ChemMedChem最新文献_第10页

Cathepsin Family Proteases in Prodrug Design: Recent Advances 组织蛋白酶家族蛋白酶在前药设计中的最新进展

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-17 DOI: 10.1002/cmdc.70440

Huitao Liu, Minglei Zheng, Chen Seng Ng, Teck Peng Loh

{"title":"Cathepsin Family Proteases in Prodrug Design: Recent Advances","authors":"Huitao Liu, Minglei Zheng, Chen Seng Ng, Teck Peng Loh","doi":"10.1002/cmdc.70440","DOIUrl":"https://doi.org/10.1002/cmdc.70440","url":null,"abstract":"Prodrug strategies are widely used to improve the efficacy, selectivity, and safety of therapeutic agents. Among stimulus-responsive approaches, enzyme-triggered activation has emerged as a particularly attractive method because it can couple drug release to disease-associated biochemical activity. Cathepsins, a family of lysosomal proteases including 15 types, implicated in cancer, inflammation, and other pathological processes, have become important enzymatic triggers in this area. Most cathepsin-responsive systems focused on cathepsin B, whose elevated activity in tumors and favorable intracellular localization have supported the development of peptide-cleavable prodrugs, from small-molecule prodrugs to various drug conjugates. More recent studies have extended this concept beyond cathepsin B to other cathepsins such as L, E, and S, highlighting a shift toward substrate-selective design and improved biological precision. Meanwhile, comparative studies and unnatural amino acid engineering have emphasized that successful cathepsin targeting depends not only on enzyme overexpression but also on substrate specificity, circulation stability, intracellular trafficking, and productive payload release. This review summarizes the recent advances in cathepsin-activated prodrugs with a focus on the novel therapeutic applications and major challenges limiting translation, providing insight for the future development of cathepsin-activated prodrugs.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784194","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

Structural and Biophysical Characterization of C-Glycosylic 1,2-Thiodisaccharides Reveals Determinants of Selective Binding to Galectin-7 and Galectin-8N c -糖基1,2-硫代二糖的结构和生物物理特性揭示了半乳糖凝集素-7和半乳糖凝集素- 8n选择性结合的决定因素。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-15 DOI: 10.1002/cmdc.70439

Anastasia S. Tsagkarakou, Anastassia L. Kantsadi, Vasiliki I. Theodoridou, Nikolaos Veliotis, László Lázár, János József, László Juhász, George Kontopidis, Hakon Leffler, Ulf J. Nilsson, László Somsák, Demetres D. Leonidas

{"title":"Structural and Biophysical Characterization of C-Glycosylic 1,2-Thiodisaccharides Reveals Determinants of Selective Binding to Galectin-7 and Galectin-8N","authors":"Anastasia S. Tsagkarakou, Anastassia L. Kantsadi, Vasiliki I. Theodoridou, Nikolaos Veliotis, László Lázár, János József, László Juhász, George Kontopidis, Hakon Leffler, Ulf J. Nilsson, László Somsák, Demetres D. Leonidas","doi":"10.1002/cmdc.70439","DOIUrl":"10.1002/cmdc.70439","url":null,"abstract":"Achieving isoform selectivity within the galectin family remains a central challenge in glycomimetic drug design due to the highly conserved architecture of their carbohydrate recognition domains. Here, we define the structural and thermodynamic basis of recognition of a series of C-glycosylic 1,2-thiodisaccharides targeting human galectin-7 and the N-terminal domain of galectin-8 (galectin-8N). Using an integrated approach combining fluorescence polarization, isothermal titration calorimetry, and high-resolution X-Ray crystallography, we establish a clear structure–activity relationship across the ligand series. Compound 17 emerges as the most potent galectin-8N ligand (Kd = 13 μM), outperforming thiodigalactoside, while compound 13 shows preferential binding to galectin-7, demonstrating tunable isoform bias. Structural analysis reveals a conserved anchoring mechanism in which the β-galactoside unit (Gly-1) drives affinity through a rigid hydrogen-bonding and π-stacking network, whereas the second sugar (Gly-2) modulates potency by adopting distinct orientations in galectin-specific extended binding sites. Notably, ligand binding converges on conserved motifs while leaving nonconserved regions unexploited, highlighting clear opportunities for structure-guided optimization. Collectively, this work establishes C-glycosylic thiodisaccharides as a robust platform for selective galectin targeting and provides actionable design principles for next-generation inhibitors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70439","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757238","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

Inducing Metabolic Dysfunction in Breast Cancer Cells Through Targeted Inhibition of α- and β-Glucosidase and Amylase: Novel Carbohydrate (C8N) Isomers Designed via Intramolecular aza-Michael-Type Reaction 通过靶向抑制α-和β-葡萄糖苷酶和淀粉酶诱导乳腺癌细胞代谢功能障碍：通过分子内aza- michael型反应设计的新型碳水化合物（C8N）异构体

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-15 DOI: 10.1002/cmdc.70422

Emel Karakılıç, Gökay Aydın, Gamze Güney Eskiler, Sinan Başçeken, Arif Baran

{"title":"Inducing Metabolic Dysfunction in Breast Cancer Cells Through Targeted Inhibition of α- and β-Glucosidase and Amylase: Novel Carbohydrate (C8N) Isomers Designed via Intramolecular aza-Michael-Type Reaction","authors":"Emel Karakılıç, Gökay Aydın, Gamze Güney Eskiler, Sinan Başçeken, Arif Baran","doi":"10.1002/cmdc.70422","DOIUrl":"10.1002/cmdc.70422","url":null,"abstract":"Natural products such as glucosidase inhibitors and aminoglycoside antibiotics are target agents that play an important role in the development of new drugs. A novel class of glucosidase inhibitors based on aminocyclitols was synthesized using a new method. This method involves arranging the α-, β-unsaturated structure by attacking the ammonia compound on the acetate group in the γ-position forming, to form the amide in the β-position. The method has enabled the synthesis of new types of C8N, such as C7N (C8N generally exhibits structural and characteristic biological properties similar to C7N) compounds. After purification and structure elucidation of the resulting substances, α-, β-glucosidase, and amylase tests were performed against acarbose; additionally, an enzyme kinetic study of well-active compounds was conducted. Subsequently, the anticancer activity of substances was analyzed using a viability assay and AO/PI staining. Our results suggest that different derivatives of new carbosugar isomers exert potential enzymatic and anticancer activity against breast cancer cells.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758343","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

From Fragments to Function: Novel Hydrazone Derivatives as Monoamine Oxidase Inhibitors 从片段到功能：新型腙衍生物作为单胺氧化酶抑制剂。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-15 DOI: 10.1002/cmdc.70416

Hasan Erdinç Sellitepe, Ahmet Buğra Aksel, Ezgi Pehlivanlar Yavrucu, Hilal Zıvalı, Begüm Nurpelin Sağlık Özkan, İnci Selin Doğan

{"title":"From Fragments to Function: Novel Hydrazone Derivatives as Monoamine Oxidase Inhibitors","authors":"Hasan Erdinç Sellitepe, Ahmet Buğra Aksel, Ezgi Pehlivanlar Yavrucu, Hilal Zıvalı, Begüm Nurpelin Sağlık Özkan, İnci Selin Doğan","doi":"10.1002/cmdc.70416","DOIUrl":"10.1002/cmdc.70416","url":null,"abstract":"Monoamine oxidase (MAO) catalyzes the breakdown of neurotransmitters, including serotonin, dopamine, and norepinephrine. There are two isoforms of this enzyme: MAO-A and MAO-B. MAO efficacy is widely investigated in neurodegenerative (MAO-B) and depressive (MAO-A) disorders. Upon examining the structures of known inhibitors, it becomes evident that many share an aliphatic amine structure. Furthermore, the literature suggests that compounds with naphthalene skeletons, phenolic structures, and hydrazone moieties exhibit MAO inhibitory activity. In this study, 12 N-acylhydrazone derivatives (5a–f, 6a–f) were designed using ligand-based design methods. Based on biological activity studies, the MAO-A inhibition of the compounds was calculated to be 0.073–2.54 µM, and the MAO-B inhibition was 0.064–3.147 µM. Among all compounds, the derivatives bearing a naphthalene ring (5d–f, 6d–f) exhibited MAO enzyme inhibition at levels comparable to those of the reference compounds. The compound with the highest activity, 6e, had IC50 values of 0.073 ± 0.002 and 0.064 ± 0.002 µM against MAO-A and MAO-B, respectively. Due to its superior potency against human MAO-B, enzyme kinetic studies were further conducted on compound 6e. Consequently, the pronounced inhibitory potency, reversible competitive kinetics, and favorable pharmacokinetic profile of compound 6e designate it as a strong lead candidate for advanced preclinical evaluation.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70416","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758585","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

Proline-Derived N-Heterocyclic Carbene Gold(I) Complexes With Dual DNA Binding and Thioredoxin Reductase Inhibition 脯氨酸衍生n -杂环卡宾金(I)配合物与双DNA结合及硫氧还蛋白还原酶抑制。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-15 DOI: 10.1002/cmdc.70432

Giacomo Cassarà, María Gil-Moles, Thomas Scattolin, M. Concepción Gimeno

{"title":"Proline-Derived N-Heterocyclic Carbene Gold(I) Complexes With Dual DNA Binding and Thioredoxin Reductase Inhibition","authors":"Giacomo Cassarà, María Gil-Moles, Thomas Scattolin, M. Concepción Gimeno","doi":"10.1002/cmdc.70432","DOIUrl":"10.1002/cmdc.70432","url":null,"abstract":"A new family of proline-derived N-heterocyclic carbene (NHC) gold(I) complexes was synthesized and fully characterized by multinuclear NMR spectroscopy and HRMS analysis. The incorporation of a proline-based fragment into the NHC scaffold enabled the generation of both neutral and cationic Au(I) complexes with distinct electronic and steric properties. Stability studies demonstrated that the complexes remain stable under physiological-like conditions for at least 48 h. Biological evaluation against A549 lung adenocarcinoma and MDA-MB-231 triple-negative breast cancer cells revealed that the cationic complexes 3 and 4 display remarkable cytotoxic activity, with IC50 values in the low micromolar range, outperforming cisplatin and, in some cases, auranofin. Mechanistic investigations showed that complex 4 induces apoptotic cell death associated with intracellular reactive oxygen species (ROS) generation and depolarization of the mitochondrial membrane potential, indicating a mitochondria-mediated pathway. In addition, DNA-binding studies demonstrated that all complexes interact with calf thymus DNA predominantly through an intercalative mode, with complexes 2, 3, and 4 exhibiting the highest binding affinities. In addition, thioredoxin reductase inhibition assays revealed significant enzyme inhibition for the cationic complex 4, supporting disruption of cellular redox homeostasis. Overall, these results identify proline-functionalized Au(I)–NHC complexes as promising multifunctional anticancer agents.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70432","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756788","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

Evaluation of Novel Isatin–Schiff Base Derivatives: Monoamine Oxidase Inhibition and Antimicrobial Assessment 新型istin - schiff碱衍生物的评价：单胺氧化酶抑制和抗菌评价。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-15 DOI: 10.1002/cmdc.70437

Marthinus J. Jooste, Stephanus J. Cloete, Anél Petzer, Jacobus P. Petzer, Theunis T. Cloete

{"title":"Evaluation of Novel Isatin–Schiff Base Derivatives: Monoamine Oxidase Inhibition and Antimicrobial Assessment","authors":"Marthinus J. Jooste, Stephanus J. Cloete, Anél Petzer, Jacobus P. Petzer, Theunis T. Cloete","doi":"10.1002/cmdc.70437","DOIUrl":"10.1002/cmdc.70437","url":null,"abstract":"Five novel series of isatin–Schiff base derivatives (1a–5e) were synthesized, and their neuroprotective and anti-infective potential was evaluated. Their half-maximal inhibitory concentration (IC50) was determined against both monoamine oxidase A (MAO-A) and MAO-B targets for the treatment of depression and Parkinson's disease, respectively. The anti-infective potential of the synthesized derivatives was evaluated by measuring their IC50 values against urease, an enzyme utilized by specific pathogenic bacteria as a virulence factor. The minimum inhibitory concentration for each compound was assessed against a panel of human pathogens. Most derivatives had potent in vitro activity against MAO-A and MAO-B, even greater than the positive control, isatin. The 4-chloroisatin substituted series (2a–d) showed exceptional MAO-A inhibition (2d: 0.040 ± 0.002 µM), while the unsubstituted, 5-, 6-, and 7-chloroisatin analogues (1a–e, 3a–c, 4a–b, and 5a–e) demonstrated high potency and selectivity toward MAO-B, the most active being 5d (0.018 ± 0.003 µM; selectivity index = 15 389). Kinetic analysis confirmed a competitive and reversible mode of inhibition. None of the derivatives showed urease inhibition or significant antibacterial activity. These findings highlight the isatin–Schiff base derivatives as promising agents for potent and selective MAO inhibitors with therapeutic potential for neurodegenerative disorders.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757288","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

Novel C3-Aminated Galantamine Derivatives as Selective Butyrylcholinesterase Inhibitors With Neuroprotective Effects 新型c3 -氨基加兰他明衍生物作为具有神经保护作用的选择性丁基胆碱酯酶抑制剂。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-15 DOI: 10.1002/cmdc.70431

Fu-Lian Tang, Li-Jun Huang, Yan-Xu Wang, Su-Mei Wang, Wan-Sheng Ji, Feng Gao, Lian Sun, Jin-Bu Xu

{"title":"Novel C3-Aminated Galantamine Derivatives as Selective Butyrylcholinesterase Inhibitors With Neuroprotective Effects","authors":"Fu-Lian Tang, Li-Jun Huang, Yan-Xu Wang, Su-Mei Wang, Wan-Sheng Ji, Feng Gao, Lian Sun, Jin-Bu Xu","doi":"10.1002/cmdc.70431","DOIUrl":"10.1002/cmdc.70431","url":null,"abstract":"To explore natural-inspired novel anti-AD bioactive molecules, a series of galantamine derivatives 6a–6u were synthesized via Pd-catalyzed Buchwald–Hartwig cross-coupling, with various nitrogen-containing functional groups installed at the C3 position of galantamine. Compared with galantamine, these compounds showed greatly enhanced selective BChE inhibition activity, suggesting that the C3 position of galantamine might be a key modifiable site for developing new selective BChE inhibitors. Among them, the derivative 6l which contained a 3,5-difluoroaniline structure moiety exhibited promising selective inhibitory activity against eqBChE, with an IC50 of 0.88 μM and a selectivity index of 26.2. Molecular docking and molecular dynamics simulations were performed to elucidate the interaction model between compound 6l and BChE. Moreover, 6l also showed favorable neuroprotection potency against H2O2 injured SH-SY5Y cells. Preliminary mechanistic study revealed that compound 6l could mitigate oxidative stress and suppress cellular apoptosis. This work not only offers a novel galantamine analog with promising in vitro cholinesterase inhibitory and neuroprotective effects for further anti-AD study, but also provides new insights into the structure optimization of natural drug galantamine.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756915","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

Synthesis and Biological Activity of 2,6-Disubstituted and 2,6,9-Trisubstituted 7-Deazapurine Nucleobases 2,6-二取代和2,6,9-三取代7-去氮杂嘌呤核碱基的合成及其生物活性

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-13 DOI: 10.1002/cmdc.70419

Ugnė Šinkevičiūtė, Kateřina Burgetová Ječmeňová, Soňa Gurská, Lenka Poštová Slavětínská, Vincent Baran, Pavel Polishchuk, Petr Džubák, Michal Hocek, Marián Hajdúch, Michal Tichý

{"title":"Synthesis and Biological Activity of 2,6-Disubstituted and 2,6,9-Trisubstituted 7-Deazapurine Nucleobases","authors":"Ugnė Šinkevičiūtė, Kateřina Burgetová Ječmeňová, Soňa Gurská, Lenka Poštová Slavětínská, Vincent Baran, Pavel Polishchuk, Petr Džubák, Michal Hocek, Marián Hajdúch, Michal Tichý","doi":"10.1002/cmdc.70419","DOIUrl":"https://doi.org/10.1002/cmdc.70419","url":null,"abstract":"High-throughput screening of the IMTM compound library for modulatory activity on adenosine receptors (ARs) identified two deazapurine hits based on 2,6-diaryl-7-deazapurines. In this study, a series of 16 new 2,6-diaryl-7-deazapurine nucleobases together with four N-9 substituted derivatives were synthesized. The synthesis was based on regioselective Suzuki cross-coupling into position 6 followed by a second Suzuki cross-coupling at position 2 under harsher conditions. Both cross-couplings were performed on N-9 protected nucleobases. Biological activity profiling identified several potent antagonists of all four subtypes of ARs and four compounds as sub-micromolar and very selective antagonists of A3. Several final compounds showed potent in vitro cytotoxic activity on a small panel of cancer cell lines, but with no selectivity against nonmalignant fibroblasts BJ and MRC-5.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70419","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719246","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

Topliss-Guided Optimization of Acetanilide-Based Soluble Epoxide Hydrolase Inhibitors: Exploring the Pentafluorosulfanyl Group as a Potency-Enhancing Motif toppliss引导下乙酰苯胺基可溶性环氧化物水解酶抑制剂的优化：探索五氟磺胺基作为电位增强基序

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-13 DOI: 10.1002/cmdc.70430

Alba López-Ruiz, Eugènia Pujol, Cristian Ramos, Valeria Rizzo, Christophe Morisseau, Cristina Val, Tiziana Ginex, Javier Vázquez, Sandra Codony, Andreea L. Turcu, Belén Pérez, Elena Sáez, Antonio Pineda-Lucena, Bruce D. Hammock, F. Javier Luque, M. Isabel Loza, José Brea, Santiago Vázquez

{"title":"Topliss-Guided Optimization of Acetanilide-Based Soluble Epoxide Hydrolase Inhibitors: Exploring the Pentafluorosulfanyl Group as a Potency-Enhancing Motif","authors":"Alba López-Ruiz, Eugènia Pujol, Cristian Ramos, Valeria Rizzo, Christophe Morisseau, Cristina Val, Tiziana Ginex, Javier Vázquez, Sandra Codony, Andreea L. Turcu, Belén Pérez, Elena Sáez, Antonio Pineda-Lucena, Bruce D. Hammock, F. Javier Luque, M. Isabel Loza, José Brea, Santiago Vázquez","doi":"10.1002/cmdc.70430","DOIUrl":"https://doi.org/10.1002/cmdc.70430","url":null,"abstract":"The inhibition of soluble epoxide hydrolase (sEH) has emerged as an attractive therapeutic strategy through the stabilization of endogenous bioactive epoxyeicosatrienoic acids. Most of the inhibitors developed to date contain a central urea pharmacophore; however, these compounds often suffer from physicochemical limitations, particularly limited aqueous solubility. Herein, we report the design, synthesis, and biological evaluation of a new family of 2-(1-benzylpiperidin-4-yl)acetamides inspired by the reference sEH inhibitor 1-(1-propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (TPPU). Replacement of the urea pharmacophore in TPPU with an amide significantly improved aqueous solubility but reduced inhibitory potency. Surprisingly, substitution of the trifluoromethyl group of TPPU with a pentafluorosulfanyl substituent restored potency against human sEH, leading to the identification of a promising hit compound. Subsequent structure–activity relationship studies guided by the Topliss Batchwise Scheme (TBS) enabled systematic optimization of the aromatic substitution pattern and revealed that electronic effects are the main drivers of inhibitory potency, leading to several analogs displaying strong activity across human, mouse, and rat sEH. However, their further development was discontinued due to safety-related liabilities identified during the screening cascade. Nevertheless, these results highlight the utility of the underexplored pentafluorosulfanyl group and the TBS strategy for optimizing amide-based sEH inhibitors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70430","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719245","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

Tetramic Acid-Derived Blue-Emitting Fluorescent Probe for Selective Lipid Droplet Imaging in Live Cells and Zebrafish 四羧酸衍生的蓝色荧光探针用于活细胞和斑马鱼的选择性脂滴成像。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-12 DOI: 10.1002/cmdc.70418

Marija Grozdanić, Jelena Dinić, Miloš Jović, Ana Podolski-Renić, Aleksandra Divac Rankov, Mila Ljujić, Milica Pešić, Igor M. Opsenica, Života Selaković

{"title":"Tetramic Acid-Derived Blue-Emitting Fluorescent Probe for Selective Lipid Droplet Imaging in Live Cells and Zebrafish","authors":"Marija Grozdanić, Jelena Dinić, Miloš Jović, Ana Podolski-Renić, Aleksandra Divac Rankov, Mila Ljujić, Milica Pešić, Igor M. Opsenica, Života Selaković","doi":"10.1002/cmdc.70418","DOIUrl":"10.1002/cmdc.70418","url":null,"abstract":"Lipid droplets (LDs) are dynamic intracellular organelles involved in lipid storage and metabolism, and their imaging is essential for studying metabolic processes in health and disease. Here, we describe four novel fluorescent tetramic acid derivatives as potential LD markers for live imaging in cellular and whole-organism systems, and designate the compound with the most favorable properties, 1a, for further characterization. The probe 1a was evaluated in multiple cell lines, where it enabled clear visualization of intracellular LDs and showed strong colocalization with established lipid markers such as Nile Red and BODIPY 493/503. Photophysical characterization revealed photostability and signal-to-noise characteristics enabling fluorescence imaging applications. In addition, cytotoxicity assays indicated minimal acute and delayed effects at imaging concentrations. Importantly, 1a was successfully applied in a zebrafish model, enabling visualization of lipid-rich structures in a whole-organism context. Together, these findings identify 1a as a useful LD fluorescent marker for live imaging applications both in vitro and in vivo.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 15","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719631","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