RSC medicinal chemistry最新文献_第2页

Design of galectin-1-conjugated nanoparticles as potential immunomodulatory agents. 半乳糖凝集素-1缀合纳米颗粒作为潜在免疫调节剂的设计。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-26 DOI: 10.1039/d5md00539f

Chandradhish Ghosh, Ling Yao, Marilet Sigler, Santiago Di Lella, Alejandro J Cagnoni, Gabriel A Rabinovich, Peter H Seeberger

{"title":"Design of galectin-1-conjugated nanoparticles as potential immunomodulatory agents.","authors":"Chandradhish Ghosh, Ling Yao, Marilet Sigler, Santiago Di Lella, Alejandro J Cagnoni, Gabriel A Rabinovich, Peter H Seeberger","doi":"10.1039/d5md00539f","DOIUrl":"10.1039/d5md00539f","url":null,"abstract":"Autoimmune disorders are heterogeneous dynamic conditions characterized by dysregulated immune responses and caused by interruption of tolerogenic circuits. Although immunosuppressive drugs, including biological agents, are effective therapeutic options, several patients do not respond to these treatment or develop resistance mechanisms. Galectins, a family of soluble glycan-binding proteins, play central roles in the modulation of autoimmune inflammation. Galectin-1 (Gal-1), a prototype member of this family, interacts with specific N-acetyllactosamine (LacNAc) ligands present in N- and O-glycans via its conserved carbohydrate recognition domain (CRD). The immunomodulatory activity of Gal-1 involves regulation of T cell effector populations, inducing apoptosis of Th1 and Th17 cells, differentiation of tolerogenic dendritic cells and induction of myeloid-derived suppressor cells. To develop a rational galectin-based therapeutic strategy, we evaluated whether Gal-1 retains its function upon multivalent presentation on nanoparticles. Specifically, we report the design strategy, synthesis and characterization of galectin-1-conjugated glucose-stabilized gold nanoparticles, and compare their activities with unconjugated galectin-1. This formulation offers novel opportunities for treating a variety of autoimmune diseases, as well as chronic inflammatory disorders.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12507049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259001","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

Tanshinones target drug-resistant tuberculosis: efficacy, selectivity, and potential mechanism of action. 丹参酮靶向耐药结核：疗效、选择性和潜在的作用机制。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-25 DOI: 10.1039/d5md00637f

Giulia Polinário, Maiara A B C Rosa, Débora L Campos, Liliana L S Moraes, Marli M A de Campos, Ingrid Gracielle M Silva, Karine B Barros-Cordeiro, Sônia N Báo, Fernando R Pavan

{"title":"Tanshinones target drug-resistant tuberculosis: efficacy, selectivity, and potential mechanism of action.","authors":"Giulia Polinário, Maiara A B C Rosa, Débora L Campos, Liliana L S Moraes, Marli M A de Campos, Ingrid Gracielle M Silva, Karine B Barros-Cordeiro, Sônia N Báo, Fernando R Pavan","doi":"10.1039/d5md00637f","DOIUrl":"10.1039/d5md00637f","url":null,"abstract":"This study evaluates the antimycobacterial potential of tanshinone I (TI), tanshinone IIA (TIIA), and cryptotanshinone (CPT), natural compounds isolated from Salvia miltiorrhiza, against Mycobacterium tuberculosis, the primary etiological agent of tuberculosis. Given the global challenge posed by antimicrobial resistance and the complexity of current treatment regimens, we aimed to identify effective and safe alternative therapies. The compounds' in vitro activity was initially assessed via minimum inhibitory concentration (MIC90) and cytotoxicity index (CI50) determinations, yielding MIC90 values of 1.03, 0.38, and 1.21 μg mL-1 for TI, TIIA, and CPT, respectively, with low toxicity and high selectivity indices. A narrow antimicrobial spectrum was observed upon testing against representative bacteria, fungi, and non-tuberculous mycobacteria (NTM). Combination assays with rifampicin revealed synergism for TI and indifference for TIIA and CPT, as determined by the fractional inhibitory concentration index (FICI). Scanning electron microscopy (SEM) revealed morphological alterations in the bacilli's cell wall, suggesting it as a possible target of the compounds' mechanism of action. Whole genome sequencing (WGS) of resistant strains identified mutations predominantly in PE_PGRS family genes, supporting the hypothesis that tanshinones modulate cell wall structure. Finally, efficacy was confirmed against multidrug-resistant clinical isolates, with MIC90 values near 1 μg mL-1. These findings position TI, TIIA, and CPT as promising candidates for developing new therapies against drug-resistant tuberculosis.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252420","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 RNA-binding fragments using biolayer interferometry. 利用生物层干涉法发现rna结合片段。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-19 DOI: 10.1039/d5md00673b

Vipul Navinchandra Panchal, Jan-Åke Husmann, Kaja Günther, Muhammad Zeeshan, Bengt Erik Haug, Ruth Brenk

{"title":"Discovery of RNA-binding fragments using biolayer interferometry.","authors":"Vipul Navinchandra Panchal, Jan-Åke Husmann, Kaja Günther, Muhammad Zeeshan, Bengt Erik Haug, Ruth Brenk","doi":"10.1039/d5md00673b","DOIUrl":"10.1039/d5md00673b","url":null,"abstract":"Structured RNAs are increasingly explored as novel pharmacological targets for a range of diseases. Therefore, evaluating methods for RNA-focused hit discovery is crucial. Biolayer Interferometry (BLI), a label-free technique that detects biomolecular interactions by measuring changes in white light interference near the sensor surface, offers high throughput and multiplexing capabilities. While BLI has been widely adopted for protein-targeted screening, its application in RNA-targeted drug discovery remains largely unexplored. In this study, we demonstrate the effective use of BLI to investigate RNA-small molecule interactions using three different riboswitches, which are potential targets for novel antibiotics. Furthermore, we describe the successful use of BLI to identify fragment binders of these RNA targets. We combined the BLI experiments with ligand-based NMR as an orthogonal validation method and were able to identify seven competitive fragment binders of the flavin mononucleotide (FMN) riboswitch, each featuring scaffolds distinct from the previously known ligands.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207548","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

Design of a highly potent bifunctional HIV-1 entry inhibitor targeting both gp120 and gp41. 靶向gp120和gp41的高效双功能HIV-1进入抑制剂的设计。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-18 DOI: 10.1039/d5md00603a

Xinmeng Du, Qing Li, Shu Du, Huan Wang, Anqi Shi, Ming Yuan, Fei Yu, Yang Liu, Chao Wang

引用次数: 0

Recent advances in triazole hybrid molecules for the therapeutic management of neglected tropical diseases. 三唑杂化分子治疗被忽视热带病的最新进展。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-17 DOI: 10.1039/d5md00572h

Jatin Malik, Gauri Karande, Sankaranarayanan Murugesan, Kondapalli Venkata Gowri Chandra Sekhar

{"title":"Recent advances in triazole hybrid molecules for the therapeutic management of neglected tropical diseases.","authors":"Jatin Malik, Gauri Karande, Sankaranarayanan Murugesan, Kondapalli Venkata Gowri Chandra Sekhar","doi":"10.1039/d5md00572h","DOIUrl":"10.1039/d5md00572h","url":null,"abstract":"The triazole scaffold has garnered considerable attention over the preceding decade as a privileged pharmacophore in the rational design of chemotherapeutic agents targeting neglected tropical diseases (NTDs). This review provides a comprehensive elucidation of the multifaceted research dedicated to the structural optimization of the triazole nucleus and its consequential outcomes on biological efficacy. Emphasis is placed on the methodical investigation of diverse substituents appended to the triazole core, underscoring the profound influence of seemingly marginal modifications on critical pharmacological parameters. Through a comprehensive deconstruction of structure-activity relationships (SAR), this exposition identifies the essential functional moieties underpinning biological efficacy that potentiate anti-parasitic, anti-fungal, and anti-viral activities across a spectrum of NTD-relevant biological targets. These insights deepen the knowledge of triazole based hybrid molecules and guide future rational design of novel compounds. By synthesizing and analyzing findings from a wide array of studies, this review aims to serve as a valuable resource for researchers interested in the continued development of triazole derivatives to manage neglected tropical diseases effectively.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233454","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

Allosteric targeting of RIPK1: discovery of novel inhibitors via parallel virtual screening and structure-guided optimization. RIPK1的变构靶向：通过平行虚拟筛选和结构引导优化发现新的抑制剂。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-17 DOI: 10.1039/d5md00317b

R S K Vijayan, Matthew M Hamilton, Dana E Pfaffinger, Fernando G Alvarez, Naphtali J Reyna, Jennifer P Bardenhagen, Hannah Shepard, Christian Rodriguez, Sunil Goodwani, Yaima Lightfoot, Klaus Maskos, Sven Johannsson, Georg Kempf, Quanyun Alan Xu, Lars Neumann, Yongying Jiang, Mary Geck Do, Philip Jones, Richard T Lewis, William J Ray, Jason B Cross

{"title":"Allosteric targeting of RIPK1: discovery of novel inhibitors via parallel virtual screening and structure-guided optimization.","authors":"R S K Vijayan, Matthew M Hamilton, Dana E Pfaffinger, Fernando G Alvarez, Naphtali J Reyna, Jennifer P Bardenhagen, Hannah Shepard, Christian Rodriguez, Sunil Goodwani, Yaima Lightfoot, Klaus Maskos, Sven Johannsson, Georg Kempf, Quanyun Alan Xu, Lars Neumann, Yongying Jiang, Mary Geck Do, Philip Jones, Richard T Lewis, William J Ray, Jason B Cross","doi":"10.1039/d5md00317b","DOIUrl":"10.1039/d5md00317b","url":null,"abstract":"Receptor-interacting serine/threonine protein-kinase 1 (RIPK1) is a critical signalling protein that regulates inflammation and cell death in response to TNF signalling. Inhibiting RIPK1 kinase activity prevents neuronal cell death in various animal models, making it a promising therapeutic target for neurodegenerative, inflammatory, and autoimmune disorders. To identify novel allosteric RIPK1 inhibitors, we used a parallel virtual screening strategy that employed structure-based pharmacophore, shape-based, and fuzzy pharmacophore similarity approaches. Structure-guided optimization enabled by X-ray crystallography led to the discovery of a potent and selective piperidinecarboxamide inhibitor with an acceptable pharmacokinetic (PK) profile and limited brain exposure. This work highlights the effectiveness of virtual screening, followed by structure-guided optimization, in identifying progressible allosteric kinase inhibitors.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086878","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

Development of novel alpha 2B adrenergic receptor ligands by using a palladium catalyzed Buchwald Hartwig amination with a brominated benzodiazepine. 溴化苯二氮卓与钯催化Buchwald Hartwig胺化反应制备新型α 2B肾上腺素能受体配体。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-16 DOI: 10.1039/d5md00611b

Maya R T Fernando, Alexander B Vincent, Shaun G Harrington, Mubaraq A Toriola, Kayode M Medubi, Michelle J Meyer, Daniel A Webb, Leggy A Arnold

{"title":"Development of novel alpha 2B adrenergic receptor ligands by using a palladium catalyzed Buchwald Hartwig amination with a brominated benzodiazepine.","authors":"Maya R T Fernando, Alexander B Vincent, Shaun G Harrington, Mubaraq A Toriola, Kayode M Medubi, Michelle J Meyer, Daniel A Webb, Leggy A Arnold","doi":"10.1039/d5md00611b","DOIUrl":"10.1039/d5md00611b","url":null,"abstract":"Some benzodiazepines with excellent affinities to the gamma aminobutyric receptors have been reported to attenuate intracellular calcium by interacting with alpha adrenergic receptors (ARα). To identify novel benzodiazepines that selectively bind adrenergic receptors, we coupled amines to a brominated benzodiazepine starting material, and generated a library of compounds that yielded compounds with good affinity for the ARα2 subtypes. These compounds were synthesized using a Buchwald Hartwig amination reaction employing XPhos as the most successful ligand among more than twenty ligands that were tested for this purpose and were part of the Catalexis screen platform from Millipore Sigma. The most promising compound has a K i of 511 nM for the α2B subtype with a 7.7-fold selectivity over the α2A and 2.2-fold selectivity over the α2C adrenergic receptor. Functional cell-based assays identified this compound as an ARα2B antagonist. All synthesized compounds exhibited a good safety profile in vivo and did not influence sensorimotor coordination and behavior in mice. Overall, these findings confirm the adaptability of the benzodiazepine scaffold in medicinal chemistry enabling future work to fine-tune these compounds to develop a more potent and selective ARα2B ligand.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233498","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

Introduction to the themed collection on kinases 激酶主题合集简介。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-15 DOI: 10.1039/D5MD90032H

Meizhong Jin, Hayley Binch, David E. Heppner and Philip Jones

引用次数: 0

Design, synthesis, and biological evaluation of indazole-based PLK4 inhibitors. 吲哚基PLK4抑制剂的设计、合成和生物学评价。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-12 DOI: 10.1039/d5md00654f

Cunzheng Fan, Nian Liu, Ningyuan Hu, Minghui Tong, Xuan Shi, Han Wang, Wenqiang Sun, Zehui Qi, Haoyu Zhang, Yixiang Sun, Zixuan Gao, Dongmei Zhao, Maosheng Cheng

{"title":"Design, synthesis, and biological evaluation of indazole-based PLK4 inhibitors.","authors":"Cunzheng Fan, Nian Liu, Ningyuan Hu, Minghui Tong, Xuan Shi, Han Wang, Wenqiang Sun, Zehui Qi, Haoyu Zhang, Yixiang Sun, Zixuan Gao, Dongmei Zhao, Maosheng Cheng","doi":"10.1039/d5md00654f","DOIUrl":"10.1039/d5md00654f","url":null,"abstract":"Polo-like kinase 4 (PLK4), a member of the serine/threonine protein kinase family, serves as a central regulator of centriole duplication and plays a critical role in eukaryotic mitosis. Overexpression of PLK4 in several cancer types underscores its potential as a therapeutic target. In our previous studies, compound 28t demonstrated acceptable kinase inhibitory activity but exhibited poor cellular activity. Consequently, 28t was selected as a lead compound for further optimization. Through functional group migration and rational drug design strategies, we conducted structural modifications that ultimately yielded 23 novel indazole-based PLK4 inhibitors. Among these, compound C05 exhibited exceptional kinase inhibitory activity (IC50 < 0.1 nM). At the cellular level, C05 demonstrated potent antiproliferative effects against IMR-32 (neuroblastoma), MCF-7 (breast cancer), and H460 (non-small cell lung cancer) cell lines, with IC50 values of 0.948 μM, 0.979 μM, and 1.679 μM, respectively. Notably, compound C05 demonstrated favorable kinase selectivity towards PLK4 among the 10 kinases tested, achieving an inhibition rate of 87.45%. Further pharmacological experimental studies, including apoptosis induction, cell cycle arrest analysis, and clonogenic formation experiments, revealed that C05 outperformed the positive control LCR-263 in both potency and efficacy. Western blot analysis demonstrated that compound C05 effectively suppressed PLK4 autophosphorylation at 4 μM. Unfortunately, compound C05 demonstrated poor metabolic stability in human liver microsomes (HLMs), exhibiting a short half-life (T 1/2) of 2.69 minutes under standard incubation conditions. Notwithstanding the suboptimal metabolic stability, the compelling biological activity profile of compound C05 warrants further structural refinement.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12499891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245017","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

The rise of ultrashort cationic β-peptides as promising antimicrobial therapeutics. 超短阳离子β-肽作为有前途的抗菌药物的兴起。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2025-09-11 DOI: 10.1039/d5md00596e

Hadiya Amin Kantroo, Itibaw Farooq, Zahoor Ahmad

{"title":"The rise of ultrashort cationic β-peptides as promising antimicrobial therapeutics.","authors":"Hadiya Amin Kantroo, Itibaw Farooq, Zahoor Ahmad","doi":"10.1039/d5md00596e","DOIUrl":"10.1039/d5md00596e","url":null,"abstract":"Antimicrobial resistance (AMR) is a mounting global health crisis demanding novel, sustainable therapeutic strategies beyond traditional antibiotics. Ultra-short cationic β-peptides have emerged as a promising class of synthetic antimicrobial foldamers with broad-spectrum activity, remarkable proteolytic stability, and low resistance potential. Designed through rational approaches, these 2-10 residue peptides leverage amphipathicity, structural rigidity, and electrostatic interactions to disrupt microbial membranes, biofilms, and even intracellular pathogens. Notably, they exhibit synergistic effects with conventional antibiotics and minimal toxicity to mammalian cells. Emerging in vivo studies in murine models further suggest that ultra-short β-peptides can reduce pathogen burden and improve survival, although the available data remain limited and warrant careful interpretation. This review provides a comprehensive overview of their design, mechanism of action, antimicrobial spectrum, including bacteria, fungi, viruses, and protozoa, and relevance to One Health frameworks. Key translational bottlenecks, including delivery challenges, immunogenicity, pharmacokinetics, and regulatory hurdles, are critically assessed. We also identify major research gaps and propose future directions to fully harness the therapeutic potential of ultra-short β-peptides against multidrug-resistant infections.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131914","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