ChemMedChem最新文献_第5页

Design and Synthesis of Tetrahydropyrrolo[3,4-c]Pyrazole Sigma-1 Receptor Ligands.

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-30 DOI: 10.1002/cmdc.202401015

Giuseppe Cosentino, Maria Dichiara, Giuliana Costanzo, Alessandro Coco, Lorella Pasquinucci, Agostino Marrazzo, Antonio Rescifina, Emanuele Amata

{"title":"Design and Synthesis of Tetrahydropyrrolo[3,4-c]Pyrazole Sigma-1 Receptor Ligands.","authors":"Giuseppe Cosentino, Maria Dichiara, Giuliana Costanzo, Alessandro Coco, Lorella Pasquinucci, Agostino Marrazzo, Antonio Rescifina, Emanuele Amata","doi":"10.1002/cmdc.202401015","DOIUrl":"10.1002/cmdc.202401015","url":null,"abstract":"This study presents a series of tetrahydropyrrolo[3,4-c]pyrazole-based compounds designed as sigma-1 receptor (S1R) ligands, focusing on optimizing affinity and reducing off-target effects. We synthesized various derivatives from commercially available precursors and, through radioligand binding assays, assessed their binding affinity for S1R and sigma-2 receptor (S2R). Compound 19 (AD417), containing a benzyl group and an amide substituent, demonstrated notable S1R affinity (Ki=75 nM) with 6-fold selectivity over S2R. Modifications on the pyrrolidine nitrogen were crucial in enhancing receptor interaction, as the protonated nitrogen likely interacts with Glu172 within the S1R binding site. Furthermore, to address hERG potassium ion channel inhibition, a known limitation in S1R drug development, we evaluated compound 19's cardiotoxicity potential. With an experimental hERG IC50 of 5.8 μM, significantly higher than verapamil's IC50 of 0.41 μM, and haloperidol's IC50 of 0.16 μM, compound 19 showed a safer profile, suggesting a reduced risk of cardiotoxicity. These findings underscore the role of nitrogen accessibility, structural flexibility, and functional group modifications in optimizing S1R ligand interactions and provide a promising foundation for developing safer S1R-targeted therapeutics with minimized hERG-related risks.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202401015"},"PeriodicalIF":3.6,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062831","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

ABT, Elacridar and Bile-Duct Cannulated Rats: Tools to Understand Pharmacokinetics.

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-28 DOI: 10.1002/cmdc.202400995

Gilles Ouvry

引用次数: 0

Machine Learning-Driven Discovery of Structurally Related Natural Products as Activators of the Cardiac Calcium Pump SERCA2a.

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-23 DOI: 10.1002/cmdc.202400913

Carlos Cruz-Cortés, Eli Fernández-de Gortari, Rodrigo Aguayo-Ortiz, Jaroslava Šeflová, Adam Ard, Martin Clasby, Justus Anumonwo, L Michel Espinoza-Fonseca

{"title":"Machine Learning-Driven Discovery of Structurally Related Natural Products as Activators of the Cardiac Calcium Pump SERCA2a.","authors":"Carlos Cruz-Cortés, Eli Fernández-de Gortari, Rodrigo Aguayo-Ortiz, Jaroslava Šeflová, Adam Ard, Martin Clasby, Justus Anumonwo, L Michel Espinoza-Fonseca","doi":"10.1002/cmdc.202400913","DOIUrl":"10.1002/cmdc.202400913","url":null,"abstract":"A key molecular dysfunction in heart failure is the reduced activity of the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in cardiac muscle cells. Reactivating SERCA2a improves cardiac function in heart failure models, making it a validated target and an attractive therapeutic approach for heart failure therapy. However, finding small-molecule SERCA2a activators is challenging. In this study, we used a machine learning-based virtual screening to identify SERCA2a activators among 57,423 natural products. The machine learning model identified ten structurally related natural products from Zingiber officinale, Aframomum melegueta, Alpinia officinarum, Alpinia oxyphylla, and Capsicum (chili peppers) as SERCA2a activators. Initial ATPase assays showed seven of these activate SERCA at low micromolar concentrations. Notably, two natural products, Yakuchinone A and Alpinoid D displayed robust concentration-dependent responses in primary ATPase activity assays, efficient lipid bilayer binding and permeation in atomistic simulations, and enhanced intracellular Ca2+ transport in adult mouse cardiac cells. While these natural products exert off-target effects on Ca2+ signaling, these compounds offer promising avenues for the design and optimization of lead compounds. In conclusion, this study increases the array of calcium pump effectors and provides new scaffolds for the development of novel SERCA2a activators as new therapies for heart failure.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400913"},"PeriodicalIF":3.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031558","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

Systematic Review on 1,2,3-Oxadiazoles, 1,2,4-Oxadiazoles, and 1,2,5-Oxadiazoles in the Antimycobacterial Drug Discovery.

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-23 DOI: 10.1002/cmdc.202400971

Marta Kučerová-Chlupáčová

引用次数: 0

Aminocholestane and Aminoandrostane Inhibitors of the SH2 Domain-Containing Inositol 5'-Phosphatase (SHIP).

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-22 DOI: 10.1002/cmdc.202400597

Angela M Pacherille, Dennis R Viernes, Chiara Pedicone, Sandra Fernandes, Otto M Dungan, Shawn Dormann, Daniel R Wallach, Raki Sudan, Robbie Brooks, Christopher M Russo, Kyle T Howard, Michael S Cosgrove, William G Kerr, John D Chisholm

引用次数: 0

Addressing Data Point Homogeneity and Annotation Challenges to Enhance Data-Driven Approaches: The S. aureus NorA Efflux Pump Case Study.

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-22 DOI: 10.1002/cmdc.202400927

Andrea Astolfi, Giada Cernicchi, Erika Primavera, Marco Rocchi, Giuseppe Manfroni, Stefano Sabatini, Maria Letizia Barreca

引用次数: 0

Binding-Site Switch for Protein Kinase CK2 Inhibitors. 蛋白激酶CK2抑制剂的结合位点转换。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-21 DOI: 10.1002/cmdc.202400868

Dylan Grenier, Muriel Gelin, Yinshan Yang, Angélique Mularoni, Jean-François Guichou, Jean-Guy Delcros, Isabelle Krimm

{"title":"Binding-Site Switch for Protein Kinase CK2 Inhibitors.","authors":"Dylan Grenier, Muriel Gelin, Yinshan Yang, Angélique Mularoni, Jean-François Guichou, Jean-Guy Delcros, Isabelle Krimm","doi":"10.1002/cmdc.202400868","DOIUrl":"10.1002/cmdc.202400868","url":null,"abstract":"The serine/threonine protein kinase CK2, a tetramer composed of a regulatory dimer (CK2β2) bound to two catalytic subunits CK2α, is a well-established therapeutic target for various pathologies, including cancer and viral infections. Several types of CK2 inhibitors have been developed, including inhibitors that bind to the catalytic ATP-site, bivalent inhibitors that occupy both the CK2α ATP-site and the αD pocket, and inhibitors that target the CK2α/CK2β interface. Interestingly, the bivalent inhibitor AB668 shares a similar chemical structure with the interface inhibitor CCH507. In this study, we designed analogs of CCH507 using structure-based and fragment-based approaches. The ability of these analogs to bind the CK2α/CK2β interface was evaluated using biolayer interferometry and fluorescence anisotropy-based assays. Their potency to inhibit CK2 kinase activity was determined using the bioluminescent ADP-Glo assay. These experiments allowed us to investigate which chemical modifications prevent the binding of the compounds at the CK2α/CK2β interface. Seven out of sixteen compounds conserved the ability to bind at the protein-protein interface, among which three compounds exhibited better interface inhibition compared to CCH507.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400868"},"PeriodicalIF":3.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996881","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

Unveiling Gelation and Antimicrobial Potentials of α-Acyloxy Carboxamides: Findings from Experimental and Theoretical Approach. 揭示α-酰基羧胺的凝胶化和抗菌潜力：实验和理论方法的发现。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-21 DOI: 10.1002/cmdc.202400774

Sharol Sebastian, Manjeet Kumar, Feroze Hussain, Sanju Rathore, Yajat Rohila, Meenakshi, Shaurya Prakash, Antresh Kumar, Priya Bhardwaj, Mulaka Maruthi, Azaj Ansari, Manoj K Gupta

{"title":"Unveiling Gelation and Antimicrobial Potentials of α-Acyloxy Carboxamides: Findings from Experimental and Theoretical Approach.","authors":"Sharol Sebastian, Manjeet Kumar, Feroze Hussain, Sanju Rathore, Yajat Rohila, Meenakshi, Shaurya Prakash, Antresh Kumar, Priya Bhardwaj, Mulaka Maruthi, Azaj Ansari, Manoj K Gupta","doi":"10.1002/cmdc.202400774","DOIUrl":"10.1002/cmdc.202400774","url":null,"abstract":"Multicomponent reactions have long been recognized as some of the most versatile tools in organic chemistry, with extensive applications in biomedical science and the pharmaceutical industry. In this study, we explored the potential of the Passerini reaction by designing and synthesizing new low molecular mass gelators that can serve as novel formulations for prolonged anesthesia. These gelators address critical issues like poor solubility, low bioavailability, and short plasma half-life, all of which hinder therapeutic efficacy. To further understand the gelation mechanism, we performed density functional theory (DFT) calculation for confirming the presence of non-covalent interactions during gel formation. Additionally, we evaluated the antimicrobial properties of the synthesized compounds, aiming to counter the rise of infectious diseases. These innovative antimicrobial agents could offer solutions to the growing problem of antibiotic resistance, which renders many existing therapies ineffective. Overall, this study aims to develop advanced formulations and antimicrobial agents through the Passerini reaction, providing new strategies for treating infections, minimizing side effects, and combating antibiotic resistance.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400774"},"PeriodicalIF":3.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996925","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

Effects of Cholesterol on the Breast Cancer Resistance Protein: Studies through the Synthesis and Biological Evaluation of Chemical Tools. 胆固醇对乳腺癌抵抗蛋白的影响：化学工具的合成及生物学评价研究

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-21 DOI: 10.1002/cmdc.202400712

Ingrid Fatima Zattoni, Bruna Estelita Rugisnk, Isadora da Silva Zanzarini, Alan Guilherme Gonçalves, Vivian Rotuno Moure, Glaucio Valdameri, Ahcène Boumendjel

{"title":"Effects of Cholesterol on the Breast Cancer Resistance Protein: Studies through the Synthesis and Biological Evaluation of Chemical Tools.","authors":"Ingrid Fatima Zattoni, Bruna Estelita Rugisnk, Isadora da Silva Zanzarini, Alan Guilherme Gonçalves, Vivian Rotuno Moure, Glaucio Valdameri, Ahcène Boumendjel","doi":"10.1002/cmdc.202400712","DOIUrl":"10.1002/cmdc.202400712","url":null,"abstract":"The breast cancer resistance protein (BCRP/ABCG2) plays a major role in the multidrug resistance of cancers toward chemotherapeutic treatments. It was demonstrated that cholesterol regulates the ABCG2 activity, suggesting that lower levels of membrane cholesterol decrease the ABCG2 activity in mammalian cells. However, the precise mechanism remains unclear. To better understand the role of cholesterol in the ABCG2 activity, we studied the ABCG2-mediated efflux of different substrates in the presence of different concentrations of cholesterol. Moreover, we synthetized derivatives of cholesterol linked either to known ABCG2 inhibitors or fluorescents probes. A chalcone-cholesterol was synthetized to investigate the influence of cholesterol on ABCG2 inhibition, and a BODIPY-cholesterol was developed to track cholesterol trafficking on mammalian cells and investigate the behavior of cholesterol as an ABCG2 substrate. The obtained results with three different substrates of ABCG2 showed that cholesterol did not affect the intracellular amount of substrates nor the transport activity.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400712"},"PeriodicalIF":3.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996888","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

β-Glucuronidase-Responsive Albumin-Binding Prodrug of Colchicine-Site Binders for Selective Cancer Therapy. β-葡萄糖醛酸酶反应性白蛋白结合前药的秋水仙碱位点结合剂选择性癌症治疗。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-21 DOI: 10.1002/cmdc.202400969

Alexandra Bordes, Isabelle Opalinski, Fabien Thoreau, Olivier Provot, Abdallah Hamze, Mouad Alami, Sébastien Papot

引用次数: 0