ChemMedChem最新文献_第6页

Synthesis of Glycopeptide Antibiotic Peptide Substrates Using Knorr-Pyrazole Chemistry 利用克诺尔-吡唑化学合成糖肽类抗生素肽底物。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-09-05 DOI: 10.1002/cmdc.70487

Jemma Gullick, W. Ramani H. Weerasinghe, Ralf B. Schittenhelm, Julien Tailhades, Max J. Cryle

{"title":"Synthesis of Glycopeptide Antibiotic Peptide Substrates Using Knorr-Pyrazole Chemistry","authors":"Jemma Gullick, W. Ramani H. Weerasinghe, Ralf B. Schittenhelm, Julien Tailhades, Max J. Cryle","doi":"10.1002/cmdc.70487","DOIUrl":"10.1002/cmdc.70487","url":null,"abstract":"The glycopeptide antibiotics (GPAs) remain clinical antibiotics used against drug-resistant Gram-positive infections. The discovery of GPAs continues, with new type IIa and V GPAs, the kineomicins, the rimomycins, and corbomycin, being recently identified. Despite this larger repertoire of GPA scaffolds and crosslinking types, limitations remain with the in vitro exploration of the cytochrome P450 enzymes that install the essential crosslinks between the aromatic side chain residues of GPAs. While the chemoenzymatic synthesis of the more hydrophilic type I GPAs like vancomycin has aided our understanding of GPA crosslinking pathways, type II–V GPAs remain underexplored. This is due to the hydrophobic nature of these GPAs that makes access to peptidyl-CoA substrates difficult and reduces in vitro crosslinking activity. Here, we explore the use of modified Knorr-pyrazole chemistry to provide access to hydrophobic peptidyl-CoA substrates of the type II/IIa GPAs, kineomicin and actinoidin, and the type IV GPA, teicoplanin. Yields of peptidyl-CoAs were improved 3–7-fold through careful tuning of reaction solvents and the arylthiol used for displacement of the pyrazole. The type II/IIa GPA scaffolds explored in this study displayed the highest in vitro OxyC activity seen to date, likely due to both improved synthesis and their structural properties.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896202","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

Covalent Targeting and Thermostabilization of Oncogenic R280K and R273H Mutants p53 by Small Molecule RVJB59 小分子RVJB59对致癌性R280K和R273H突变体p53的共价靶向和热稳定作用

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-09-05 DOI: 10.1002/cmdc.70483

Ricardo J. F. Ferreira, Lídia M. Gonçalves, Mattia Mori, Alexandra M. M. Antunes, Ana P. Leandro, Maria M. M. Santos

{"title":"Covalent Targeting and Thermostabilization of Oncogenic R280K and R273H Mutants p53 by Small Molecule RVJB59","authors":"Ricardo J. F. Ferreira, Lídia M. Gonçalves, Mattia Mori, Alexandra M. M. Antunes, Ana P. Leandro, Maria M. M. Santos","doi":"10.1002/cmdc.70483","DOIUrl":"10.1002/cmdc.70483","url":null,"abstract":"Breast cancer is one of the most common cancers worldwide. Approximately 30%–40% of breast cancers harbor mutations in the TP53 gene, leading to structural and functional alterations in the p53 protein. These changes result in mutant proteins that are unable to perform their canonical tumor suppressor functions and, in many cases, exhibit gain-of-function properties, making mutant p53 a highly attractive therapeutic target. Among these mutations, R280K and R273H are two clinically relevant DNA-binding mutations. In this study, we extended our investigation of the (R)-tryptophanol isoindolinone derivative RVJB59 to these two p53 mutants. Differential scanning fluorimetry showed that RVJB59 thermally stabilized the R280K mutant p53 in a dose-dependent manner. Furthermore, the mechanism of action of RVJB59 was investigated by liquid chromatography coupled with high-resolution tandem mass spectrometry (LC–HRMS/MS) using the DNA‑binding domains of the R280K and R273H mutants, confirming covalent binding of the compound to Cys141 in both proteins. Computational studies with both p53 mutants suggested that RVJB59 can stably bind in proximity to Cys141, further reinforcing the results obtained by LC–HRMS/MS. Our findings further underscore the potential of RVJB59 for the development of novel therapies for the treatment of breast cancers harboring these mutations.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896216","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, Structure, and Antileishmanial Activity of Novel 1,2,4-Trioxolanes, 1,2,4,5-Tetraoxanes and Their Respective Deoxygenated Controls 新型1,2,4-三氧烷和1,2,4,5-四氧烷及其脱氧对照物的合成、结构和抗利什曼原虫活性

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-09-02 DOI: 10.1002/cmdc.70454

Inês C. C. Costa, Patrícia S. M. Amado, Philippe M. Loiseau, Sandrine Cojean, José A. Paixão, Maria L. S. Cristiano

{"title":"Synthesis, Structure, and Antileishmanial Activity of Novel 1,2,4-Trioxolanes, 1,2,4,5-Tetraoxanes and Their Respective Deoxygenated Controls","authors":"Inês C. C. Costa, Patrícia S. M. Amado, Philippe M. Loiseau, Sandrine Cojean, José A. Paixão, Maria L. S. Cristiano","doi":"10.1002/cmdc.70454","DOIUrl":"10.1002/cmdc.70454","url":null,"abstract":"Given the reluctance of pharmaceutical companies to invest in new antileishmanial drugs, due to high costs and low perspectives of financial return, there is growing interest in repurposing existing drugs, often a more cost-effective and quicker strategy to launch effective therapeutic solutions. Artemisinins, used as first-line malaria treatments, have attracted attention for their potential activity against Leishmania. The mechanisms by which artemisinins treat malaria were deeply investigated and are thought to involve peroxide cleavage with formation of radicals, alkylating molecular targets within Plasmodium. However, the action of endoperoxides on Leishmania spp. remains poorly understood. To gain insight, we undertook the synthesis and structural characterization of 1,2,4-trioxolanes, 1,2,4,5-tetraoxanes, and respective deoxygenated controls. The compounds were evaluated in vitro against axenic and intracellular forms of Leishmania donovani and Leishmania major. Their selectivity indexes (SIs) were determined. Among 29 compounds, tetraoxanes 27, 29, 30, 32, and 33 exhibited the highest potency against both Leishmania species, but most showed limited selectivity (SI < 10) toward the parasite. Nevertheless, 33 demonstrated strong efficacy against L. major (SI of 13.7). Comparing peroxides versus their ether controls often revealed similar activities, suggesting involvement of other mechanisms beyond the iron-dependent peroxide activation, unlike what is described for Plasmodium.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878700","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

Structure-Guided Optimization of PDE9A Inhibitors Tackling Neuroinflammation: A Combined Computational and In Vitro Study 结构导向优化PDE9A抑制剂治疗神经炎症：一项计算和体外联合研究。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-31 DOI: 10.1002/cmdc.70461

Giovanni Ribaudo, Elisa Landucci, Margrate Anyanwu, Costanza Mazzantini, Matteo Giannangeli, Stefano Rosa, Francesca Mainolfi, Maura Calvani, Maurizio Memo, Domenico E. Pellegrini-Giampietro, Alessandra Gianoncelli

{"title":"Structure-Guided Optimization of PDE9A Inhibitors Tackling Neuroinflammation: A Combined Computational and In Vitro Study","authors":"Giovanni Ribaudo, Elisa Landucci, Margrate Anyanwu, Costanza Mazzantini, Matteo Giannangeli, Stefano Rosa, Francesca Mainolfi, Maura Calvani, Maurizio Memo, Domenico E. Pellegrini-Giampietro, Alessandra Gianoncelli","doi":"10.1002/cmdc.70461","DOIUrl":"10.1002/cmdc.70461","url":null,"abstract":"Oxidative stress and inflammation are key players in central nervous system (CNS) diseases and in neurodegeneration. In this field, the search for novel targets and therapeutic tools is wide open. In this study, the identification of potential inhibitors of phosphodiesterase 9 (PDE9), a target of growing interest in CNS diseases, was done by using a rational virtual screening approach that employed ligand- and structure-based methodologies. Furthermore, a novel method to evaluate PDE9A activity based on high-performance liquid chromatography (HPLC) was developed to address the need for a time- and cost-effective assay to evaluate inhibitors. One of the candidates identified by virtual screening demonstrated potent enzymatic inhibition, and subsequent in vitro tests proved its significant PDE9A-dependent anti-neuroinflammatory effects as it acted on pro-inflammatory mediators such as COX-2, IL-1β, TNFα, and IL-6. The results of this multidisciplinary study underscore the potential of developing PDE9A inhibitors to modulate cyclic guanosine monophosphate (cGMP) signaling pathways implicated in neuroinflammation and also potentially in synaptic plasticity and cognitive functions, paving the way for novel PDE9A-targeting inhibitors addressing neurodegenerative diseases.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862750","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

Discovery of a 4′-Azido Fleximer Nucleoside Analog With Broad-Spectrum Antiviral Activity Against DENV, EBOV, and Other RNA Viruses 对DENV、EBOV和其他RNA病毒具有广谱抗病毒活性的4′-叠氮多弗莱昔默核苷类似物的发现

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-31 DOI: 10.1002/cmdc.70435

Kyle A. Davis, Ryan L. Slack, Thomas R. Foulkes, Tereza Frčková, Lenka Tomková, Jessica L. Smith, Meareg Amare, Grayson D. Pipher, Peter Halfmann, Alec J. Hirsch, Luděk Eyer, Stefan G. Sarafianos, Katherine L. Seley-Radtke

{"title":"Discovery of a 4′-Azido Fleximer Nucleoside Analog With Broad-Spectrum Antiviral Activity Against DENV, EBOV, and Other RNA Viruses","authors":"Kyle A. Davis, Ryan L. Slack, Thomas R. Foulkes, Tereza Frčková, Lenka Tomková, Jessica L. Smith, Meareg Amare, Grayson D. Pipher, Peter Halfmann, Alec J. Hirsch, Luděk Eyer, Stefan G. Sarafianos, Katherine L. Seley-Radtke","doi":"10.1002/cmdc.70435","DOIUrl":"10.1002/cmdc.70435","url":null,"abstract":"The ongoing emergence and reemergence of RNA viruses from multiple viral families highlights the urgent need for broad-spectrum antiviral therapeutics. To address this issue, a series of 4′-azido fleximer nucleoside analogs were synthesized and evaluated for broad-spectrum antiviral activity against pathogens of epidemic/pandemic concern. One compound, KAD-039, featuring a 2′, 3′-diisobutyrate-5′-ProTide prodrug, exhibited potent antiviral activity across flaviviruses, filoviruses, and coronaviruses, with EC50 values ranging from 1 to 10 µM and minimal cytotoxicity (CC50 > 50 µM). Pharmacokinetic evaluation of KAD-039 demonstrated high plasma stability in dog, monkey, and human plasma, with half-lives ranging from 19.9 to 28 h but exhibited poor stability in human liver microsomes (t1/2 = 6.1 min). To help elucidate the mechanism of action of KAD-039 against these viral families, computational molecular docking studies were performed using the expected triphosphate active form within the cap/GTP-binding pockets of several viral methyltransferases and showed that KAD-039TP docked into all of the viral MTases with similar or higher predicted affinity compared to the natural substrate. In addition, KAD-039TP displayed reduced predicted affinity for the human N7 methyltransferase, suggesting low host toxicity. These results highlight 4′-azido fleximer analogs as promising broad-spectrum antivirals, potentially functioning through viral methyltransferase inhibition, and support further investigation.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862694","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

Spirooxindole Derivatives as Emerging Scaffolds in Drug Discovery: Synthetic Strategies, Structure–Activity Relationship, and Biological Activities 螺旋菌吲哚衍生物在药物发现中的应用：合成策略、构效关系和生物活性。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-31 DOI: 10.1002/cmdc.70468

Rakesh Chandra Kalita, Sarbanga Bezbaruah, Deepshikha Patle

{"title":"Spirooxindole Derivatives as Emerging Scaffolds in Drug Discovery: Synthetic Strategies, Structure–Activity Relationship, and Biological Activities","authors":"Rakesh Chandra Kalita, Sarbanga Bezbaruah, Deepshikha Patle","doi":"10.1002/cmdc.70468","DOIUrl":"10.1002/cmdc.70468","url":null,"abstract":"Spirooxindoles are a class of spirocyclic scaffolds in drug discovery, as the rigid frame and well-defined substitution pattern can interact with various biological targets. Recent advances in synthetic methodologies, including multicomponent 1,3-dipolar cycloadditions, organocatalytic cascades, and one-pot protocols, have facilitated the efficient synthesis of a wide variety of derivatives for SAR studies. A diverse range of classes, including pyrrolidine, cyclopropyl carboxamide, carbamate, oxadiazoline, pyrrolizidine, and furan derivatives, show cytotoxicity in the submicromolar-to-low micromolar range with good selectivity. The SAR studies suggest that substitution on the isatin core generally enhances biological activity in individual series, especially with electron-withdrawing groups, but these effects are scaffold dependent. Furthermore, spirooxindole derivatives have been reported to show antibacterial activity, including TrpRS inhibition, antimicrobial, acetylcholinesterase inhibition, α-glucosidase inhibition, antiviral, and anticonvulsant activities. The recent patents, especially on MDM2 inhibitors and other anticancer agents with nanomolar potency, provide further evidence for the continued interest in spirooxindole-based drug discovery. This review highlights the recent advancements in spirooxindole chemistry involving synthetic strategies, SAR, biological activities, and recent patents.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862761","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

Oxadiazolone-Triazole Derivatives as a New Scaffold for Modulation of Angiotensin II-Induced Vascular Contraction 恶二唑酮-三唑衍生物作为调节血管紧张素ii诱导的血管收缩的新支架。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-31 DOI: 10.1002/cmdc.70460

Larissa F. L. Ferreira, Daiana G. de A. Vasconcelos, Ruth C. A. Santos, Jivaldo G. Ferreira, Alice V. Araújo, Janaína V. dos Anjos

{"title":"Oxadiazolone-Triazole Derivatives as a New Scaffold for Modulation of Angiotensin II-Induced Vascular Contraction","authors":"Larissa F. L. Ferreira, Daiana G. de A. Vasconcelos, Ruth C. A. Santos, Jivaldo G. Ferreira, Alice V. Araújo, Janaína V. dos Anjos","doi":"10.1002/cmdc.70460","DOIUrl":"10.1002/cmdc.70460","url":null,"abstract":"In this study, a series of novel angiotensin II type 1 receptor (AT1R) antagonist candidates containing the 1,2,4-oxadiazol-5-one nucleus and a 1,2,3-triazole moiety was designed, synthesized, and evaluated. Compounds 7a–j were obtained via a semiconvergent synthetic route employing copper-catalyzed azide–alkyne cycloaddition (click chemistry), yielding the target molecules in moderate to good yields. Biological activity was assessed through vascular reactivity assays using rat aortic rings in the presence of angiotensin II. Most compounds reduced angiotensin II-induced contraction, consistent with a putative AT1 receptor antagonist profile. Among them, compound 7f, bearing a methylenedioxyphenyl substituent, exhibited the most favorable biological profile within the series. The results indicate that electron-donating groups favor activity, while strongly electron-withdrawing substituents, such as nitro, are detrimental. Molecular docking studies predicted consistent interactions with key residues, particularly Arg167 and Tyr87, providing a plausible structural rationale for the observed biological activity. In silico ADME predictions indicated acceptable drug-like properties, including compliance with drug-likeness filters and a predicted bioavailability score, and no blood–brain barrier permeation.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862748","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

Identification of New Putative Autotaxin Inhibitors via Structure-Based Virtual Screening and Evaluation of Their Antiproliferative Properties Against Ovarian and Breast Cancer Cells 通过基于结构的虚拟筛选和评估其对卵巢癌和乳腺癌细胞的抗增殖特性，鉴定新的假定的自taxin抑制剂。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-31 DOI: 10.1002/cmdc.70474

Angelina Boccarelli, Adriana Coricello, Francesca Alessandra Ambrosio, Valentina Leo, Salvatore Mirabile, Rosaria Gitto, Modesto de Candia, Marco Catto, Francesco Ortuso, Cosimo D. Altomare, Stefano Alcaro

{"title":"Identification of New Putative Autotaxin Inhibitors via Structure-Based Virtual Screening and Evaluation of Their Antiproliferative Properties Against Ovarian and Breast Cancer Cells","authors":"Angelina Boccarelli, Adriana Coricello, Francesca Alessandra Ambrosio, Valentina Leo, Salvatore Mirabile, Rosaria Gitto, Modesto de Candia, Marco Catto, Francesco Ortuso, Cosimo D. Altomare, Stefano Alcaro","doi":"10.1002/cmdc.70474","DOIUrl":"10.1002/cmdc.70474","url":null,"abstract":"Autotaxin (ATX), a lysophospholipase D playing an important role in several inflammatory diseases, as well as in tumor invasion, progression, and metastasis, is an attractive therapeutic target. Herein, we report a virtual screening study of an in-house molecular database. In silico simulations highlighted five putative ATX inhibitors. The enzyme assay showed that compound 3 achieves inhibition potency in the submicromolar range (IC50 = 0.534 µM), whereas all the other test compounds proved to be moderate (2) or weak (1, 4, and 5) inhibitors of ATX at 10 µM concentration. These compounds, evaluated for the in vitro antiproliferative activity in four ATX-expressing cancer cell lines, namely the ovarian cancer cell lines A2780 and SK-OV-3, the breast cancer cells MCF-7, and immortalized mouse embryonic fibroblast cell line NIH/3T3, demonstrated preliminary phenotypic effects, inhibiting cell proliferation with IC50 values mostly in the low micromolar range. Compound 4 (IC50 = 11.5 µM against SK-OV-3) significantly reduced the motility of SK-OV-3 ovarian carcinoma cells in the wound-healing assay, suggesting that it may represent a hit structure for the development of potential antimetastatic agents.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862740","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

The Pyrazolone Scaffold: A Privileged Motif for Molecular Hybridization in Drug Discovery 吡唑酮支架：药物发现中分子杂交的特殊基序。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-31 DOI: 10.1002/cmdc.70466

Ke Tang, Yao Liu, Jingning Luo, Shiqin Cong

{"title":"The Pyrazolone Scaffold: A Privileged Motif for Molecular Hybridization in Drug Discovery","authors":"Ke Tang, Yao Liu, Jingning Luo, Shiqin Cong","doi":"10.1002/cmdc.70466","DOIUrl":"10.1002/cmdc.70466","url":null,"abstract":"Pyrazolone and its keto-enol tautomers constitute a privileged class of scaffolds in contemporary medicinal chemistry, characterized by remarkable structural plasticity. This review comprehensively summarizes recent advancements in the structural optimization of pyrazolone-based compounds, highlighting how molecular hybridization drives polypharmacology against complex conditions, including neurodegenerative disorders, inflammation, metabolic syndromes, cancer, and infectious diseases. By detailing structure–activity relationships, the review elucidates how the strategic pharmacophore merging at the N-1, C-3, and C-4 positions transforms the pyrazolone core into highly potent therapeutics. Mechanistically, these hybrid molecules exhibit diverse capabilities, such as inhibiting key survival kinases, blocking pathogenic protein aggregation, antagonizing immune checkpoints, and restoring cellular redox homeostasis via robust reactive oxygen species scavenging. Ultimately, this review underscores the critical role of molecular hybridization in overcoming drug resistance, minimizing systemic toxicity, and driving the future discovery of pyrazolone-based precision therapeutics.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862834","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 Ro 41-0960, a Non-Steroidal Inhibitor of the Na+/K+-ATPase Na+/K+- atp酶的非甾体抑制剂Ro 41-0960的发现

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-28 DOI: 10.1002/cmdc.70442

Carlos Cruz-Cortés, Jaroslava Šeflová, Guadalupe Guerrero-Serna, Eric N. Jimenez-Vazquez, Justus Anumonwo, L. Michel Espinoza-Fonseca

{"title":"Discovery of Ro 41-0960, a Non-Steroidal Inhibitor of the Na+/K+-ATPase","authors":"Carlos Cruz-Cortés, Jaroslava Šeflová, Guadalupe Guerrero-Serna, Eric N. Jimenez-Vazquez, Justus Anumonwo, L. Michel Espinoza-Fonseca","doi":"10.1002/cmdc.70442","DOIUrl":"https://doi.org/10.1002/cmdc.70442","url":null,"abstract":"The Na+/K+-ATPase (NKA) is a central regulator of cardiac ion homeostasis and a validated target for heart failure. Yet, cardiotonic steroids used in clinical practice are limited by a narrow therapeutic window and pro-arrhythmic effects. Here, we identify Ro 41-0960 as a non-steroidal inhibitor of NKA with a distinct mechanistic profile. The compound inhibits NKA activity with IC50 values of 17.9 ± 1.1 µM for purified enzyme and 10.3 ± 1.1 µM in microsomal preparations. ATP-dependent activity measurements revealed a non-monotonic response in which inhibition was most pronounced at ATP concentrations below 4 mM and diminished at the highest ATP concentrations tested. Docking and molecular dynamics simulations suggest that Ro 41-0960 can access both the cardiotonic steroid-binding pocket and the nucleotide-binding site; however, the ATP-dependence data are not consistent with a simple ATP-competitive mechanism. Furthermore, the compound shows only weak inhibition of SERCA (IC50 > 100 µM) and does not alter electrophysiological parameters in human iPSC-derived cardiomyocytes at concentrations producing near-maximal NKA inhibition, providing initial evidence of a favorable cardiac safety profile. Together, these findings identify Ro 41-0960 as an NKA inhibitor with a distinct chemical scaffold and provide a framework for the development of non-steroidal NKA modulators.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 17","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849287","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