Pub Date : 2026-03-01Epub Date: 2025-12-05DOI: 10.1016/j.bmcl.2025.130498
Mevlüt Akdağ , Merve Güneş Çam , Derya Ergen , Yeliz Demir , Şükrü Beydemir , Azime Berna Özçelik
Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway via aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using in vitro kinetic assays. Among the tested molecules, compound 4, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with Ki values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π–π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.
{"title":"Synthesis of new Pyridazinone derivatives and their dual inhibitory activity on aldose reductase and α-glucosidase","authors":"Mevlüt Akdağ , Merve Güneş Çam , Derya Ergen , Yeliz Demir , Şükrü Beydemir , Azime Berna Özçelik","doi":"10.1016/j.bmcl.2025.130498","DOIUrl":"10.1016/j.bmcl.2025.130498","url":null,"abstract":"<div><div>Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway <em>via</em> aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using <em>in vitro</em> kinetic assays. Among the tested molecules, compound <strong>4</strong>, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with K<sub>i</sub> values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π–π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130498"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699488","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}
Pub Date : 2026-03-01Epub Date: 2025-12-08DOI: 10.1016/j.bmcl.2025.130502
Xiu-Jun Wang , Meng-Xin Lu , Qiu-yue Jin , Zi-Yan Lang , Ming-Li Yang , Jing Ji
In this study, five novel SKF-83566 derivatives (8a–8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using 1H NMR, 13C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical cancer) and MDA-MB-231 (breast cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast cancer treatment, providing a foundation for the development of new antitumor therapies.
{"title":"Synthesis and antitumor activity of derivatives of SKF-83566","authors":"Xiu-Jun Wang , Meng-Xin Lu , Qiu-yue Jin , Zi-Yan Lang , Ming-Li Yang , Jing Ji","doi":"10.1016/j.bmcl.2025.130502","DOIUrl":"10.1016/j.bmcl.2025.130502","url":null,"abstract":"<div><div>In this study, five novel SKF-83566 derivatives (8a–8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using <sup>1</sup>H NMR, <sup>13</sup>C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical cancer) and MDA-MB-231 (breast cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast cancer treatment, providing a foundation for the development of new antitumor therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130502"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719949","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}
Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd 1, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp3 carbons (Fsp3). Initial structure–activity relationship (SAR) exploration led to the identification of Cpd 17. Target specificity studies of Cpd 17 indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd 21, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp3 compared to Cpd 1. These results highlight Cpd 21 as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.
{"title":"A potent and selective RORγ inhibitor for the treatment of autoimmune diseases","authors":"Taku Ikenogami , Masahiro Yokota , Shingo Fujioka , Naoki Ogawa , Masato Noguchi , Akihiro Nomura , Tsuyoshi Adachi , Yoshiaki Katsuda , Kojo Arita , Naoki Miyagawa , Yusuke Aratsu , Kota Asahina , Paul Crowe , Haiyan Tao , Scott Thacher , Makoto Shiozaki","doi":"10.1016/j.bmcl.2025.130494","DOIUrl":"10.1016/j.bmcl.2025.130494","url":null,"abstract":"<div><div>Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd <strong>1</strong>, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp<sup>3</sup> carbons (Fsp<sup>3</sup>). Initial structure–activity relationship (SAR) exploration led to the identification of Cpd <strong>17</strong>. Target specificity studies of Cpd <strong>17</strong> indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd <strong>21</strong>, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp<sup>3</sup> compared to Cpd <strong>1</strong>. These results highlight Cpd <strong>21</strong> as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130494"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719970","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}
Pub Date : 2026-03-01Epub Date: 2025-11-09DOI: 10.1016/j.bmcl.2025.130468
Xiyan Tang, Jie Pang, Yanmin Huang, Jianguo Cui, Chunfang Gan, Zhiping Liu
Three novel classes of coumarin [3,4]-fused tetrahydroheterocyclics were synthesized in one step using donor-acceptor cyclopropane diesters as 1,3-dipoles via a facile [3 + 2]/[3 + 3] annulation/lactonization strategies. The antibacterial activities of these compounds were evaluated against two species of animal-derived pathogenic bacteria (Staphylococcus aureus, Escherichia coli) and three species of plant-derived pathogenic bacteria (Xanthomonas citri, Pseudomonas oryzae, Fusarium oxysporum). The results showed that coumarin-fused tetrahydrofuran compounds (e.g., 3aa, 3ac and 3ae) exhibited significant selective antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 2 μg/mL, while no obvious inhibitory effect was observed against other tested strains. Coumarin-fused tetrahydropyridazines (e.g., 7ad, 7ae, 7ah and 7ag) displayed excellent antibacterial activity against Pseudomonas oryzae and Fusarium oxysporum, with an MIC value of 2 μg/mL for all, and their antibacterial effect was significantly superior to that of osthol (the positive control). In contrast, coumarin-fused tetrahydro-1,2-oxazines showed relatively weak antibacterial activity, only compounds 5 ac and 5ak exerted moderate inhibitory effects on Staphylococcus aureus and Pseudomonas oryzae, both with an MIC value of 4 μg/mL. The findings of this study provide an important theoretical basis for the design and synthesis of novel coumarin-fused tetrahydroheterocyclic antibacterial agents.
本研究系统评价了三类香豆素融合物[3,4]-四氢杂环化合物对两种动物源致病菌——金黄色葡萄球菌和大肠杆菌，以及三种植物致病菌——柑橘黄单胞菌、稻谷假单胞菌和尖孢镰刀菌的抑菌活性。结果表明，香豆素融合的四氢呋喃衍生物（如3aa、3 ac和3ae； MIC = 2 μg/mL）对金黄色葡萄球菌具有明显的选择性抗菌活性。与香豆素融合的四氢吡啶类化合物对稻瘟病假单胞菌和尖孢镰刀菌均有较强的抑菌活性，其最低抑菌浓度（MIC）为2 μg/mL（如7ae、7ah和7ag），显著优于阳性对照虫床子素。相比之下，香豆素融合的四氢-1,2-恶嗪类似物表现出相对较弱的广谱抗菌活性。这些发现为设计和合成新型香豆素类杂环抗菌剂提供了坚实的理论基础，并为今后的研究方向提供了有价值的指导。
{"title":"Evaluation of the antibacterial activity of diverse coumarin [3,4]-fused tetrahydroheterocycles","authors":"Xiyan Tang, Jie Pang, Yanmin Huang, Jianguo Cui, Chunfang Gan, Zhiping Liu","doi":"10.1016/j.bmcl.2025.130468","DOIUrl":"10.1016/j.bmcl.2025.130468","url":null,"abstract":"<div><div>Three novel classes of coumarin [3,4]-fused tetrahydroheterocyclics were synthesized in one step using donor-acceptor cyclopropane diesters as 1,3-dipoles <em>via</em> a facile [3 + 2]/[3 + 3] annulation/lactonization strategies. The antibacterial activities of these compounds were evaluated against two species of animal-derived pathogenic bacteria (<em>Staphylococcus aureus</em>, <em>Escherichia coli</em>) and three species of plant-derived pathogenic bacteria (<em>Xanthomonas citri</em>, <em>Pseudomonas oryzae</em>, <em>Fusarium oxysporum</em>). The results showed that coumarin-fused tetrahydrofuran compounds (e.g., <strong>3aa</strong>, <strong>3</strong><strong>ac</strong> and <strong>3ae</strong>) exhibited significant selective antibacterial activity against <em>Staphylococcus aureus</em> with a minimum inhibitory concentration (MIC) of 2 μg/mL, while no obvious inhibitory effect was observed against other tested strains. Coumarin-fused tetrahydropyridazines (e.g., <strong>7ad</strong>, <strong>7ae</strong>, <strong>7ah</strong> and <strong>7ag</strong>) displayed excellent antibacterial activity against <em>Pseudomonas oryzae</em> and <em>Fusarium oxysporum</em>, with an MIC value of 2 μg/mL for all, and their antibacterial effect was significantly superior to that of osthol (the positive control). In contrast, coumarin-fused tetrahydro-1,2-oxazines showed relatively weak antibacterial activity, only compounds <strong>5 ac</strong> and <strong>5ak</strong> exerted moderate inhibitory effects on <em>Staphylococcus aureus</em> and <em>Pseudomonas oryzae</em>, both with an MIC value of 4 μg/mL. The findings of this study provide an important theoretical basis for the design and synthesis of novel coumarin-fused tetrahydroheterocyclic antibacterial agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130468"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494233","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}
Pub Date : 2026-03-01Epub Date: 2025-12-08DOI: 10.1016/j.bmcl.2025.130504
Wenjie Zhou , Yanyan Li , Wenli Shi , Binghua Cheng , Jiaming Liang , Zeyu Zhou , Hui Tian , Ximing Shao , Hongchang Li , Lijing Fang , Ke Liu
Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stimuli or pharmaceutical interventions serves as a key trigger for their internalization and degradation, this process critically influences their function and turnover. Inspired by this natural process, we developed a modular, protein-of-interest (POI) targeting degradation strategy by using a bifunctional chimera molecule composed of a POI-binding ligand and a self-assembling peptide (WIII/YIII). We term this strategy SAILTAC (Self-Assembling Peptide Induced Lysosomal Targeting Chimera) and demonstrate that these chimeras could efficiently degrade membrane-anchored GFP and the therapeutically relevant immune checkpoint PD-L1. An optimized dimeric chimera (YIII-BMS)₂ potently reduced PD-L1 across multiple cancer cell lines through the lysosomal pathway. Collectively, the SAILTAC strategy offers a versatile and targeted approach to degrade plasma membrane proteins, providing a new tool for nanomedicine application.
{"title":"A self-assembling peptide platform enables plasma membrane protein degradation","authors":"Wenjie Zhou , Yanyan Li , Wenli Shi , Binghua Cheng , Jiaming Liang , Zeyu Zhou , Hui Tian , Ximing Shao , Hongchang Li , Lijing Fang , Ke Liu","doi":"10.1016/j.bmcl.2025.130504","DOIUrl":"10.1016/j.bmcl.2025.130504","url":null,"abstract":"<div><div>Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stimuli or pharmaceutical interventions serves as a key trigger for their internalization and degradation, this process critically influences their function and turnover. Inspired by this natural process, we developed a modular, protein-of-interest (POI) targeting degradation strategy by using a bifunctional chimera molecule composed of a POI-binding ligand and a self-assembling peptide (WIII/YIII). We term this strategy SAILTAC (Self-Assembling Peptide Induced Lysosomal Targeting Chimera) and demonstrate that these chimeras could efficiently degrade membrane-anchored GFP and the therapeutically relevant immune checkpoint PD-L1. An optimized dimeric chimera (YIII-BMS)₂ potently reduced PD-L1 across multiple cancer cell lines through the lysosomal pathway. Collectively, the SAILTAC strategy offers a versatile and targeted approach to degrade plasma membrane proteins, providing a new tool for nanomedicine application.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130504"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719910","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}
Pub Date : 2026-02-25DOI: 10.1016/j.bmcl.2026.130600
Joseph Manu, Uma S Singh, Elizabeth Agboluaje, Matthew K Whittaker, Eileen Kennedy, Chung K Chu, May Xiong
Gemcitabine (GEM) is a first line drug to treat pancreatic cancer (PC). However, its long-term efficacy and potency is plagued with reported chemoresistance. To circumvent this issue, the novel GEM analog called troxacitabine (TROX) was evaluated alone and in combination with the epigenetic drug 3'-deazaneplanocin (DZNep) against PANC-1 cancer cells. Herein, we report on the synergistic interplay between these two nucleoside analogs in combination (i.e. unprimed combinations) and investigate further the effect of priming PANC-1 cells with DZNep at 8 h versus 24 h followed by TROX (i.e. primed combination). Specific doses at 8 h primed combinations displayed the greatest degree of synergy and were observed between 1.25 and 5 μM DZNep and 0.5-2 μM TROX in the HSA model, and 1.25-5 μM DZNep and 0.12-0.5 μM TROX in the Loewe model. Data revealed that 8 h primed combinations of DZNep/TROX also reduced self-renewal capability, migratory, and invasive properties of PANC-1 cells more effectively than unprimed (simultaneous) combinations. Proper timed combination of DZNep and TROX may pave the path for an alternative treatment option for GEM-resistant PC.
{"title":"In vitro investigations of troxacitabine (TROX) and 3'-deazanepanocin (DZNep) combination for pancreatic cancer therapy.","authors":"Joseph Manu, Uma S Singh, Elizabeth Agboluaje, Matthew K Whittaker, Eileen Kennedy, Chung K Chu, May Xiong","doi":"10.1016/j.bmcl.2026.130600","DOIUrl":"https://doi.org/10.1016/j.bmcl.2026.130600","url":null,"abstract":"<p><p>Gemcitabine (GEM) is a first line drug to treat pancreatic cancer (PC). However, its long-term efficacy and potency is plagued with reported chemoresistance. To circumvent this issue, the novel GEM analog called troxacitabine (TROX) was evaluated alone and in combination with the epigenetic drug 3'-deazaneplanocin (DZNep) against PANC-1 cancer cells. Herein, we report on the synergistic interplay between these two nucleoside analogs in combination (i.e. unprimed combinations) and investigate further the effect of priming PANC-1 cells with DZNep at 8 h versus 24 h followed by TROX (i.e. primed combination). Specific doses at 8 h primed combinations displayed the greatest degree of synergy and were observed between 1.25 and 5 μM DZNep and 0.5-2 μM TROX in the HSA model, and 1.25-5 μM DZNep and 0.12-0.5 μM TROX in the Loewe model. Data revealed that 8 h primed combinations of DZNep/TROX also reduced self-renewal capability, migratory, and invasive properties of PANC-1 cells more effectively than unprimed (simultaneous) combinations. Proper timed combination of DZNep and TROX may pave the path for an alternative treatment option for GEM-resistant PC.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130600"},"PeriodicalIF":2.2,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147315685","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}
Pub Date : 2026-02-24DOI: 10.1016/j.bmcl.2026.130590
Fangyi Jiang, Chenghong Zheng, Ying Wang, Xinxin Hu, Xuefu You, Yucheng Wang, Mei Zhu, Minghua Wang, Guoning Zhang, Juxian Wang
Two series of N-aryl-L-threonine derivatives bearing a triazole fragment are described as LpxC inhibitors targeting Gram-negative pathogens. Most compounds demonstrated stronger antibacterial activities against E. coli (MICs: ≤0.03-16 μg/mL). Compounds a5, b1 and b2 exhibited pronounced antibacterial activity against Escherichia coli (MICs: ≤0.03-0.5 μg/mL), Klebsiella pneumoniae (MICs: 1-16 μg/mL), and Pseudomonas aeruginosa (MICs: 1-8 μg/mL). Meanwhile, a5 displayed the lowest cytotoxicity toward A549, HepG2, and HEK293 mammalian cells. Molecular docking analyses revealed that a5 simultaneously chelated the catalytic zinc ion and established extensive non-covalent interactions within the LpxC active site. This study provides a basis for further research on 1,2,3-triazole compounds.
{"title":"Design, synthesis and antibacterial activity of novel LpxC inhibitors containing 1,2,3-triazole moieties.","authors":"Fangyi Jiang, Chenghong Zheng, Ying Wang, Xinxin Hu, Xuefu You, Yucheng Wang, Mei Zhu, Minghua Wang, Guoning Zhang, Juxian Wang","doi":"10.1016/j.bmcl.2026.130590","DOIUrl":"https://doi.org/10.1016/j.bmcl.2026.130590","url":null,"abstract":"<p><p>Two series of N-aryl-L-threonine derivatives bearing a triazole fragment are described as LpxC inhibitors targeting Gram-negative pathogens. Most compounds demonstrated stronger antibacterial activities against E. coli (MICs: ≤0.03-16 μg/mL). Compounds a5, b1 and b2 exhibited pronounced antibacterial activity against Escherichia coli (MICs: ≤0.03-0.5 μg/mL), Klebsiella pneumoniae (MICs: 1-16 μg/mL), and Pseudomonas aeruginosa (MICs: 1-8 μg/mL). Meanwhile, a5 displayed the lowest cytotoxicity toward A549, HepG2, and HEK293 mammalian cells. Molecular docking analyses revealed that a5 simultaneously chelated the catalytic zinc ion and established extensive non-covalent interactions within the LpxC active site. This study provides a basis for further research on 1,2,3-triazole compounds.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130590"},"PeriodicalIF":2.2,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300132","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}
Pub Date : 2026-02-01Epub Date: 2025-11-18DOI: 10.1016/j.bmcl.2025.130478
Tiancheng Sun , Zhonghua Li , Bingyu Xiao , Jige Yang , Mengyu Han , Jiaxin Zhang , Sijia Liu , Jinlian Ma , Pan Wang
Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medicines like Atractylodes macrocephala (AM) offer promising candidates for AD drug development, given their structural diversity and neuroprotective potential. Our prior work involved systematic phytochemical isolation of AM and preliminary anti-AD activity evaluation, through which we identified atractylenolide A1 as a neuroprotective lead. To further optimize efficacy, we herein synthesized a small series of novel atractylenolide derivatives via structural modification of A1's exocyclic. Among derivatives, B7 exhibited the broadest activity such as inhibiting self- and Cu2+-induced Aβ aggregation, protecting neurons and microglia, and mitigating Aβ toxicity in vivo. The exocyclic ester of A1 proves a viable modification site, with B7 emerging as a promising multi-target lead for AD therapy
{"title":"Structural modification of atractylenolides: synthesis and evaluation of derivatives with potent anti-Aβ aggregation and neuroprotective activities against Alzheimer's disease","authors":"Tiancheng Sun , Zhonghua Li , Bingyu Xiao , Jige Yang , Mengyu Han , Jiaxin Zhang , Sijia Liu , Jinlian Ma , Pan Wang","doi":"10.1016/j.bmcl.2025.130478","DOIUrl":"10.1016/j.bmcl.2025.130478","url":null,"abstract":"<div><div>Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medicines like <em>Atractylodes macrocephala</em> (AM) offer promising candidates for AD drug development, given their structural diversity and neuroprotective potential. Our prior work involved systematic phytochemical isolation of AM and preliminary anti-AD activity evaluation, through which we identified atractylenolide A1 as a neuroprotective lead. To further optimize efficacy, we herein synthesized a small series of novel atractylenolide derivatives via structural modification of A1's exocyclic. Among derivatives, B7 exhibited the broadest activity such as inhibiting self- and Cu<sup>2+</sup>-induced Aβ aggregation, protecting neurons and microglia, and mitigating Aβ toxicity in vivo. The exocyclic ester of A1 proves a viable modification site, with B7 emerging as a promising multi-target lead for AD therapy</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130478"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145561965","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}
Pub Date : 2026-02-01Epub Date: 2025-10-14DOI: 10.1016/j.bmcl.2025.130438
Dao C. To , Minh Q. Pham , Phuong D.N. Nguyen , Phi H. Nguyen , Huu T. Nguyen , Viet T. Trinh , Le M. Hoang , Hoa T. Nguyen , Thi V.H. Truong
This study investigates potential inhibitors of nitric oxide (NO) production, α-glucosidase, and protein tyrosine phosphatase 1B (PTP1B) from Amanita abrupta and Amanita pantherina. Sixteen compounds (1–16) were isolated by chromatographic techniques and high-performance liquid chromatography (HPLC), and their structures were elucidated by nuclear magnetic resonance (NMR) and literature comparison. Biological activities were evaluated via in vitro assays: the Griess assay for NO inhibition, the p-nitrophenol assay for α-glucosidase, and enzymatic assays for PTP1B. Molecular docking was employed to investigate protein–ligand interactions. The isolates included alanine (1), threonine (2), 2-amino-4-pentynoic acid (3), 4-hydroxy-2-pyrrolidinone (4), ibotenic acid (5), serotonin (6), uracil (7), hypoxanthine (8), bufotenine (9), β-sitosterol (10), stigmasterol (11), cycloeucalenol (12), spinasterol (13), daucosterol (14), stigmasterol-3-O-β-D-glucoside (15), and betulin (16). Compounds 1 and 2 exhibited weak NO inhibition (IC50 = 68.76 and 52.47 μM). Compound 14 displayed the strongest α-glucosidase inhibition (IC50 = 10.56 μM), while compounds 10–13 and 16 showed moderate effects (IC50 = 19.52–32.14 μM). Serotonin (6) also had moderate activity (IC50 = 78.23 μM). For PTP1B inhibition, betulin (16) was most potent (IC50 = 16.80 μM), followed by compounds 10, 11, and 13 with weaker activities (IC50 = 36.28–48.17 μM). Overall, selected compounds (1, 2, 10–14, and 16) exhibited promising bioactivities, warranting further docking studies against inducible nitric oxide synthase (iNOS), PTP1B, and 3AJ7. ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions supported favorable pharmacokinetic properties and potential drug-likeness, highlighting these molecules as leads for anti-inflammatory and anti-diabetic drug discovery.
{"title":"Inflammation and diabetic inhibitors from Amanita abrupta and Amanita pantherina: experimental and computational results","authors":"Dao C. To , Minh Q. Pham , Phuong D.N. Nguyen , Phi H. Nguyen , Huu T. Nguyen , Viet T. Trinh , Le M. Hoang , Hoa T. Nguyen , Thi V.H. Truong","doi":"10.1016/j.bmcl.2025.130438","DOIUrl":"10.1016/j.bmcl.2025.130438","url":null,"abstract":"<div><div>This study investigates potential inhibitors of nitric oxide (NO) production, <em>α</em>-glucosidase, and protein tyrosine phosphatase 1B (PTP1B) from <em>Amanita abrupta</em> and <em>Amanita pantherina</em>. Sixteen compounds (<strong>1</strong>–<strong>16</strong>) were isolated by chromatographic techniques and high-performance liquid chromatography (HPLC), and their structures were elucidated by nuclear magnetic resonance (NMR) and literature comparison. Biological activities were evaluated <em>via in vitro</em> assays: the Griess assay for NO inhibition, the <em>p</em>-nitrophenol assay for <em>α</em>-glucosidase, and enzymatic assays for PTP1B. Molecular docking was employed to investigate protein–ligand interactions. The isolates included alanine (<strong>1</strong>), threonine (<strong>2</strong>), 2-amino-4-pentynoic acid (<strong>3</strong>), 4-hydroxy-2-pyrrolidinone (<strong>4</strong>), ibotenic acid (<strong>5</strong>), serotonin (<strong>6</strong>), uracil (<strong>7</strong>), hypoxanthine (<strong>8</strong>), bufotenine (<strong>9</strong>), <em>β</em>-sitosterol (<strong>10</strong>), stigmasterol (<strong>11</strong>), cycloeucalenol (<strong>12</strong>), spinasterol (<strong>13</strong>), daucosterol (<strong>14</strong>), stigmasterol-3-O-<em>β</em>-D-glucoside (<strong>15</strong>), and betulin (<strong>16</strong>). Compounds <strong>1</strong> and <strong>2</strong> exhibited weak NO inhibition (IC<sub>50</sub> = 68.76 and 52.47 μM). Compound <strong>14</strong> displayed the strongest <em>α</em>-glucosidase inhibition (IC<sub>50</sub> = 10.56 μM), while compounds <strong>10</strong>–<strong>13</strong> and <strong>16</strong> showed moderate effects (IC<sub>50</sub> = 19.52–32.14 μM). Serotonin (<strong>6</strong>) also had moderate activity (IC<sub>50</sub> = 78.23 μM). For PTP1B inhibition, betulin (<strong>16</strong>) was most potent (IC<sub>50</sub> = 16.80 μM), followed by compounds <strong>10</strong>, <strong>11</strong>, and <strong>13</strong> with weaker activities (IC<sub>50</sub> = 36.28–48.17 μM). Overall, selected compounds (<strong>1</strong>, <strong>2</strong>, <strong>10</strong>–<strong>14</strong>, and <strong>16</strong>) exhibited promising bioactivities, warranting further docking studies against inducible nitric oxide synthase (iNOS), PTP1B, and 3AJ7. ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions supported favorable pharmacokinetic properties and potential drug-likeness, highlighting these molecules as leads for anti-inflammatory and anti-diabetic drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130438"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306457","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}
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