Szafran","doi":"10.1016/j.bmcl.2025.130349","DOIUrl":"10.1016/j.bmcl.2025.130349","url":null,"abstract":"<div><div>Breast cancer is the second most prevalent cancer in the world. Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer accounts for 15–20 % of all diagnosed breast cancer cases. Chemotherapy is standard of care for TNBC patients with metastatic disease and poly (ADP-ribose) polymerase inhibitors are approved in patients with BRCA1/2 mutations. Despite initial response, clinical resistance rapidly develops, and few options exist as later-line treatments. Therefore, new targeted approaches are urgently needed to treat TNBC. Clofarabine, a purine nucleoside analog developed at Southern Research, is an FDA-approved treatment for relapsed or refractory pediatric acute lymphoblastic leukemia but has lower therapeutic index when tested against TNBC cells <em>in vitro</em> due to its significant cytotoxicity against normal mammary epithelial cells. Our preliminary structure-activity relationship study resulted in the identification of analog <strong>9</strong> with enhanced activity against TNBC cells and improved cytotoxicity. One major advantage of analog <strong>9</strong> is that a pilot dose range finding study demonstrated that this analog elicited no signs of toxicity, whereas clofarabine was not well tolerated.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130349"},"PeriodicalIF":2.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764243","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 the new active ingredient tigolaner, an allosteric modulator of the GABA-gated chloride channel for use as a spot-on ectoparasiticide in animal health","authors":"Anne Décor ,&nbsp;Michael Maue ,&nbsp;Hans-Georg Schwarz ,&nbsp;Ulrich Ebbinghaus-Kintscher ,&nbsp;Klaus Raming ,&nbsp;Andreas Turberg ,&nbsp;Norbert Mencke ,&nbsp;Julia Hahn Neumann ,&nbsp;Reiner Fischer ,&nbsp;Werner Hallenbach ,&nbsp;Johannes Köbberling ,&nbsp;Walter Hübsch ,&nbsp;Thomas Bretschneider ,&nbsp;Kerstin Ilg ,&nbsp;Peter Lösel ,&nbsp;Ulrich Görgens ,&nbsp;Niels Lindner ,&nbsp;Katharina Wölfel ,&nbsp;Martin Adamczewski","doi":"10.1016/j.bmcl.2025.130352","DOIUrl":"10.1016/j.bmcl.2025.130352","url":null,"abstract":"<div><div>Parasiticides play a crucial role in animal health. The need for innovative ectoparasiticides for companion animals has been growing, driven by the risks posed by parasites to both animals and humans. We detail here the discovery pathway of tigolaner, an ectoparasiticide, offering up to 13 weeks protection against fleas and ticks to cats. Felpreva® employs this active ingredient for ectoparasite control together with the endoparasiticides emodepside and praziquantel. It was approved by the European Medicines Agency in November 2021. The discovery of tigolaner resulted from research at Bayer focused on finding novel molecules inhibiting GABA-gated chloride channels (GABA-Cls), with an improved toxicological profile and resistance-breaking potential when compared to dieldrin and fipronil. A high-throughput <em>in vitro</em> screening campaign on GABA-Cls, followed by a “mix-match” synthetic approach, led to the identification of several lead compounds acting as allosteric modulators. The GABA lead class compounds showed a different binding site when compared to fipronil. They have a unique chemotype based on a pyrazole moiety. Further variations of the central ring led to the discovery of tigolaner. Selected structure-activity relationships from the project are presented. Some synthetic pathways for tigolaner and its analogs are also described. This publication also outlines the efficacy of tigolaner against various parasites, making it a key compound of the Felpreva® product.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130352"},"PeriodicalIF":2.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758832","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 anti-HIV-1 Vif inhibitors based on prodrug strategy","authors":"Weilin Wang ,&nbsp;Rui Deng ,&nbsp;Rong-Hua Luo ,&nbsp;Hongjia Zhang ,&nbsp;Dan Luo ,&nbsp;Shirui Wang ,&nbsp;Su Yu ,&nbsp;Xinyu Ma ,&nbsp;Chunlan Pu ,&nbsp;Yuanyuan Liu ,&nbsp;Qing Huang ,&nbsp;Liu-Meng Yang ,&nbsp;Yong-Tang Zheng ,&nbsp;Rui Li","doi":"10.1016/j.bmcl.2025.130351","DOIUrl":"10.1016/j.bmcl.2025.130351","url":null,"abstract":"<div><div>In this work, we describe the design, synthesis, and biological evaluation of a series of novel dual-target prodrugs that simultaneously target HIV-1 viral infection factors (Vif) and reverse transcriptase (RT). Among them, the two most effective compounds, <strong>A1</strong> and <strong>A7</strong>, were found to inhibit HIV-1IIIB at nanomolar concentrations (EC₅₀ = 8.1 nM, EC₅₀ = 9.4 nM) in C8166 cells, which were 95 and 81 times higher than the parent drug <strong>6</strong> <strong>m</strong>, respectively, and 2.7 and 2.3 times higher than that of stavudine (<strong>d4T</strong>). The stability of compound <strong>A1</strong> in the medium suggests that it can effectively release the parent drugs <strong>6</strong> <strong>m</strong> and stavudine with a half-life of 6 h, suggesting that it is a potential dual-target prodrug targeting HIV Vif and reverse transcriptase.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130351"},"PeriodicalIF":2.2,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740769","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 novel isoflavene derivatives with anti-tumour activity","authors":"Valerio Falasca ,&nbsp;Daniel S. Wenholz ,&nbsp;Tsz Tin Yu ,&nbsp;Naresh Kumar","doi":"10.1016/j.bmcl.2025.130350","DOIUrl":"10.1016/j.bmcl.2025.130350","url":null,"abstract":"<div><div>A novel series of isoflavonoid derivatives were generated through click chemistry modifications of the biologically active isoflavene phenoxodiol (PXD). PXD is an effective anticancer and anti-inflammatory agent with estrogen modulating properties which has been evaluated in phase II and III clinical trials. This novel series of analogues was designed to improve PDX's potency and selectivity against estrogen-positive cancers. Although the resulting compounds demonstrated poor estrogen receptor binding affinity, in vitro evaluation nonetheless yielded hit compounds with a 19-fold improvement in anticancer activity compared to PXD (IC₅₀ = 1.5 μM in T-47-D), along with an understanding of the underlying structure activity relationships (SAR).</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130350"},"PeriodicalIF":2.2,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723845","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 anthraquinone-triazene derivatives as novel antitumor agents causing DNA damage","authors":"Zi-Han Jia ,&nbsp;Qing Xu ,&nbsp;Yun-Hao Liu ,&nbsp;Ri-Lei Yu ,&nbsp;Qin Wang ,&nbsp;Ya-Mu Xia ,&nbsp;Wei-Wei Gao","doi":"10.1016/j.bmcl.2025.130347","DOIUrl":"10.1016/j.bmcl.2025.130347","url":null,"abstract":"<div><div>In this study, 40 anthraquinone-triazene derivatives were designed, and <strong>AT-9</strong> and <strong>AT-10</strong> were screened out as potential antitumor candidates based on their strong binding affinities to DNA and topoisomerase II using molecular docking and molecular dynamics simulations. Antiproliferative assays revealed that <strong>AT-9</strong> and <strong>AT-10</strong> exhibited significantly stronger inhibitory effects on A549 and HeLa cell lines compared to the reference mitoxantrone. The binding modes of <strong>AT-9</strong> and <strong>AT-10</strong> with DNA were confirmed by spectra and gel electrophoresis. Metabolic pathway investigations showed that <strong>AT-9</strong> and <strong>AT-10</strong> were susceptible to nucleophilic attack by water molecules, leading to the release of nitrogen and degradation into an anthraquinone-amide compound. Thus, the synergistic antitumor mechanism arises from the DNA intercalation of the anthraquinone ring and the alkylating effect mediated by the triazene moiety. Furthermore, ADME analysis revealed that <strong>AT-9</strong> and <strong>AT-10</strong> possessed favorable drug-likeness and pharmacokinetic properties, indicating strong potential for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130347"},"PeriodicalIF":2.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144712848","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, molecular docking and suppression on NF-κB activity of sinomenine hybrid derivatives","authors":"Jian Tang ,&nbsp;Chunbao Jiang ,&nbsp;Yuling Zhu ,&nbsp;Chongwei Wen ,&nbsp;Xiuquan Xu ,&nbsp;Haiping Xia","doi":"10.1016/j.bmcl.2025.130348","DOIUrl":"10.1016/j.bmcl.2025.130348","url":null,"abstract":"<div><div>Sinomenine possesses potent suppression on the nuclear factor kappa-B (NF-κB) pathway. The phenylpropanoid moiety was introduced into sinomenine for building dual-structure sinomenine hybrid derivatives. The software AutoDock Vina was used to dock the sinomenine hybrid derivatives with 3 key proteins (1VKX, 4KIK and 6YMN) of NF-κB activation, and the virtually screened derivatives were tested via molecular dynamics simulation. Three series of derivatives were synthesized by Heck cross-coupling reaction, and evaluated for their suppressive effects on NF-κB in HEK 293 cells transfected with plasmid pNF-κB-luc. Some 1-acrylate sinomenine derivatives showed more active suppressive effects than the parent sinomenine. Derivatives <strong>1</strong>–<strong>3</strong> of sinomenine series were more active on NF-κB than other three series. Derivative <strong>3</strong> with 1-phenethyl acrylate was the most active one.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130348"},"PeriodicalIF":2.2,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717138","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}