Bioorganic & Medicinal Chemistry Letters最新文献_第5页

An alkaline phosphatase-activatable photosensitizer based on 2-anthrol for selective targeting of cancer cells 一种基于2-人酚的碱性磷酸酶可激活光敏剂，用于选择性靶向癌细胞。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-12 DOI: 10.1016/j.bmcl.2025.130371

Yusha Li, Yuki Masuda, Yuzuha Miyazawa, Daisuke Takahashi, Kazunobu Toshima

引用次数: 0

A virtual screening strategy to repurpose antifolate compounds as W. bancrofti DHFR inhibitors 一个虚拟筛选策略，重新利用抗叶酸化合物作为W. Bancrofti DHFR抑制剂。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-12 DOI: 10.1016/j.bmcl.2025.130370

Salma Kwarteng , Jacquelyn Wilhelm , Merna Salama , Monika Salama , Klarissa Hollander , Karen S. Anderson , Nina M. Goodey , Kathleen M. Frey

{"title":"A virtual screening strategy to repurpose antifolate compounds as W. bancrofti DHFR inhibitors","authors":"Salma Kwarteng , Jacquelyn Wilhelm , Merna Salama , Monika Salama , Klarissa Hollander , Karen S. Anderson , Nina M. Goodey , Kathleen M. Frey","doi":"10.1016/j.bmcl.2025.130370","DOIUrl":"10.1016/j.bmcl.2025.130370","url":null,"abstract":"<div><div>Lymphatic filariasis, caused by <em>Wuchereria bancrofti,</em> remains a global health challenge. The enzyme <em>Wuchereria bancrofti</em> dihydrofolate reductase (WbDHFR) is a potential therapeutic target due to DHFR's critical role in folate metabolism and DNA synthesis. In this study, we employed a virtual screening workflow to repurpose antifolate compounds as WbDHFR inhibitors. Using structural data from the Protein Data Bank, we constructed a library of 194 antifolates and docked them to the WbDHFR folate binding site. Compounds methotrexate, TSD001, TSD10, and TSD25, with docking scores ranging from −9 to −8 kcal/mol, were selected for experimental validation. Inhibition assays demonstrated nanomolar activity with methotrexate and low micromolar activity with TSD001 (K<sub>i</sub> = 1 μM). Crystallographic studies revealed high-resolution structures of WbDHFR in complex with methotrexate (2.4 Å), TSD001 (2.9 Å), TSD10 (1.8 Å) and TSD25 (2.1 Å), providing detailed insights into binding interactions. Major interactions common for the inhibitors include hydrogen bonds with Glu32. These findings highlight the effectiveness of the virtual screening workflow and establish a foundation for optimizing these antifolate compounds for WbDHFR inhibition. This workflow can be applied to other parasitic DHFR enzymes, advancing drug discovery efforts against neglected tropical diseases.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130370"},"PeriodicalIF":2.2,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854110","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}

引用次数: 0

Antiplasmodial activity of tambjamines, dihydro-β-agarofurans and pyrroloazepines derived from Australian plant and marine species 从澳大利亚植物和海洋物种中提取的铃黄胺、二氢-β-琼脂呋喃和吡咯氮平的抗疟原虫活性。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-12 DOI: 10.1016/j.bmcl.2025.130369

Jacinta R. Macdonald , Gillian M. Fisher , Sasha Hayes , Tina S. Skinner-Adams , Rohan A. Davis , Katherine T. Andrews

{"title":"Antiplasmodial activity of tambjamines, dihydro-β-agarofurans and pyrroloazepines derived from Australian plant and marine species","authors":"Jacinta R. Macdonald , Gillian M. Fisher , Sasha Hayes , Tina S. Skinner-Adams , Rohan A. Davis , Katherine T. Andrews","doi":"10.1016/j.bmcl.2025.130369","DOIUrl":"10.1016/j.bmcl.2025.130369","url":null,"abstract":"<div><div>Malaria is a significant cause of morbidity and mortality, with 263 million cases and 597,000 deaths estimated in 2023. While effective drug combinations are available to prevent and treat malaria, <em>Plasmodium</em> parasite drug resistance is compromising all current options. This situation means that new drugs that act on novel <em>Plasmodium</em> drug targets are needed. Natural products, including artemisinin, derived from <em>Artemisia annua</em>, and its derivatives, have been an important source of antimalarials. In this study we investigated a panel of 43 compounds from the NatureBank natural product library for <em>in vitro</em> activity against asexual stage <em>P. falciparum</em> parasites. Four compounds isolated from Australian plant and marine samples were identified with novel antiplasmodial activity - tambjamine F (IC<sub>50</sub> 1.06 μM) and tambjamine C (IC<sub>50</sub> 3.40 μM) from the marine ascidian <em>Sigillina signifera,</em> bilocularin B (IC<sub>50</sub> 2.18 μM) from the rainforest plant <em>Maytenus bilocularis</em> and hymenialdisine (IC<sub>50</sub> 2.90 μM) from the marine sponge <em>Acanthella costata</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130369"},"PeriodicalIF":2.2,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854112","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}

引用次数: 0

Development of dihydroquinazoline compounds as novel therapeutics against Naegleria fowleri 二氢喹唑啉类化合物治疗福氏奈格里菌的研究进展

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-11 DOI: 10.1016/j.bmcl.2025.130363

Megan M. Voisinet , Caroline M. Palmentiero , Jillian E.M. McKeon , Colm P. Roster , Haley M. Carlson , Thomas D. Brzezinski , Kaylin M. Burton , James C. Morris , R. Adam Mosey

引用次数: 0

Structure-activity relationship study of HIF-2α inhibitors with tricyclic scaffold 三环支架HIF-2α抑制剂的构效关系研究。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-09 DOI: 10.1016/j.bmcl.2025.130366

Zhijie Wu, Changwei Chen, Jian Yan, Peipei Zhu, Min Xiong, Dong Liu, Shaojiang Deng

引用次数: 0

Novel small molecule analogs for advancing apelin receptor antagonism with enhanced plasma and microsomal stability 新型小分子类似物促进Apelin受体拮抗，增强血浆和微粒体稳定性。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-08 DOI: 10.1016/j.bmcl.2025.130367

Ganesh Bist , Ahmed Elsheikh , Sewon Kim, Ruea-Yea Huang, Donna Ruszaj, Sukyung Woo , Youngjae You

{"title":"Novel small molecule analogs for advancing apelin receptor antagonism with enhanced plasma and microsomal stability","authors":"Ganesh Bist , Ahmed Elsheikh , Sewon Kim, Ruea-Yea Huang, Donna Ruszaj, Sukyung Woo , Youngjae You","doi":"10.1016/j.bmcl.2025.130367","DOIUrl":"10.1016/j.bmcl.2025.130367","url":null,"abstract":"<div><div>The apelin receptor (APJ), a G protein-coupled receptor, has emerged as a promising therapeutic target in oncology due to its role in tumor growth, angiogenesis, metastasis, and resistance to anti-VEGF therapy. However, ML221, the only reported small-molecule APJ antagonist, exhibits extremely poor plasma (<1 % remaining after 1 h) and liver microsomal (t<sub>1/2</sub> < 1 min) stability, limiting its translational potential. To address this, we designed and synthesized a focused series of ML221 analogs incorporating amide, ether, and sulfonate linkages to block esterase-mediated degradation aiming to improve metabolic stability while maintaining APJ antagonistic activity. Among them, sulfonate-linked analogs <strong>21</strong> and <strong>22</strong> retained strong β-arrestin inhibition (IC<sub>50</sub> = 3.1 μM and 3.2 μM; 90.1 % and 80.1 % inhibition, respectively) while exhibiting significantly enhanced metabolic stability (100 % remaining in plasma after 1 h; liver microsomal t<sub>1/2</sub> = 5 min). These compounds selectively inhibited APJ-overexpressing cancer cells (OVCAR8) and suppressed apelin-induced endothelial cell migration (OVCAR3 and HUVEC), with compound <strong>21</strong> showing the most potent inhibition of cell migration. Overall, this study establishes the sulfonate linkage as a particularly favorable scaffold modification and a metabolically stable ester bioisostere that enhances stability without compromising APJ antagonism. These analogs represent promising candidate for further in-vivo optimization and advancement as next-generation APJ antagonists for cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130367"},"PeriodicalIF":2.2,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815436","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}

引用次数: 0

Design, synthesis and anti-influenza A virus activity of N-containing heterocyclic glycyrrhetinic acid derivatives 含n杂环甘草次酸衍生物的设计、合成及抗甲型流感病毒活性研究。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-07 DOI: 10.1016/j.bmcl.2025.130364

Juan Zhang , Le Mi , Zhenwei Wang , Xiaohui Zhang , Xiaoyun Chai , Qingjie Zhao , Jishun Yang , Zhi Liu , Qingguo Meng , Yan Song

{"title":"Design, synthesis and anti-influenza A virus activity of N-containing heterocyclic glycyrrhetinic acid derivatives","authors":"Juan Zhang , Le Mi , Zhenwei Wang , Xiaohui Zhang , Xiaoyun Chai , Qingjie Zhao , Jishun Yang , Zhi Liu , Qingguo Meng , Yan Song","doi":"10.1016/j.bmcl.2025.130364","DOIUrl":"10.1016/j.bmcl.2025.130364","url":null,"abstract":"<div><div>Glycyrrhetinic acid (GA), a bioactive triterpenoid derived from <em>Glycyrrhiza glabra</em>, exhibits broad-spectrum antiviral properties but suffers from poor solubility and bioavailability. To enhance its anti-influenza activity, we designed and synthesized 12 novel nitrogen-containing heterocyclic GA derivatives through structural modifications at the A-ring (C-2/C-3) and C-30 position. All compounds were evaluated against influenza A/H1N1 virus in 293T cells. At 10 μM, 10 derivatives outperformed ribavirin, with compound <strong>12b</strong> (bearing an A-ring furazan and C-30 imidazole ester) showing the highest potency (IC<sub>50</sub> = 2.9 μM, selectivity index SI = 38.6) representing a 7.1-fold improvement over GA (IC<sub>50</sub> = 9.6 μM) and 3.7-fold superiority to ribavirin. Molecular docking revealed that <strong>12b</strong> binds strongly to neuraminidase (PDB:<span><span>1NN2</span><svg><path></path></svg></span>; binding energy: −8.11 kcal/mol) via hydrogen bonds with Glu413, Asp125, and Phe100, suggesting NA as a potential target. This study demonstrates that A-ring furazan modification combined with C-30 nitrogen-containing heterocyclic incorporation significantly enhances anti-influenza activity, providing a promising lead compound (<strong>12b</strong>) for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130364"},"PeriodicalIF":2.2,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811416","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}

引用次数: 0

Recent advances of the respiratory syncytial virus inhibitors 呼吸道合胞病毒抑制剂的研究进展。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-07 DOI: 10.1016/j.bmcl.2025.130365

Zhongling Shi , Anchao Ge , Xin Li , Jinyuan Wu , Zhao Wang , Dongwei Kang , Xinyong Liu

引用次数: 0

Synthesis and antibacterial activity of novel benzodioxin-containing oxazolidinones against M. abscessus 新型含苯并二恶唑烷酮类化合物的合成及对脓疡分枝杆菌的抑菌活性研究。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-06 DOI: 10.1016/j.bmcl.2025.130359

Connor M. Winkelhake , Binayak Rimal , Ben A. Thomas , Joe B. Huisken , Gyanu Lamichhane , J. Thomas Ippoliti

引用次数: 0

In vitro anti-influenza potential of glyceroglycolipids from cyanobacteria Limnospira fusiformis 梭形藻蓝藻甘油三酯的体外抗流感潜力。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-05 DOI: 10.1016/j.bmcl.2025.130358

Suresh Chandra V.A.R. Annam , Ahmed Elbermawi , Jungmoo Huh , Jin Zhang , Zulfiqar Ali , Ikhlas A. Khan , Nirmal D. Pugh , Amar G. Chittiboyina

引用次数: 0