Bioorganic & Medicinal Chemistry Letters最新文献_第4页

Synthesis and biological evaluation of novel nitrogen-containing heterocyclic derivatives as potential anticancer agents 新型含氮杂环衍生物潜在抗癌药物的合成及生物学评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-26 DOI: 10.1016/j.bmcl.2025.130388

Qiu Li , Minghui Li , Yafang Xiao , Jing Ma , Chenxing Fu , Weisheng Guo

{"title":"Synthesis and biological evaluation of novel nitrogen-containing heterocyclic derivatives as potential anticancer agents","authors":"Qiu Li , Minghui Li , Yafang Xiao , Jing Ma , Chenxing Fu , Weisheng Guo","doi":"10.1016/j.bmcl.2025.130388","DOIUrl":"10.1016/j.bmcl.2025.130388","url":null,"abstract":"<div><div>Based on screening results, a series of nitrogen-containing five-membered heterocyclic compounds were designed and synthesized for anticancer evaluation. Among them, <strong>7</strong><strong>s</strong>, featuring a 1,2,3-triazole scaffold, exhibited the most potent antiproliferative activity against four human cancer cell lines (IC₅₀ < 10 μM). Mechanistic studies revealed that <strong>7</strong><strong>s</strong> downregulated phosphorylated AKT (p-AKT) protein at 5 μM. It also demonstrated moderate metabolic stability (T₁/₂ = 38.9 min, clearance = 23.4 mL/min/kg) and acceptable aqueous solubility (2.6 mg/100 mL). SwissADME predictions confirmed its good oral bioavailability and gastrointestinal absorption. Importantly, <strong>7</strong><strong>s</strong> showed low cytotoxicity toward normal HEK293 cells (IC₅₀ = 56.2 μM), suggesting a favorable safety. These results support <strong>7</strong><strong>s</strong> as a promising lead compound for further development in anticancer drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130388"},"PeriodicalIF":2.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937660","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, Ssynthesis and Ddocking study of 1,2,3-triazole incorporated benzoxazole-oxazole derivatives and evaluation as potential anticancer agents 1,2,3-三唑类含苯并恶唑-恶唑衍生物的设计、合成与对接研究及潜在抗癌药物的评价

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-25 DOI: 10.1016/j.bmcl.2025.130376

Adurthi Suryakumari , Chithaluri Sudhakar , Bijaya Ketan Sahoo

{"title":"Design, Ssynthesis and Ddocking study of 1,2,3-triazole incorporated benzoxazole-oxazole derivatives and evaluation as potential anticancer agents","authors":"Adurthi Suryakumari , Chithaluri Sudhakar , Bijaya Ketan Sahoo","doi":"10.1016/j.bmcl.2025.130376","DOIUrl":"10.1016/j.bmcl.2025.130376","url":null,"abstract":"<div><div>The study reports the design and synthesis of a new library of triazole in-corporated benzoxazole oxazole compounds (<strong>11a–j</strong>) and their <em>in vitro</em> cytotoxic activity evaluation. The structural reliability of the synthesized compounds was confirmed by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and mass spectral data. We have selected ER-α and CDK2 proteins for molecular docking study of the active compounds to examine their binding interactions. We have also screened the preliminary cytotoxic activity of compounds <strong>11a–j</strong> against four human cancer cell lines: MCF-7, A549, Colo-205, and A2780 by the MTT assay with etoposide, a well-known chemotherapy drug, as a control. All the molecules have shown strong binding interactions with A binding affinity of −8.9 to −9.4 kcal/mol with the proteins ER-α and CDK2 using CB-Dock2 online server. In our findings all the compounds demonstrated selective activity whereas four of the synthesized compounds, namely <strong>11a, 11b, 11c</strong>, and <strong>11d</strong>, have exhibited greater cytotoxic activity against the cancer cells with IC50 ranging from 0.18 to 3.67 μM. Drug likeliness and ADME studies infer that the compounds can be frameworks for the development of anticancer medication.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130376"},"PeriodicalIF":2.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917943","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

Discovery of GLPG4471, a potent and selective IRAK4 inhibitor for the treatment of inflammatory and autoimmune diseases 发现GLPG4471，一种有效的选择性IRAK4抑制剂，用于治疗炎症和自身免疫性疾病。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-23 DOI: 10.1016/j.bmcl.2025.130386

Oscar Mammoliti , Florence Bonnaterre , Gregory Newsome , Rhalid Akkari , Miriam López-Ramos , Marielle Babel , Hélène Jary , Laëtitia Cherel , Elsa De Lemos , Mislav Oršulić , Marijana Komac , Đenana Vrban , Lionel Trottet , Line Oste , Emanuelle Wakselman , Monica Borgonovi , Catherine Jagerschmidt , Anna Pereira Fernandes , Roland Blanqué , Kris Nys , Nicolas Desroy

{"title":"Discovery of GLPG4471, a potent and selective IRAK4 inhibitor for the treatment of inflammatory and autoimmune diseases","authors":"Oscar Mammoliti , Florence Bonnaterre , Gregory Newsome , Rhalid Akkari , Miriam López-Ramos , Marielle Babel , Hélène Jary , Laëtitia Cherel , Elsa De Lemos , Mislav Oršulić , Marijana Komac , Đenana Vrban , Lionel Trottet , Line Oste , Emanuelle Wakselman , Monica Borgonovi , Catherine Jagerschmidt , Anna Pereira Fernandes , Roland Blanqué , Kris Nys , Nicolas Desroy","doi":"10.1016/j.bmcl.2025.130386","DOIUrl":"10.1016/j.bmcl.2025.130386","url":null,"abstract":"<div><div>Interleukin-1 receptor associated kinase 4 (IRAK4) is a key mediator of the secretion of cytokines and interferons <em>via</em> Toll-like receptor and interleukin-1 receptor signaling pathways. Modulation of IRAK4 activity has been investigated for the treatment of inflammatory and autoimmune diseases and of malignancies.</div><div>Here, new IRAK4 inhibitors were identified from a high throughput screening campaign. Initial structure-activity relationship efforts aimed at improving potency and lipophilic efficiency on IRAK4. Then, structural modifications were made to increase stability towards amide cleavage upon incubation in hepatocytes, and to decrease human ether-a-go-go related gene (hERG) inhibition. Optimization of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties led to compound <strong>21</strong> (GLPG4471), a potent IRAK4 inhibitor that showed excellent selectivity when tested against a panel of 369 kinases. Compound <strong>21</strong> exhibited potent inhibition of cytokine secretion in cellular and whole blood phenotypic assays. Compound <strong>21</strong> displayed dose-dependent activity <em>in vivo</em> in a mouse model of collagen-induced arthritis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130386"},"PeriodicalIF":2.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937610","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

Solid-phase synthesis of a pyrrole library and identification of bioactive compounds 吡咯文库的固相合成及生物活性化合物的鉴定

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-23 DOI: 10.1016/j.bmcl.2025.130387

Sukhyun Lee, Lisa M. Eubanks, Kim D. Janda

引用次数: 0

Study of the reversal of metallo-β-lactamase-mediated resistance in Gram-negative bacteria by EDTMP EDTMP逆转革兰氏阴性菌金属β-内酰胺酶介导的耐药性的研究

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-21 DOI: 10.1016/j.bmcl.2025.130374

Chen Wu , Yuzhou Hu , Zouyi Sun , Miaomiao Zhao , Yuxuan Wei , Hanhua Lu , Jinyi Zhou , Haoyuan Wang , Haiquan Kang , Cheng Chen , Youzhen Ma

{"title":"Study of the reversal of metallo-β-lactamase-mediated resistance in Gram-negative bacteria by EDTMP","authors":"Chen Wu , Yuzhou Hu , Zouyi Sun , Miaomiao Zhao , Yuxuan Wei , Hanhua Lu , Jinyi Zhou , Haoyuan Wang , Haiquan Kang , Cheng Chen , Youzhen Ma","doi":"10.1016/j.bmcl.2025.130374","DOIUrl":"10.1016/j.bmcl.2025.130374","url":null,"abstract":"<div><div>Metallo-β-lactamases (MBLs) are major causes of carbapenem resistance in Gram-negative bacteria. In this study, a simple and practical method was developed to synthesize the fluorescent probe CE-HF, which was proven effective for detecting the activity of the MBL NDM-1. Using this probe, ethylenediamine tetra(methylene phosphonic acid) (EDTMP) was identified as a potent MBL inhibitor with strong activity (IC₅₀ = 0.68 μM against NDM-1). Antibacterial assays, including inhibition zone, MIC, and MBC tests, revealed that EDTMP significantly enhanced the efficacy of meropenem and other β-lactam antibiotics by lowering their MIC values and exhibiting synergistic effects. Checkerboard assays further demonstrated that EDTMP reduced the MIC of meropenem by 256-fold at 8 μg/mL, whereas zinc ion rescue experiments confirmed that EDTMP exerts its inhibitory effect by chelating zinc ions at the active site of MBLs. Moreover, EDTMP restored the antibacterial activity of meropenem against recombinant <em>E. coli</em> strains expressing L1, ImiS, IMP-1, and VIM-2, as well as clinical isolates of <em>Stenotrophomonas maltophilia</em> producing VIM-2. These findings highlight EDTMP as a broad-spectrum MBL inhibitor and offer a new strategy to combat β-lactamase-mediated antibiotic resistance.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130374"},"PeriodicalIF":2.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896238","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

Novel azabicyclic series of potent SHP2 allosteric inhibitors 新型azabicyclic系列有效的SHP2变构抑制剂

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-19 DOI: 10.1016/j.bmcl.2025.130383

Alessio Sferrazza , Ilaria Rossetti , Danilo Fabbrini , Esther Torrente , Nicola Relitti , Federica Ferrigno , Paola Fezzardi , Costanza Iaccarino , Monica Bisbocci , Antonella Cellucci , Davide Ventre , Luca Anzillotti , Simone Palombo , Martina Nibbio , Cristina Alli , Christian Montalbetti , Carlo Toniatti , Alessia Petrocchi

{"title":"Novel azabicyclic series of potent SHP2 allosteric inhibitors","authors":"Alessio Sferrazza , Ilaria Rossetti , Danilo Fabbrini , Esther Torrente , Nicola Relitti , Federica Ferrigno , Paola Fezzardi , Costanza Iaccarino , Monica Bisbocci , Antonella Cellucci , Davide Ventre , Luca Anzillotti , Simone Palombo , Martina Nibbio , Cristina Alli , Christian Montalbetti , Carlo Toniatti , Alessia Petrocchi","doi":"10.1016/j.bmcl.2025.130383","DOIUrl":"10.1016/j.bmcl.2025.130383","url":null,"abstract":"<div><div>The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is a critical component of the RAS/RAF/MEK/ERK signaling pathway, functioning upstream of RAS to promote oncogenic signaling and tumor growth. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of original azabicyclic compounds was identified. Extensive preliminary SAR around the novel bicyclic basic moiety (left-hand side) and the heteroaryl portion (right-hand side) yielded a highly potent series of SHP2 inhibitors with demonstrated cellular potency (pERK inhibition, as downstream marker of MAPK pathway activity) as well as antiproliferative activity in a KYSE-520 cancer cell line. Further optimization of the physicochemical properties and reduction of <em>in vitro</em> off-target liabilities, including <em>h</em>ERG inhibition, led to the identification of a unique series of SHP2 inhibitors with strong potential for development in efficacy studies using appropriate animal models.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130383"},"PeriodicalIF":2.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896217","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-pneumonic activity evaluation of shikonin ester derivatives 紫草素酯衍生物的设计、合成及抗肺活性评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-17 DOI: 10.1016/j.bmcl.2025.130368

Xuelian Shen , Aga Er-bu , Xiaoxia Liang

引用次数: 0

Discovery of small-molecule modulators of ppGalNAc-T2 targeting the metastable states during its loop-closing process 发现ppGalNAc-T2在环闭合过程中靶向亚稳态的小分子调节剂。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-16 DOI: 10.1016/j.bmcl.2025.130373

Danfeng Shi , Xialin Luo , Lu Wang , Zhenjun Gong , Zhitong Bing , Wenjuan Jia , Jiaqi Tian

{"title":"Discovery of small-molecule modulators of ppGalNAc-T2 targeting the metastable states during its loop-closing process","authors":"Danfeng Shi , Xialin Luo , Lu Wang , Zhenjun Gong , Zhitong Bing , Wenjuan Jia , Jiaqi Tian","doi":"10.1016/j.bmcl.2025.130373","DOIUrl":"10.1016/j.bmcl.2025.130373","url":null,"abstract":"<div><div>The polypeptide <em>N</em>-acetyl-galactosaminyltransferase 2 (ppGalNAc-T2) is a promising therapeutic target for metabolic and neurodevelopmental disorders in humans. The atomic-scale insights into metastable states of ppGalNAc-T2 during the loop-closing process had been revealed by the Markov state model previously. Here, we further applied the metastable conformations of ppGalNAc-T2 for the discovery of novel small-molecule modulators. A coexistent pocket with high druggability was detected and applied in the structure-based virtual screening against five metastable conformations. Based on a weighted scoring strategy considering the conformational population of metastable states, chemical entities of 29 candidate compounds were selected for experimental validation. Two inhibitors (compounds <strong>10</strong> and <strong>15</strong>) with IC<sub>50</sub> values of 9.25 ± 3.83 μM and 7.11 ± 2.58 μM respectively, and an activator (compound <strong>12</strong>) with the maximal activity of threefold of the baseline were identified for the first time. Further molecular modeling studies revealed that compound <strong>12</strong> and <strong>15</strong> interacted with metastable conformations in the similar binding modes to luteolin in the crystal structure, and differed in dynamic stabilities when binding to metastable conformations. These findings not only provide a feasible strategy for the virtual screening against multiple metastable states but also expand the structural diversity of small-molecule modulators of ppGalNAc-T2.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130373"},"PeriodicalIF":2.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870702","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

Identification of potent and orally bioavailable GSPT1 molecular glue degraders 有效和口服生物利用的GSPT1分子胶水降解剂的鉴定。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-16 DOI: 10.1016/j.bmcl.2025.130375

Run-Duo Gao , Wenzhong Liu , Yuanyuan Liu , Grace Xie , Haotian Fang , Xingxing Xu , Meilu Yan , Shu-Li You

引用次数: 0

Synthesis of novel 4/5-substituted 3-arylidene-2-oxindole derivatives and their biological evaluation as NQO2 ligands and NLRP3 downregulators 新型4/5取代3-芳基烯-2-氧吲哚衍生物的合成及其作为NQO2配体和NLRP3下调因子的生物学评价

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-14 DOI: 10.1016/j.bmcl.2025.130372

Elena N. Bezsonova , Meriam Dubar , Daria D. Melekhina , Mariia A. Salykina , Ivan V. Boichenko , Denis A. Babkov , Roman D. Danilov , Alexander A. Spasov , Natalia A. Lozinskaya

引用次数: 0