RSC medicinal chemistry最新文献

{"title":"Small molecule drug discovery for Ebola virus disease","authors":"Destiny Durante, Venkatesh Murugesh, Tyler Kalanquin, Irina N. Gaisina, Lijun Rong and Terry W. Moore","doi":"10.1039/D5MD00533G","DOIUrl":"10.1039/D5MD00533G","url":null,"abstract":"<p >Known for its widespread outbreaks, including the 2013–2016 epidemic that infected almost 29 000 individuals and resulted in approximately 11 300 deaths, Ebola virus (EBOV) and related filoviruses remain a current threat as consecutive filoviral outbreaks have occurred between 2021 through 2025. Due to high fatality rates of 40–90% among infected individuals, researchers have invested significant efforts to discover effective treatments for Ebola virus disease. Small molecules hold great potential for treating Ebola virus disease because they can target various stages of the filoviral life cycle, such as entry, transcription, replication, and egress; however, the FDA has not yet approved any small molecule treatments for EBOV. In this review, we report both historic and recent progress in the discovery of small molecule drugs for EBOV.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4571-4598"},"PeriodicalIF":3.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12365685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966886","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}

{"title":"Hinge binder modification into imidazopyridine for targeting actionable mutations of RET kinase.","authors":"Arunkranthi Maturi, Vinay Pogaku, Surendra Kumar, Mi-Hyun Kim","doi":"10.1039/d5md00397k","DOIUrl":"10.1039/d5md00397k","url":null,"abstract":"<p><p>The RET proto-oncogene is a critical oncogenic driver in the development of several types of cancer. Despite the existence of clinically approved RET inhibitors, their limited response rates and emergence of resistance due to diverse actionable mutations underscore the need for novel therapeutics. Herein, we report substituted imidazo[1,2-<i>a</i>]pyridine derivatives as new RET inhibitors exhibiting IC₅₀ values as low as 11 nM against three distinct point mutations and three important RET fusions. The binding mode and measured potency were elucidated by induced-fit docking simulations and cardiotoxicity was evaluated.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076203","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}

{"title":"Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease <i>via</i> improving mitochondrial fusion.","authors":"Pradeep Kodam, Vaishali Kumar, Paramita Pattanayak, Praharsh Vitta, Tanmay Chatterjee, Shuvadeep Maity","doi":"10.1039/d5md00345h","DOIUrl":"10.1039/d5md00345h","url":null,"abstract":"<p><p>Mitochondrial dysfunction is one of the primary cellular conditions involved in developing Huntington's disease (HD) pathophysiology. The accumulation of mutant huntingtin protein with abnormal PolyQ repeats resulted in the death of striatal neurons with enhanced mitochondrial fragmentation. In search of neuroprotective molecules against HD conditions, we synthesized a set of isoxazole-based small molecules to screen their suitability as beneficial chemicals improving mitochondrial health. Systematic characterization of one of these isoxazole derivatives, C-5, demonstrated improved mitochondrial health with reduced apoptosis <i>via</i> rebalancing fission-fusion dynamics in HD condition. Gene and protein expression analysis confirmed that C-5 treatment enhanced the expression of mitochondrial fusion regulators (MFN1/2) <i>via</i> transcriptional upregulation of PGC-1α, a transcriptional co-activator controlling mitochondrial biogenesis. Collectively, this novel fusion agonist can potentially become a new therapeutic alternative for treating PolyQ-mediated mitochondrial dysfunction, a hallmark of HD pathology.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12415771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030671","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}

{"title":"Exploring novel thiazole-based minor groove binding agents as potential therapeutic agents against pathogenic Acanthamoeba castellanii","authors":"Hasan Y. Alniss, Ruqaiyyah Siddiqui, Meshal Daalah, Hadeel M. Al-Jubeh, Yousef A. Msallam, Bader S. Alawfi, Sreedevi Sajeev, Anil Ravi and Naveed A. Khan","doi":"10.1039/D5MD00475F","DOIUrl":"10.1039/D5MD00475F","url":null,"abstract":"<p >Due to limited advances in diagnosis and targeted therapy, as well as poor understanding of pathophysiology, infections due to <em>Acanthamoeba</em> have remained a medical concern. With their ability to selectively bind to DNA sequences, minor groove binders have emerged as useful therapeutic agents against parasitic infections. Herein, 6 novel thiazole-based minor groove binders were synthesized. Purification of intermediate compounds was accomplished by utilising silica gel column chromatography, while thin-layer chromatography was utilised to monitor reactions. The purification of the final products was achieved using liquid chromatography. Confirmation of structures was achieved by NMR spectroscopy and mass spectrometry. All compounds were evaluated against pathogenic <em>A. castellanii via in vitro</em> assays. At micromolar concentrations, selected minor groove binder derivatives revealed potent effects against (i) <em>A. castellanii</em> trophozoites as observed using amoebicidal assays, (ii), against <em>A. castellanii</em> cysts as observed using excystation assays, and (iii) against <em>A. castellanii</em>-mediated host cell death utilising human cerebrovascular endothelial cells, but (iv) showed limited effects against host cells alone, using cytotoxicity assays. The binding interaction between minor groove binders and DNA was studied using isothermal titration calorimetry and molecular docking simulations to provide insights into their binding affinity and mode of interaction. The findings of our study underscore the therapeutic value of thiazole-based minor groove binders as potent agents against <em>A. castellanii</em>, demonstrating effective antiamoebic activity with a low propensity for human cell damage, thus supporting their further development as antiamoebic agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 5084-5096"},"PeriodicalIF":3.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144967158","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":"Cyclometalated complexes: promising metallodrugs in the battle against cancer.","authors":"Andrés Amaya-Flórez, Jordi R-Galindo, Elkin Sanchez-Yocue, Adrian Ruiz-Martinez, Juan S Serrano-García, Adriana Romo-Pérez, Patricia Cano-Sanchez, Viviana Reyes-Marquez, Ronan Le Lagadec, David Morales-Morales","doi":"10.1039/d5md00178a","DOIUrl":"10.1039/d5md00178a","url":null,"abstract":"<p><p>Metal-based compounds are excellent alternative drugs for oncological treatment and research. The successful use of cisplatin and its derivatives clearly exemplifies the important role of such compounds in cancer therapy. However, the low selectivity, side effects, and resistance associated with this drug have led to the search for new strategies to overcome these limitations. For this reason, organometallic compounds are gaining significant attention as potential antitumor agents. Compared to platinum-based drugs, these compounds often exhibit greater stability, better lipophilicity, higher selectivity, and reduced resistance in cancer cells. This review aims to illustrate the antitumor properties of cyclometalated compounds containing metals from groups 8, 9, and 10. It also highlights various biochemical studies that attempted to explain how these compounds can enter cells, their different molecular targets, and the types of cell death that they can trigger.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001409","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}

{"title":"Discovery of a potent and selective PROTAC degrader for STAT3†","authors":"Kefeng Wang, Yuxin Zheng, Wenli Mao, Jing Xu and Yukun Wang","doi":"10.1039/D5MD00260E","DOIUrl":"10.1039/D5MD00260E","url":null,"abstract":"<p >The signal transducer and activator of transcription 3 (STAT3) protein and the p53 protein play opposite roles in the regulation of cell pathways. Activation of STAT3 upregulates survival pathways, while activation of p53 triggers apoptosis pathways. Therefore, STAT3 inhibition of p53 expression may play a central role in tumor development, and targeting STAT3 represents a promising therapeutic method for p53 reactivation in many cancers. Here, we report the design of <strong>S3D5</strong>, a BP-1-102-based proteolysis targeting chimera (PROTAC) that induces time- and dose-dependent degradation of STAT3 in HepG2 cells without significant effects on other STAT proteins. Preliminary mechanism studies show that <strong>S3D5</strong> degradation of the STAT3 protein is mediated by the ubiquitin–proteasome system (UPS). <strong>S3D5</strong> exhibits good anti-hepatocellular carcinoma cell proliferation activity, which can be explained by activating the p53 pathway. These findings demonstrate the utility and importance of PROTACs as preliminary chemical tools to investigate the function of the STAT3 protein. Further, <strong>S3D5</strong> may serve as a potential anti-hepatocellular carcinoma agent, laying a practical foundation for further development of potent STAT3-targeting PROTACs.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4872-4877"},"PeriodicalIF":3.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776169","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":"Toward routine utilisation of native mass spectrometry as an enabler of contemporary drug development.","authors":"Louise M Sternicki, Sally-Ann Poulsen","doi":"10.1039/d5md00617a","DOIUrl":"10.1039/d5md00617a","url":null,"abstract":"<p><p>As therapeutic modalities increasingly diversify, the need for biophysical tools for routine characterisation of the underlying biomolecular targets and their noncovalent interactions is growing. In this Opinion article we discuss the role of native mass spectrometry (nMS), a mass spectrometry technique where the intact biomolecule and its noncovalent interactions are preserved during the analysis, to gain important insights to guide drug discovery and development. We conclude that nMS is one of the most powerful technologies available with potential to rapidly advance multiple stages of therapeutic discovery and development, yet it is arguably underutilised. Specifically, we highlight how nMS may progress research for contemporary therapeutic modalities including those implicated in targeted protein degradation, fragment-based drug discovery and mRNA therapies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12319726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789844","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}

{"title":"Target agnostic cellular screening in the era of chemically induced proximity","authors":"Meizhong Jin","doi":"10.1039/D5MD00529A","DOIUrl":"10.1039/D5MD00529A","url":null,"abstract":"<p >We have enjoyed much success with target centric drug discovery as the leading approach in the past few decades. Target centric drug discovery starts with specific protein targets which are typically identified through diseases associated with human genetic changes such as mutations, or through genetic knock down or knock out methods, followed by additional functional validation. Despite successes, significant challenges remain: we often identify new protein targets that are deemed “undruggable”; also, for certain diseases, lack of clear understanding of underlying mechanisms prevents a target centric approach. Target agnostic cellular screening, as an alternative approach, has also been utilized in drug discovery to uncover unknown mechanisms behind a specific disease phenotype. While there have been noticeable successes, its application has been limited by the often perceived daunting process of mechanism-of-action deconvolution. Recently, a number of publications revealed examples of small molecules, identified from target agnostic cellular screenings, eliciting their function <em>via</em> “chemically induced proximity”. In many cases, the small molecules enable new protein–protein interactions that do not exist in the native cells, thus creating a “gain-of-function” effect that may not be recapitulated from knock down or knock out methods. In this perspective article, recent findings and their implications for drug discovery are discussed. Additionally, a general framework for target agnostic screening in the context of “chemically induced proximity” is proposed, aiming to maximize the efficiency of hit finding by balancing screening efforts with mechanism-of-action deconvolution, including key factors such as the nature of compounds for screening, assay format, and readout.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4532-4539"},"PeriodicalIF":3.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776084","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":"Small molecule antipathogenic agents against Staphylococcus aureus infections","authors":"Paulo Anastácio Furtado Pacheco, Charlotte Uldahl Jansen, Morten Rybtke, Tim Tolker-Nielsen and Katrine Qvortrup","doi":"10.1039/D5MD00272A","DOIUrl":"10.1039/D5MD00272A","url":null,"abstract":"<p > <em>Staphylococcus aureus</em>, a Gram-positive bacterium, is a pathogen capable of infecting nearly all host tissues, causing severe morbidity and mortality. Antibiotic resistant <em>S. aureus</em> are abundant, and multidrug resistant strains are emerging worldwide. The emergence and spread of antibiotic resistant bacterial strains is a growing public health concern, and new approaches are urgently needed to combat this threat. One promising strategy is to develop so-called ‘antipathogenic’ drugs, which acts by blocking bacterial virulence factors. <em>S. aureus</em> produces an array of virulence factors that enhance bacterium survival and spreading in the host by degrading host tissue, liberating nutrients from the host, and evading host immune responses. In contrast to antibiotics, antipathogenic drugs do not kill bacteria or stop their growth and are assumed not to impose a strong selection for resistance traits. Thus, by targeting virulence factors, it may be possible to reduce the severity of bacterial infections, giving the immune system an upper hand, without promoting the development of resistance. This review describes work done on developing small molecules that target three virulence categories: pore-forming toxins, immune evasion, and quorum sensing. We discuss the structure–activity relationships (SAR) of the various compounds investigated, focusing on their mechanisms of action and therapeutic potential. The review highlights the potential of targeting virulence factors as a promising strategy to combat antibiotic resistant infections, and suggests directions for further research to identify new compounds with improved efficacy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3852-3883"},"PeriodicalIF":3.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776171","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":"Amphiphilic nebramine analogs synergize with β-lactam/β-lactamase inhibitor combinations, including cefepime–taniborbactam and meropenem–xeruborbactam against metallo-β-lactamase-carrying Pseudomonas aeruginosa†","authors":"Christian Lozeau, Danzel Ramirez, Danyel Ramirez, Gulshan Kumar, Rajat Arora, George Zhanel, Gilbert Arthur and Frank Schweizer","doi":"10.1039/D5MD00375J","DOIUrl":"10.1039/D5MD00375J","url":null,"abstract":"<p >Cefepime–taniborbactam (FEP–TAN) and meropenem–xeruborbactam (MEM–XER) are β-lactam–β-lactamase inhibitor (BL–BLI) combinations currently in development and both projected to treat metallo-β-lactamase (MBL)-producing Gram-negative pathogens. Among Gram-negative pathogens, the low permeability of the outer membrane of <em>Pseudomonas aeruginosa</em> poses unique challenges to drug discovery in general and to BL–BLIs in particular. This study set out to augment β-lactam antibiotic potency by enhancing outer membrane permeability of <em>P. aeruginosa</em> using novel amphiphilic aminoglycoside-based outer membrane permeabilizers. Amphiphilic nebramines acting as outer membrane permeabilizers, were synthesized and evaluated in combination with β-lactam antibiotics and BL–BLIs against <em>P. aeruginosa</em> clinical isolates harbouring a number of resistance determinants, including MBLs. Dually guanidinylated and C-5-alkylated analogs of nebramine were able to sensitize MBL-carrying <em>P. aeruginosa</em> to various BL–BLIs. The amphiphilic nebramine derivative, compound <strong>4</strong>, synergized with multiple β-lactam antibiotics and BL–BLIs including aztreonam–avibactam (ATM–AVI), FEP–TAN and MEM–XER against multidrug-resistant <em>P. aeruginosa</em> isolates. In particular, compound <strong>4</strong> + ATM–AVI, restored susceptibility to all nine β-lactamase (including MBL)-harbouring <em>P. aeruginosa</em> strains that were previously resistant to aztreonam. Compound <strong>4</strong> was found to be less toxic than both polymyxin B and its corresponding amphiphilic tobramycin counterpart (compound <strong>7</strong>) in human renal cell lines, RPTEC and HK-2. Overall, our study suggests that addition of compound <strong>4</strong> alongside next-generation BL–BLIs such as FEP–TAN, MEM–XER as well as the recently approved ATM–AVI combination can overcome intrinsic and acquired <em>in vitro P. aeruginosa</em> resistance determinants that confer high-level resistance to β-lactam antibiotics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4492-4509"},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744605","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}