ChemMedChem最新文献_第3页

Sertraline as a Scaffold for Antitrypanosoma Cruzi Drug Development: Design of Novel Derivatives and Computational Target Screening. 舍曲林作为抗克氏锥虫药物开发的支架：新衍生物的设计和计算靶点筛选。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-09 DOI: 10.1002/cmdc.202500408

Ali S Mijoba, Zuleyma Blanco, Nereida J Parra-Giménez, Katiuska E Chávez, Alirica I Suárez, Esteban Fernandez-Moreira, Hegira Ramírez, Xenón A Serrano, Sandra Espinosa, Jaime E Charris

{"title":"Sertraline as a Scaffold for Antitrypanosoma Cruzi Drug Development: Design of Novel Derivatives and Computational Target Screening.","authors":"Ali S Mijoba, Zuleyma Blanco, Nereida J Parra-Giménez, Katiuska E Chávez, Alirica I Suárez, Esteban Fernandez-Moreira, Hegira Ramírez, Xenón A Serrano, Sandra Espinosa, Jaime E Charris","doi":"10.1002/cmdc.202500408","DOIUrl":"https://doi.org/10.1002/cmdc.202500408","url":null,"abstract":"Due to the advantages of drug repurposing, the discovery of new chemotherapeutic agents for the treatment of Chagas disease based on approved drugs has become a strategy for identifying new candidates. In this work, the antidepressant drug sertraline is reported, with an IC50 of 7.8 ± 1.7 µM against the amastigote forms of Trypanosoma cruzi. The optimization of activity through the formation of tertiary amides results in a small library of compounds, where two compounds, SMBT and SM04, show increases of 4.3 and 2.7 times in vitro activity against the amastigote form of the parasite, and a safety index of >55.6 and 25.4, respectively, compared to sertraline. Due to hindered rotation around the (O)CN bond, the tertiary amides exist as a mixture of E/Z rotamers, typically inseparable, which display separate signals in their NMR spectra. The differential assignment of the 1H resonances of the E/Z rotamers is based on the magnitude of anisotropic solvent-induced shift effects and confirmed by 2D nuclear Overhauser effect spectroscopy. Computational analysis of the hit compounds reveals that SMBT showed significant affinity for three targets (galactopyranose mutase, dihydrofolate reductase, and squalene synthase), while SM04 displays notable interaction with one (squalene synthase). These results not only suggest a plausible mechanism of action for the studied compounds but also provide valuable insights for the rational design of new derivatives with potentially enhanced trypanocidal activity.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500408"},"PeriodicalIF":3.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028675","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

Biaryl Phosphate-Based Inhibitors of the Transcription Factor STAT4. 基于磷酸二芳基的转录因子STAT4抑制剂。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-09 DOI: 10.1002/cmdc.202500672

Nadiya Brovchenko, Anne Maria Oelsch, Christoph Protzel, Thorsten Berg

引用次数: 0

Optimizing Amphipathic Antimicrobial Peptides via Helical Wheel Rotation. 螺旋轮旋转优化两亲抗菌肽。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-08 DOI: 10.1002/cmdc.202500316

Hai Bui Thi Phuong, Nguyen-Thi Phuong, Le Minh Bui, Hue Pham Thi, Thi Thu Phuong Tran, Thang Nguyen Quoc, Hiep Tuan Tran, Minh Nguyen Hong, Huy Luong Xuan

{"title":"Optimizing Amphipathic Antimicrobial Peptides via Helical Wheel Rotation.","authors":"Hai Bui Thi Phuong, Nguyen-Thi Phuong, Le Minh Bui, Hue Pham Thi, Thi Thu Phuong Tran, Thang Nguyen Quoc, Hiep Tuan Tran, Minh Nguyen Hong, Huy Luong Xuan","doi":"10.1002/cmdc.202500316","DOIUrl":"https://doi.org/10.1002/cmdc.202500316","url":null,"abstract":"Antimicrobial peptides (AMPs) have emerged as promising candidates for combating drug-resistant pathogens and certain cancer types. However, their therapeutic applications are often limited by undesired hemolytic activity, while many AMPs exhibit only moderate potency. Herein, the \"helical wheel rotation\" strategy as a simple, cost-effective, and modular approach to optimize the pharmacological properties of amphipathic α-helical AMPs without altering their amino acid composition is explored. Using BP52 as a model peptide, six rotational variants (BP52-A1 to BP52-A6) and two sequence-modified derivatives (BP52-B1 and BP52-B2) are developed to assess their antimicrobial, anticancer, and hemolytic properties. Several derivatives, especially BP52-A6, exhibit enhanced antimicrobial activity and reduced hemolysis while maintaining or improving potency toward cancer cells. Importantly, all derivatives show substantially reduced hemolytic activity compared to BP52. These findings highlight the potential of helical wheel rotation as a valuable peptide engineering strategy to fine-tune selectivity and multifunctionality of AMPs for therapeutic applications.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500316"},"PeriodicalIF":3.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022488","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

Synthesis of Urea-Containing Derivatives and their Application as Potential Anti-Methicillin-Resistant Staphylococcus Aureus Agents. 含尿素衍生物的合成及其作为耐甲氧西林金黄色葡萄球菌潜在药物的应用

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-05 DOI: 10.1002/cmdc.202500521

Jorge A González-Cruz, Gerardo González-Gallardo, J Ricardo Pérez-Velázquez, Carlos D García-Mejía, José Manuel Guevara-Vela, Jesús A Oria-Hernández, Adriana Castillo-Villanueva, Tomás Rinza-Rocha, Eduardo Hernández-Vázquez

{"title":"Synthesis of Urea-Containing Derivatives and their Application as Potential Anti-Methicillin-Resistant Staphylococcus Aureus Agents.","authors":"Jorge A González-Cruz, Gerardo González-Gallardo, J Ricardo Pérez-Velázquez, Carlos D García-Mejía, José Manuel Guevara-Vela, Jesús A Oria-Hernández, Adriana Castillo-Villanueva, Tomás Rinza-Rocha, Eduardo Hernández-Vázquez","doi":"10.1002/cmdc.202500521","DOIUrl":"https://doi.org/10.1002/cmdc.202500521","url":null,"abstract":"We describe the synthesis and activity against methicillin-resistant Staphylococcus aureus (MRSA) of a collection of urea-containing amides. The approach considered the ureido group as a bioisoster of known FabI inhibitors. NMR characterization and density functional theory studies demonstrated the presence of s-cis and s-trans rotamers in the N-benzyl examples (series 2). Preliminary screening showed the ability of series 1 and 3 (N-aryl and N-arilpiperidone derivatives, respectively) to inhibit the bacterial growth of two MRSA strains (a clinical isolate and ATCC 33591). Compound 3b inhibited 50% of the clinical strain and 34% of the ATCC. Subsequent biological assays let us determine the IC50 values of the most active ureas in both strains, standing out compounds 1a (45.8 ± 2.3 μM) and 3b (43.6 ± 2.0 μM). Finally, molecular docking suggests FabI as a possible molecular target for the designed compounds.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500521"},"PeriodicalIF":3.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999340","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

Synthesis of a Conformationally Fixed Bicyclomarin Derivative. 一种构象固定的双环香素衍生物的合成。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-03 DOI: 10.1002/cmdc.202500493

Jennifer Greve, Alexander F Kiefer, Uli Kazmaier

引用次数: 0

Molecular Docking and Target-Specific Binding Profiles of Benzosuberane-Based Compounds. 苯并亚胺类化合物的分子对接和靶向结合谱。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-03 DOI: 10.1002/cmdc.202500365

Michail A Saragatsis, Gemma K Kinsella, James F Curtin, Tao Zhang

{"title":"Molecular Docking and Target-Specific Binding Profiles of Benzosuberane-Based Compounds.","authors":"Michail A Saragatsis, Gemma K Kinsella, James F Curtin, Tao Zhang","doi":"10.1002/cmdc.202500365","DOIUrl":"https://doi.org/10.1002/cmdc.202500365","url":null,"abstract":"Cancer, a leading cause of global mortality, is characterized by uncontrolled cell proliferation and remains a significant therapeutic challenge due to drug resistance and treatment failures. Despite advancements in targeted therapies, novel agents are still in strong demand. Benzosuberane, a bicyclic scaffold present in natural products such as colchicine and theaflavin, has emerged as a promising structural core in cancer therapeutics due to its structural flexibility and diverse biological activities, including antitumor, anti-inflammatory, and antimicrobial effects. This review consolidates the computational insights driving the design of benzosuberane-based compounds as effective antitumor agents. Focusing on molecular docking studies, it highlights the interaction profiles with various target classes, including antivascular agents, kinase inhibitors, receptor modulators, and DNA-intercalators. These interactions regulate critical oncogenic pathways, offering mechanistic details that highlight the compounds' potential for enhanced specificity and therapeutic efficacy. Among the cancer targets, benzosuberane-based compounds acting as antivascular agents and DNA-targeting agents emerged as the most promising, based on consistent binding affinities, cytotoxicity, and binding interaction profiles across breast, lung, and colon cancer cell lines. By summarizing the structural and molecular requirements for benzosuberane-mediated modulation of cancer pathway and identifying promising compounds, this work aims to guide future research and advance drug discovery pipelines.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500365"},"PeriodicalIF":3.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990960","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

Hybrid Conjugates of Ibuprofen and 3,5-Diarylidene-4-Piperidone: A New Avenue in Anti-Inflammatory Drug Discovery. 布洛芬与3,5-二芳基吡啶-4-哌啶酮的杂化偶联物：消炎药发现的新途径。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-03 DOI: 10.1002/cmdc.202500342

Julio C Chavez, Adel S Girgis, Marian N Aziz, Shilpi Khurana, Brandon Carr, Guido F Verbeck, Siva S Panda

{"title":"Hybrid Conjugates of Ibuprofen and 3,5-Diarylidene-4-Piperidone: A New Avenue in Anti-Inflammatory Drug Discovery.","authors":"Julio C Chavez, Adel S Girgis, Marian N Aziz, Shilpi Khurana, Brandon Carr, Guido F Verbeck, Siva S Panda","doi":"10.1002/cmdc.202500342","DOIUrl":"https://doi.org/10.1002/cmdc.202500342","url":null,"abstract":"Nonsteroidal anti-inflammatory drugs (NSAIDs) have been crucial in managing inflammation, pain, and fever since their introduction in 1897. Despite their widespread use, NSAIDs often face limitations due to gastrointestinal side effects from the nonselective inhibition of cyclooxygenase (COX) isoenzymes, COX-1 and COX-2. While selective COX-2 inhibitors reduce gastrointestinal toxicity, they come with increased cardiovascular risks. This study investigates the synthesis and biological evaluation of novel hybrid NSAID conjugates incorporating 3,5-diarylidene-4-piperidinone, ibuprofen, and amino acids. These hybrid molecules are designed to enhance anti-inflammatory efficacy while minimizing adverse effects. The synthesized compounds are evaluated for COX inhibition and their effects on inflammatory mediators such as interleukin-6, tumor necrosis factor-alpha, and nitric oxide. Computational studies, including molecular docking and ADME (absorption, distribution, metabolism, and excretion) analyses, are performed to clarify the mechanisms of action and to predict pharmacokinetic properties. The findings indicate that some hybrid conjugates display promising anti-inflammatory properties, necessitating further investigation for their potential therapeutic applications.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500342"},"PeriodicalIF":3.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990929","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 Keap1-Nrf2 Protein-Protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-Inflammatory Effects. 基于萘-2-乙酰胺支架活化细胞内Nrf2的Keap1-Nrf2蛋白-蛋白相互作用抑制剂的研制及其抗炎作用

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-03 DOI: 10.1002/cmdc.202500474

Daisuke Yasuda, Kai Toyoshima, Koujin Kojima, Hanako Ishida, Kazuma Kaitoh, Riyo Imamura, Kayoko Kanamitsu, Hirotatsu Kojima, Megumi Funakoshi-Tago, Masanori Osawa, Tomoyuki Ohe, Tomoya Hirano

{"title":"Development of Keap1-Nrf2 Protein-Protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-Inflammatory Effects.","authors":"Daisuke Yasuda, Kai Toyoshima, Koujin Kojima, Hanako Ishida, Kazuma Kaitoh, Riyo Imamura, Kayoko Kanamitsu, Hirotatsu Kojima, Megumi Funakoshi-Tago, Masanori Osawa, Tomoyuki Ohe, Tomoya Hirano","doi":"10.1002/cmdc.202500474","DOIUrl":"https://doi.org/10.1002/cmdc.202500474","url":null,"abstract":"Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) axis is an attractive therapeutic target for various intractable diseases. Although protein-protein interaction inhibitors against Keap1-Nrf2 have been developed over the past decade, more structural expansion is needed to improve efficacy. In this article, several candidate compounds are designed and synthesized as novel Nrf2 activators and their intracellular Nrf2-activating effects are evaluated. Among the synthesized compounds, a novel naphthalene-1,4-(4-ethoxybenzensulfonamide) bearing a tertiary acetamide side chain at the 2-position strongly activated intracellular Nrf2. Particularly, the pyrrolidine-type acetamide compound showed the strongest intracellular Nrf2 activation. X-ray cocrystallography revealed that this compound can bind to the DC domain of Keap1. Additionally, the pyrrolidine-type acetamide compound induced the mRNA expression of the representative Nrf2 target genes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Moreover, the compound exhibited anti-inflammatory effects in a lipopolysaccharide-stimulated macrophage cell line. Conclusively, these results suggest that the pyrrolidine-type naphthalene-2-acetamide is a promising compound for the development of Nrf2 activators that can be applied to treat inflammatory diseases.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500474"},"PeriodicalIF":3.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990951","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

Sulfonamide Inhibitors of Amyloid Aggregation: A Promising Path against Neurodegenerative Diseases. 淀粉样蛋白聚集的磺胺抑制剂：治疗神经退行性疾病的一个有希望的途径。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-01 DOI: 10.1002/cmdc.202500324

Joana Smirnovienė, Daumantas Matulis

{"title":"Sulfonamide Inhibitors of Amyloid Aggregation: A Promising Path against Neurodegenerative Diseases.","authors":"Joana Smirnovienė, Daumantas Matulis","doi":"10.1002/cmdc.202500324","DOIUrl":"https://doi.org/10.1002/cmdc.202500324","url":null,"abstract":"Protein amyloid aggregation is a critical pathological process implicated in nearly 50 amyloid-related diseases, including Alzheimer's and Parkinson's diseases. This review highlights the potential of sulfonamides, a versatile class of compounds recognized for their diverse pharmacological properties, as modulators of protein aggregation. We provide an overview of studies examining the efficacy of sulfonamide derivatives in inhibiting the aggregation of various amyloidogenic proteins, including amyloid-beta, tau, alpha-synuclein, insulin, and transthyretin. In vitro assays, such as Thioflavin T fluorescence and high-resolution imaging techniques, have shown that certain sulfonamides can significantly inhibit fibril formation and promote the stabilization of non-aggregated protein states. The potential for sulfonamides to serve as multi-target agents offers new avenues for therapeutic development. By integrating findings from current research, we support a proposal that sulfonamide-based compounds could play a pivotal role in addressing the multifaceted nature of amyloid-related neurodegenerative diseases, paving the way for innovative therapeutic strategies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500324"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937262","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 Insights in Multi-Target Drugs in Pharmacology and Medicinal Chemistry 多靶点药物在药理学和药物化学中的最新进展。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-01 DOI: 10.1002/cmdc.202500447

Sadık Hüseyin Cemali, Samet Poyraz, Samet Belveren, Senanur Taş, Mehmet Ali Tamer, Naciye Yaktubay Döndaş, H. Ali Döndaş, Jose Miguel Sansano

引用次数: 0