ChemMedChemPub Date : 2025-01-30DOI: 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":"<p><p>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 (K<sub>i</sub>=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 IC<sub>50</sub> of 5.8 μM, significantly higher than verapamil's IC<sub>50</sub> of 0.41 μM, and haloperidol's IC<sub>50</sub> 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.</p>","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}
ChemMedChemPub Date : 2025-01-28DOI: 10.1002/cmdc.202400995
Gilles Ouvry
{"title":"ABT, Elacridar and Bile-Duct Cannulated Rats: Tools to Understand Pharmacokinetics.","authors":"Gilles Ouvry","doi":"10.1002/cmdc.202400995","DOIUrl":"https://doi.org/10.1002/cmdc.202400995","url":null,"abstract":"<p><p>Optimizing pharmacokinetics is an integral part of drug design, albeit a lesser understood one from the medicinal chemist's perspective. Over the years, molecular tools and experimental strategies have been developed to better understand the fate of compounds. Among these, the use of aminobenzotriazole (ABT), elacridar and bile-duct cannulated rats have been instrumental in gaining valuable PK insights, with a direct impact on drug design.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400995"},"PeriodicalIF":3.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057603","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}
ChemMedChemPub Date : 2025-01-23DOI: 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":"<p><p>A key molecular dysfunction in heart failure is the reduced activity of the cardiac sarcoplasmic reticulum Ca<sup>2+</sup>-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 Ca<sup>2+</sup> transport in adult mouse cardiac cells. While these natural products exert off-target effects on Ca<sup>2+</sup> 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.</p>","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}
ChemMedChemPub Date : 2025-01-23DOI: 10.1002/cmdc.202400971
Marta Kučerová-Chlupáčová
{"title":"Systematic Review on 1,2,3-Oxadiazoles, 1,2,4-Oxadiazoles, and 1,2,5-Oxadiazoles in the Antimycobacterial Drug Discovery.","authors":"Marta Kučerová-Chlupáčová","doi":"10.1002/cmdc.202400971","DOIUrl":"10.1002/cmdc.202400971","url":null,"abstract":"<p><p>Tuberculosis remains a leading global health threat, exacerbated by the emergence of multi-drug-resistant strains. The search for novel therapeutic agents is critical in addressing this challenge. This review systematically summarizes the potential of oxadiazole derivatives as promising candidates in antimycobacterial drug discovery. We focus on various classes of oxadiazoles, especially 1,2,3-oxadiazoles, 1,2,4-oxadiazoles, and 1,2,5-s in structure-activity relationship studies are discussed, emphasizing the mechanisms of antimycobacterial action. Additionally, the synergistic potential of 1,2,4-oxadiazoles in enhancing the efficacy of existing tuberculosis treatment with ethionamide is also discussed. By integrating insights from recent research, this review aims to provide a comprehensive overview of the role of oxadiazoles in the fight against tuberculosis, paving the way for future investigations and the development of effective therapeutic strategies.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400971"},"PeriodicalIF":3.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021329","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}
ChemMedChemPub Date : 2025-01-22DOI: 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
{"title":"Aminocholestane and Aminoandrostane Inhibitors of the SH2 Domain-Containing Inositol 5'-Phosphatase (SHIP).","authors":"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","doi":"10.1002/cmdc.202400597","DOIUrl":"10.1002/cmdc.202400597","url":null,"abstract":"<p><p>The SH2-containing inositol phosphatase (SHIP) has become an actively researched therapeutic target for a number of disorders, including Alzheimer's Disease, Graft-vs-Host disease, obesity and cancer. Analogs of the aminosteroid SHIP inhibitor 3α-aminocholestane (3AC) have been synthesized and tested. Analogs with improved water solubility have been identified. Deletion of the C17 alkyl group from the cholestane skeleton improves water solubility, however these compounds inhibit both SHIP1 and SHIP2. Enzyme kinetics imply that these molecules are competitive inhibitors of SHIP, binding at a site near where the substrate binds to the phosphatase. A model of the binding of the inhibitors within the active site of SHIP1 is proposed to explain the structure activity studies. Overall this work provides more water soluble aminosteroid pan-SHIP1/2 inhibitors that can be used for future studies of SHIP activity.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400597"},"PeriodicalIF":3.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021320","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}
ChemMedChemPub Date : 2025-01-22DOI: 10.1002/cmdc.202400927
Andrea Astolfi, Giada Cernicchi, Erika Primavera, Marco Rocchi, Giuseppe Manfroni, Stefano Sabatini, Maria Letizia Barreca
{"title":"Addressing Data Point Homogeneity and Annotation Challenges to Enhance Data-Driven Approaches: The S. aureus NorA Efflux Pump Case Study.","authors":"Andrea Astolfi, Giada Cernicchi, Erika Primavera, Marco Rocchi, Giuseppe Manfroni, Stefano Sabatini, Maria Letizia Barreca","doi":"10.1002/cmdc.202400927","DOIUrl":"10.1002/cmdc.202400927","url":null,"abstract":"<p><p>In this study, we analyzed publicly accessible data related to the Staphylococcus aureus NorA protein, a well-known efflux pump involved in antimicrobial resistance. Our analysis revealed several inconsistencies in data annotation, and significant issues concerning the homogeneity across datasets, which compromise the reliability of data-driven approaches aimed at identifying novel Staphylococcus aureus NorA efflux pump inhibitors (EPIs). To address these challenges, we propose a standardized pipeline for experimental procedures and data annotation, designed to enhance the consistency and quality of EPI datasets submitted to repositories, thereby increasing the utility of publicly available datasets for the discovery of potential EPIs. By implementing this framework, the findings reported herein aim to foster more reliable and reproducible research outcomes in drug discovery projects targeting NorA or other efflux pumps.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400927"},"PeriodicalIF":3.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021316","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}
{"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":"<p><p>The serine/threonine protein kinase CK2, a tetramer composed of a regulatory dimer (CK2β<sub>2</sub>) 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.</p>","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}
{"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":"<p><p>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.</p>","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}
ChemMedChemPub Date : 2025-01-21DOI: 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":"<p><p>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.</p>","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}
{"title":"β-Glucuronidase-Responsive Albumin-Binding Prodrug of Colchicine-Site Binders for Selective Cancer Therapy.","authors":"Alexandra Bordes, Isabelle Opalinski, Fabien Thoreau, Olivier Provot, Abdallah Hamze, Mouad Alami, Sébastien Papot","doi":"10.1002/cmdc.202400969","DOIUrl":"10.1002/cmdc.202400969","url":null,"abstract":"<p><p>The development of novel therapeutic strategies enabling the selective destruction of tumors while sparing healthy tissues is of great interest to improve the efficacy of cancer chemotherapy. In this context, we designed a β-glucuronidase-responsive albumin-binding prodrug programmed to release a potent Isocombretastatin A-4 analog within the tumor microenvironment. When injected at a non-toxic dose in mice bearing orthotopic triple-negative mammary tumors, this prodrug produced a significant anticancer activity, therefore offering a valuable alternative to the systemic administration of the parent drug.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400969"},"PeriodicalIF":3.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996929","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}