ChemMedChem最新文献_第8页

Advancing Accurate Quantification of Protein-Ligand Interactions: Differential Scanning Calorimetry as a Precision Screening Tool Using BCL-2 as a Model System 推进精确定量的蛋白质-配体相互作用：差示扫描量热法作为精确筛选工具使用BCL-2作为模型系统。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-03 DOI: 10.1002/cmdc.202500744

Bircan Dinc, Berna Dogan, Thomas Mavromoustakos, Serdar Durdağı

{"title":"Advancing Accurate Quantification of Protein-Ligand Interactions: Differential Scanning Calorimetry as a Precision Screening Tool Using BCL-2 as a Model System","authors":"Bircan Dinc, Berna Dogan, Thomas Mavromoustakos, Serdar Durdağı","doi":"10.1002/cmdc.202500744","DOIUrl":"10.1002/cmdc.202500744","url":null,"abstract":"Accurate and reliable quantification of protein–ligand energetics at the screening stage is often complicated by ligand aggregation, hydrophobicity-driven artifacts, and the need for cosolvents. Here, differential scanning calorimetry (DSC) as a quantitative, label-free screening method is evaluated using BCL-2 as a model oncogenic target. Nine inhibitors (i.e., venetoclax, navitoclax; and seven previously prioritized BCL-2 hit inhibitors by our research group) are profiled across solvent systems, including neat DMSO, 10% DMSO, and a ternary matrix (S3: 10% DMSO, 90% sulfobutylether-β-cyclodextrin (SBE-β-CD) in saline). DSC yielded thermal transition temperatures and thermodynamic parameters (ΔH, ΔG) that enabled ranking of binding strength. Solubility challenges are addressed by S3, which improved thermal signal quality. Comparisons with time-resolved fluorescence energy transfer (TR-FRET) analysis, in vitro assays, and MM/GBSA binding free energy results confirmed DSC's accuracy in detecting binding energetics. Collectively, these results position DSC as a robust, material-efficient tool for thermodynamic screening of BCL-2 ligands and other poorly soluble compounds, and as a practical complement to isothermal titration calorimetry when solubility or kinetic limitations prevail.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343061","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

We Licked the Toads so You Don’t Have to: A Comprehensive Analysis of the Chemical Syntheses of the Classical Psychedelics Bufotenin(e) and 5-Methoxy-N,N-Dimethyltryptamine 《我们舔蟾蜍，这样你就不用舔了：经典迷幻药丁氟tenin(e)和5-甲氧基- n， n -二甲基色胺化学合成的综合分析》。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-01 DOI: 10.1002/cmdc.202500525

Anton Homon, Jaxon Laramie, John J. Hayward, John F. Trant

{"title":"We Licked the Toads so You Don’t Have to: A Comprehensive Analysis of the Chemical Syntheses of the Classical Psychedelics Bufotenin(e) and 5-Methoxy-N,N-Dimethyltryptamine","authors":"Anton Homon, Jaxon Laramie, John J. Hayward, John F. Trant","doi":"10.1002/cmdc.202500525","DOIUrl":"10.1002/cmdc.202500525","url":null,"abstract":"Bufotenin (also spelt as bufotenine) and its methylated derivative, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are potent psychedelics that are found in many plants but also excreted by some species of toads. The compounds are regulated differently around the world, and although used in traditional medicine, 20th-century prohibition culture has slowed research into their utility for ameliorating psychological disorders and inflammatory and neurodegenerative diseases. However, the global trend toward legalization and a renewed interest in the therapeutic potential of psychedelics has increased the number of clinical and preclinical studies of these and related materials. This necessitates access to large amounts of these compounds, but they are not commercially available on scale, leaving researchers with a need to either contract out, or make their own. The first bufotenin synthesis was reported in 1935 by Hoshino and coworkers, and novel syntheses are still being disclosed in the 2020s. This is the first effort to collate and compare all extant academic and patent syntheses (as of fall 2024) into a single review so that researchers can identify the most appropriate route for their own purposes. We conclude by highlighting outstanding challenges that are ripe for solutions to reduce the cost of any future commercial-scale production.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12950517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324120","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

Exploring Coumarin-Triazole Derivatives as Selective Inhibitors of Carbonic Anhydrase IX and XII 香豆素-三唑衍生物作为碳酸酐酶IX和XII选择性抑制剂的研究。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-25 DOI: 10.1002/cmdc.202500959

Vadakattu Manasa, Shaik Mahammad Ghouse, Niccolò Paoletti, Kareena Sinha, Srikanth Danaboina, Nitesh Tamang, Devandla Soujanya, Venkata Madhavi Yaddanapudi, Claudiu T. Supuran, Srinivas Nanduri

{"title":"Exploring Coumarin-Triazole Derivatives as Selective Inhibitors of Carbonic Anhydrase IX and XII","authors":"Vadakattu Manasa, Shaik Mahammad Ghouse, Niccolò Paoletti, Kareena Sinha, Srikanth Danaboina, Nitesh Tamang, Devandla Soujanya, Venkata Madhavi Yaddanapudi, Claudiu T. Supuran, Srinivas Nanduri","doi":"10.1002/cmdc.202500959","DOIUrl":"10.1002/cmdc.202500959","url":null,"abstract":"Human carbonic anhydrases (hCAs), particularly the cancer-linked isoforms hCA IX and XII, are essential in regulating the abnormal metabolism and pH gradient in cancer cells, facilitating tumor progression, invasiveness, and resistance to chemotherapy. In this study, we designed and synthesized twenty novel 6-functionalized coumarin derivatives bearing 1,2,3-triazole moieties via amide linkers of varying alkyl chain lengths. These molecules were screened for inhibitory effects on hCA isoforms I, II, IX, and XII. The data demonstrated selective inhibition to the cancer-related isoforms hCA IX and XII (Ki values ranging from 79 to 96 nM), with negligible activity against the off-target isoforms hCA I and II (Ki > 100 µM). Among the synthesized compounds, 6d, 7d, and 6f showed the highest potency of Ki 79.5, 81.8, and 94.4 nM against hCA IX and 83.5, 88.3, and 79.5 nM against hCA XII, respectively. Structure–activity relationship analysis highlighted that shorter linkers and electron-withdrawing substituents enhanced potency. Our study confirms the promise of the coumarin-triazole scaffold as a selective and reliable platform for developing anticancer CA inhibitors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147288869","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

4-(5-Chloro-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-yl)benzenesulfonamide: A Novel Polypharmacology Agent to Target Carbonic Anhydrase IX and XII With Improved Selectivity, Wnt/β-Catenin Signaling Pathway, and P-Glycoprotein 4-（5-氯-3-（3,4,5-三甲氧基苯甲酰）- 1h -吲哚-1-基）苯磺酰胺：一种选择性靶向碳酸酐酶IX和XII的新型多药理学药物，Wnt/β-Catenin信号通路，p -糖蛋白。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-25 DOI: 10.1002/cmdc.202500996

Michela Puxeddu, Rosa Bordone, Claudia Colla, Gabriele Rotili, Antonio Coluccia, Pietro Sciò, Petra Cuřínová, Alessio Nocentini, Claudiu T. Supuran, Serena Filiberti, Marta Turati, Roberto Ronca, Joanna Kopecka, Chiara Riganti, Lucia Jimenez, Wolfgang Link, Chiara Bigogno, Giulio Dondio, Martina Barba, Gianluca Canettieri, Romano Silvestri, Giuseppe La Regina

{"title":"4-(5-Chloro-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-yl)benzenesulfonamide: A Novel Polypharmacology Agent to Target Carbonic Anhydrase IX and XII With Improved Selectivity, Wnt/β-Catenin Signaling Pathway, and P-Glycoprotein","authors":"Michela Puxeddu, Rosa Bordone, Claudia Colla, Gabriele Rotili, Antonio Coluccia, Pietro Sciò, Petra Cuřínová, Alessio Nocentini, Claudiu T. Supuran, Serena Filiberti, Marta Turati, Roberto Ronca, Joanna Kopecka, Chiara Riganti, Lucia Jimenez, Wolfgang Link, Chiara Bigogno, Giulio Dondio, Martina Barba, Gianluca Canettieri, Romano Silvestri, Giuseppe La Regina","doi":"10.1002/cmdc.202500996","DOIUrl":"10.1002/cmdc.202500996","url":null,"abstract":"We synthesized novel pyrrole (5–11) and indole (12–16) derivatives based on a polypharmacology approach aimed to obtain inhibitors of human carbonic anhydrase (hCA) with improved selectivity toward the IX and XII isoforms, Wnt/β-catenin pathway, and P-glycoprotein (P-gp). Inspection of the binding sites of the hCA I, II, IX, and XII isoforms highlighted small but significant differences of cavity volumes that guided the introduction of small substituents at Position 4 of the 3-phenyl ring of the pyrrole and at Position 5 of the indole. Compound 15 exhibited potent and selective inhibition of both hCA IX and XII isoforms compared to the parent compound. It inhibited the Wnt/β-catenin pathway abrogating the association of β-catenin with TCF-4 and the multidrug-resistant P-gp-expressing cancer cells. Compound 15 showed strong inhibition of viability of SW620, SW480, and HCT116 CRC and TNBC cell lines, restored the sensitivity to doxorubicin (DOX) in HT29/DX P-gp-overexpressing cells, and showed medium metabolic stability in both human and mouse microsomes and acceptable predicted oral bioavailability. Compound 15 is a robust lead compound for the development of new antitumor agents based on the polypharmacology approach.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12935169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147288808","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

Investigating the Ligand-Binding Properties of N-arylbenzimidazoles as Novel Elastase Inhibitors. 新型弹性酶抑制剂n -芳基苯并咪唑的配体结合特性研究。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-25 Epub Date: 2025-12-21 DOI: 10.1002/cmdc.202500879

Giovanna Pitasi, Sonia Floris, Francesca Mancuso, Giulia Savoca, Rosaria Gitto, Antonella Fais, Laura De Luca

{"title":"Investigating the Ligand-Binding Properties of N-arylbenzimidazoles as Novel Elastase Inhibitors.","authors":"Giovanna Pitasi, Sonia Floris, Francesca Mancuso, Giulia Savoca, Rosaria Gitto, Antonella Fais, Laura De Luca","doi":"10.1002/cmdc.202500879","DOIUrl":"10.1002/cmdc.202500879","url":null,"abstract":"Human elastase 1 has been shown to possess an important role in maintaining skin stability and elasticity through the proteolytic cleavage of elastin (ELN), a hydrophobic protein that serves as a key component of extracellular matrix in the skin. The development of antielastase agents represents a promising therapeutic approach for treating skin pathologies characterized by elastin degradation, with applications in both dermatology and cosmetology. Reversible inhibitors represent a therapeutic strategy, offering selective inhibition of elastase proteolytic activity while preserving the function of other physiologically essential serine proteases. Using porcine pancreatic elastase (PPE) as a well-established surrogate of human skin elastase, a focused series of noncovalent inhibitors designed to bind the catalytic area of PPE is assayed. Several compounds display an antielastase activity, including N-(2-bromophenyl)-2-(6-chloro-1-(3,5-dimethylbenzyl)-1H-benzo[d]imidazol-2-ylthio)acetamide (7) that exhibits the most potent inhibitory effects (IC50 = 41.1 µM), similar to standard compound oleanolic acid (IC50 value of 25.7 µM). The observed structure-activity relationship is further validated through molecular docking and dynamic studies, which provide mechanistic understanding of the binding interactions and establish suggestions for further rational drug design.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500879"},"PeriodicalIF":3.4,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12913230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802638","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

Gram-Scale Synthesis of an Arylsulfonamide-Type Alkaline Phosphatase Inhibitor 一种芳基磺酰胺型碱性磷酸酶抑制剂的克级合成。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-25 DOI: 10.1002/cmdc.202500328

Zsolt Rapi, Krisztina Fülöp, Zoltán Mucsi

{"title":"Gram-Scale Synthesis of an Arylsulfonamide-Type Alkaline Phosphatase Inhibitor","authors":"Zsolt Rapi, Krisztina Fülöp, Zoltán Mucsi","doi":"10.1002/cmdc.202500328","DOIUrl":"10.1002/cmdc.202500328","url":null,"abstract":"Alkaline phosphatases (ALP) are present in most living organisms. This family of metalloenzymes catalyzes transphosphorylation reactions and hydrolyzes phosphate monoesters. ALP enzymes have significant roles in several physiological processes and disease states. Inhibition of these enzymes makes it possible to prevent or treat certain diseases, and their role in normal physiology can also be examined. Several inhibitors with diverse chemical structures have been reported. One of them, known as SBI-425, has a low IC50 value (16 nM). An alternative, scalable method was established to prepare SBI-425 in larger amounts for in vivo experiments. In three simple steps, 4-chloroanisole was transformed to the appropriate sulfonyl chloride, which was used to acylate 3-aminonicotinamide. Without the need for chromatography or crystallization, the desired inhibitor was obtained with >90% purity (based on UPLC-MS analysis). The synthesis could also be carried out on a 10-fold scale, with identical outcomes. The final product was subjected to biological testing, and it was found to be effective in inhibiting ALP activity in mouse serum.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12935166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147288911","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

Therapeutic Approaches to Treat SARS-CoV-2 SARS-CoV-2的治疗方法

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-25 DOI: 10.1002/cmdc.202500387

Lekhnath Sharma, Neelesh Maheshwari, Nupur Maheshwari, Ghanshyam Teli, Venkatesh Chelvam

{"title":"Therapeutic Approaches to Treat SARS-CoV-2","authors":"Lekhnath Sharma, Neelesh Maheshwari, Nupur Maheshwari, Ghanshyam Teli, Venkatesh Chelvam","doi":"10.1002/cmdc.202500387","DOIUrl":"10.1002/cmdc.202500387","url":null,"abstract":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), also known as COVID-19, spread across the globe, leading to a pandemic. Initially, the drug remdesivir is approved by the FDA for the treatment of SARS-CoV-2. Significant efforts have been directed toward epidemiology of the SARS-CoV-2 virus to discover potential drug targets that may contribute to the development of effective prevention and treatment strategies. The structure and functions of SARS-CoV-2 proteins that may be potential drug targets, including the spike protein, main protease, papain-like protease, RNA-dependent RNA polymerase, host proteins like angiotensin-converting enzyme 2, and transmembrane protease and serine 2, have been thoroughly studied. Biological screening platforms and repurposing have resulted in the discovery of drugs such as nirmatrelvir-ritonavir (Paxlovid), remdesivir (Veklury), molnupiravir (Lagevrio), anakinra (Kineret), vilobelimab (Gohibic), baricitinib (Olumiant), and tocilizumab (Actemra). The present analysis provides details on the pathogenesis, prevention, diagnosis, clinical characteristics, and potential treatment options currently available worldwide.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147288883","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

Novel β-L-2′-deoxyribonucleoside Reverse Fleximers with Inhibitory Activity Against HBV, BKV, and Other Viruses 新型β-L-2'-脱氧核糖核苷逆柔剂对HBV， BKV和其他病毒具有抑制活性。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-23 DOI: 10.1002/cmdc.202500829

Christianna H. M. Kutz, Grayson D. Pipher, Anika Vedire, Katherine L. Seley-Radtke

{"title":"Novel β-L-2′-deoxyribonucleoside Reverse Fleximers with Inhibitory Activity Against HBV, BKV, and Other Viruses","authors":"Christianna H. M. Kutz, Grayson D. Pipher, Anika Vedire, Katherine L. Seley-Radtke","doi":"10.1002/cmdc.202500829","DOIUrl":"10.1002/cmdc.202500829","url":null,"abstract":"Since their discovery as potential antiviral agents in the early 1990s, L-nucleosides have been developed as treatments for various viruses including hepatitis B virus (HBV) due to their efficacy and lower toxicity compared to their D-enantiomers. One prominent L-nucleoside is telbivudine (LdT), also known as L-thymidine, and is used for the treatment of chronic HBV infections. However, telbivudine, like many other L-nucleosides, is prone to the development of drug resistance due to commonly occurring point mutations. Additionally, for both LdT and its cytidine analogue, antiviral activity has only been reported against HBV. Looking to improve upon this scaffold, a series of novel β-L-2′-deoxyribonucleoside reverse fleximer nucleoside analogues were synthesized, and several were found to exhibit antiviral activity across several viral families including flaviviruses, filoviruses, hepadnaviruses, herpesviruses, polyomaviruses, and togaviruses. The most promising compound, CHK-02, exhibited antiviral activity again human polyomavirus 1 (BK virus) in the nanomolar range (<48 nM), low-micromolar activity against HBV (<0.32 µM), and moderate activity against several other viruses with minimal toxicity. Thus, this showed that L-nucleoside reverse fleximers may have promise as potent, broad-spectrum antiviral therapeutics. The synthesis and antiviral activity results of these novel β-L-2′-deoxyribonucleoside reverse fleximers are reported herein.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269289","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

An Imidazo[2,1-b][1,3,4]thiadiazole Derivative Inhibits the Virulence Factor α-Hemolysin by Blocking the Pullout of Its Stem Domain 咪唑[2,1-b][1,3,4]噻二唑衍生物通过阻断毒力因子α-溶血素茎结构域的拉出抑制其毒性。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-23 DOI: 10.1002/cmdc.202501098

Vadim S. Korotkov, Peer Lukat, Raffaella Di Lucrezia, Aditya Shekhar, Carsten Degenhart, Randi Diestel, Ursula Bilitewski, Klaus Dinkel, Wulf Blankenfeldt, Mark Brönstrup

{"title":"An Imidazo[2,1-b][1,3,4]thiadiazole Derivative Inhibits the Virulence Factor α-Hemolysin by Blocking the Pullout of Its Stem Domain","authors":"Vadim S. Korotkov, Peer Lukat, Raffaella Di Lucrezia, Aditya Shekhar, Carsten Degenhart, Randi Diestel, Ursula Bilitewski, Klaus Dinkel, Wulf Blankenfeldt, Mark Brönstrup","doi":"10.1002/cmdc.202501098","DOIUrl":"10.1002/cmdc.202501098","url":null,"abstract":"Staphylococcus aureus is a major human pathogen responsible for severe infections that necessitate alternative therapeutic strategies. Its key virulence factor α-hemolysin (Hla) mediates host cell damage via pore formation, making it an attractive target for antivirulence interventions. Here, we report the development of a high-throughput cellular assay measuring toxin-induced calcium influx. Its application led to the identification of thiadiazole-based small molecule inhibitors of Hla. Structure–activity relationship studies with 18 analogs led to inhibitors with a cellular potency up to 5.4 µM. X-ray crystallography of Hla in complex with compound 1 revealed that the thiadiazole bound a hydrophobic pocket at the interface of the amino latch and prestem domains, exerting a dual mechanism that blocks stem loop unfolding as well as membrane attachment. These findings introduce thiadiazoles as a novel chemical class of antivirulence therapeutics against S. aureus infections.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12926788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269220","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

Decoding Class III Phosphatidylinositol 3-Kinase (PtdIns3K) Regulation: Mechanistic Insights and Therapeutic Opportunities 解码III类磷脂酰肌醇3-激酶（PtdIns3K）调控：机制见解和治疗机会。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-22 DOI: 10.1002/cmdc.202501033

Qiao Liu, Jing Ye, Can Chen, Yanghui Zhu, Gu He, Fengbo Wu

引用次数: 0