ChemMedChem最新文献_第5页

Aspirin-Conjugated Cholic Acid Derivative Combats Polymicrobial Infections and Inflammation. 阿司匹林共轭胆酸衍生物抗多种微生物感染和炎症。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-14 DOI: 10.1002/cmdc.202500174

Sayed M Safwan, Devashish Mehta, Varsha Saini, Dolly Jain, Nikhil K Chourasiya, Amit Arora, Steffi Khatol, Mohit Singh, Vikas Verma, Avinash Bajaj

{"title":"Aspirin-Conjugated Cholic Acid Derivative Combats Polymicrobial Infections and Inflammation.","authors":"Sayed M Safwan, Devashish Mehta, Varsha Saini, Dolly Jain, Nikhil K Chourasiya, Amit Arora, Steffi Khatol, Mohit Singh, Vikas Verma, Avinash Bajaj","doi":"10.1002/cmdc.202500174","DOIUrl":"https://doi.org/10.1002/cmdc.202500174","url":null,"abstract":"Treating wound infections caused by Gram-positive and Gram-negative bacteria, along with associated inflammation, remains challenging due to the limited therapeutic efficacy of conventional antibiotics. Leveraging the unique properties of cholic acid derivatives, such as their cationic nature, hydrophobicity, and structural adaptability, a novel aspirin-derived facile amphiphile based on cholic acid (amphiphile 1) is designed and synthesized. The investigations reveal that the amphiphile 1 functions as a bacterial membrane disruptor through interacting with key components such as lipoteichoic acid and lipopolysaccharide of bacterial membranes. It is observed that amphiphile 1 can degrade both monomicrobial and polymicrobial preformed biofilms originating from Gram-positive and Gram-negative bacteria. Animal studies demonstrate that hydrogel-based delivery of amphiphile 1 effectively mitigates bacterial infections and resolves bacterial-associated inflammation. Collectively, these findings underscore that amphiphile 1 is a putative therapeutic agent for addressing the challenges of polymicrobial infections.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500174"},"PeriodicalIF":3.4,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058131","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

Strategic Design and Development of Indole-Based Compounds as Potent malic Enzyme 3 Inhibitors for Pancreatic Tumor Therapy. 吲哚类化合物作为有效的苹果酸酶3抑制剂用于胰腺肿瘤治疗的策略设计和开发。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-14 DOI: 10.1002/cmdc.202500470

Gaurav Sheth, Shailesh R Shah, Prabal Sengupta, Tushar Jarag, Sabbirhusen Chimanwala, Kalapatapu V V M Sairam, Vaibhav Jain, Rashmi Talwar, Avinash Dhanave, Mehul Raviya, Harendra Jha, Rajasekhar Reddy Chilakala, Trinadha Rao Chitturi

{"title":"Strategic Design and Development of Indole-Based Compounds as Potent malic Enzyme 3 Inhibitors for Pancreatic Tumor Therapy.","authors":"Gaurav Sheth, Shailesh R Shah, Prabal Sengupta, Tushar Jarag, Sabbirhusen Chimanwala, Kalapatapu V V M Sairam, Vaibhav Jain, Rashmi Talwar, Avinash Dhanave, Mehul Raviya, Harendra Jha, Rajasekhar Reddy Chilakala, Trinadha Rao Chitturi","doi":"10.1002/cmdc.202500470","DOIUrl":"https://doi.org/10.1002/cmdc.202500470","url":null,"abstract":"Malic enzyme 3 (ME3) plays a critical role in the survival of SMAD4-/-/ME2-/- pancreatic ductal adenocarcinoma (PDAC) cells by supporting energy production and maintaining redox homeostasis. Therefore, targeting ME3 with small-molecule inhibitors presents a promising therapeutic strategy for PDAC patients with SMAD4/ME2 deletions. Building upon our previously developed ME3 inhibitor, a systematic exploration of the structure-activity relationship (SAR) was undertaken to identify novel chemotypes. This effort led to the discovery of a new series of indole-substituted piperazine carboxamides with potent ME3 inhibitory activity, among which compound 13 emerged to be the most effective in PDAC cell lines. Furthermore, the synergistic effects of the newly identified compound 13 with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib were evaluated on Hs766T cells which revealed a significant synergism of this combination.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500470"},"PeriodicalIF":3.4,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058115","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

Improving the Catalyst Efficiency for Hyperpolarization of Pyruvate Derivatives by Means of Hydrogenative PHIP 用加氢PHIP提高丙酮酸衍生物超极化催化效率。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-12 DOI: 10.1002/cmdc.202500379

Ginevra Di Matteo, Oksana Bondar, Carla Carrera, Eleonora Cavallari, Sumit Mishra, Francesca Reineri

{"title":"Improving the Catalyst Efficiency for Hyperpolarization of Pyruvate Derivatives by Means of Hydrogenative PHIP","authors":"Ginevra Di Matteo, Oksana Bondar, Carla Carrera, Eleonora Cavallari, Sumit Mishra, Francesca Reineri","doi":"10.1002/cmdc.202500379","DOIUrl":"10.1002/cmdc.202500379","url":null,"abstract":"Hyperpolarized pyruvate is the most widely used probe for metabolic imaging in magnetic resonance (MR). Parahydrogen induced polarization- side arm hydrogenation allows to generate it through the catalytic hydrogenation of pyruvate esters. Due to the transient nature of MR hyperpolarization and to the fact that in vivo applications require a high amount of hyperpolarized substrate, a concentrated product solution must be obtained in a few seconds, therefore a high catalyst concentration is needed. The homogeneous rhodium catalyst used for the reaction can be deactivated by the hydrogenation products (or substrates) and the substrate-to-catalyst ratio becomes even lower, especially for pyruvate esters. The addition of tris-phenyl phosphine to the hydrogenation mixture prevents the catalyst deactivation, when it is due to the hydrogenation product allyl pyruvate and the amount of catalyst needed to obtain a concentrated batch of hyperpolarized pyruvate ester has been reduced significantly. Following to hydrolysis and extraction of sodium pyruvate in aqueous phase, the concentration of the hyperpolarized metabolite has been increased to about 60 mM and 13C-MRI experiments have been carried out using different dilution of the hyperpolarized metabolite in water.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 19","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500379","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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":"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":"20 19","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500521","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":"OA","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

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