European Journal of Medicinal Chemistry最新文献

{"title":"Enantiomeric C-6 fluorinated swainsonine derivatives as highly selective and potent inhibitors of α-mannosidase and α-l-rhamnosidase: Design, synthesis and structure-activity relationship study","authors":"Feng-Teng Gao ,&nbsp;Ming Zhang ,&nbsp;Yuna Shimadate ,&nbsp;Atsushi Kato ,&nbsp;Yi-Xian Li ,&nbsp;Yue-Mei Jia ,&nbsp;Chu-Yi Yu","doi":"10.1016/j.ejmech.2024.117031","DOIUrl":"10.1016/j.ejmech.2024.117031","url":null,"abstract":"<div><div>Six C-6 fluorinated <span>d</span>-swainsonine derivatives and their enantiomers have been designed based on initial docking calculations, and synthesized from enantiomeric ribose-derived aldehydes, respectively. Glycosidase inhibition assay of these derivatives with <span>d</span>-swainsonine (<strong>1</strong>) and <span>l</span>-swainsonine (<strong><em>ent</em>-1</strong>) as contrasts found that the C-6 fluorinated <span>d</span>-swainsonine derivatives with C-8 configurations as <em>R</em> (α) showed specific and potent inhibitions of jack bean α-mannosidase (model enzyme of Golgi α-mannosidase II); whereas their enantiomers with C-8 configurations as <em>S</em> (β) were powerful and selective α-<span>l</span>-rhamnosidase inhibitors. Molecular docking calculations found the C-6 fluorinated<span>d</span>-swainsonine derivatives <strong>21</strong>, <strong>24</strong> and <strong>25</strong> with highly coincident binding conformations with <span>d</span>-swainsonine (<strong>1</strong>) in their interactions with the active site of α-mannosidase (PDB ID: <span><span>1HWW</span><svg><path></path></svg></span>). Reliability of the docking results were confirmed by Molecular Dynamics (MD) simulation. Additionally, solid interactions with residues Gln-392 and Tyr-393 in the active site of α-<span>l</span>-rhamnosidase (PDB ID: <span><span>3W5N</span><svg><path></path></svg></span>) were proved to be vital for potent α-<span>l</span>-rhamnosidase inhibitions of the <span>l</span>-swainsonine derivatives. The role of C-6 fluorines in swainsonine derivatives well demonstrated the “mimic effect” of fluorine to hydrogen by minimal influence on the binding conformations and effective compensation for any possible lost interactions. This work contributes to a comprehensive understanding of the structure-activity relationship (SAR) of the fluorinated swainsonines and ever reported branched swainsonines, and has laid good foundation for development of more potent α-mannosidase and α-<span>l</span>-rhamnosidase inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117031"},"PeriodicalIF":6.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors and efficacy evaluation on a mouse model of liver injury","authors":"Yunjie Wu ,&nbsp;Lu Yang ,&nbsp;Jing You ,&nbsp;Chenyu Tian ,&nbsp;Shengyong Yang ,&nbsp;Linli Li","doi":"10.1016/j.ejmech.2024.117042","DOIUrl":"10.1016/j.ejmech.2024.117042","url":null,"abstract":"<div><div>Ferroptosis is an iron-dependent regulated cell death, which has been implicated in the onset and progression of numerous diseases. Ferroptosis inhibitors are thought as potential agents for treating these related diseases. However, the majority of currently available ferroptosis inhibitors are antioxidants or iron chelators (called classical ferroptosis inhibitors), which might have potential risks of side effects during clinical use. Herein, we report the discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors. Structure-activity relationship of these series compounds led to the discovery of the most active compound <strong>13l</strong> with an EC₅₀ value of 0.0007 μM. Mechanistically, <strong>13l</strong> could inhibit NCOA4-mediated ferritinophagy, hence protecting cells from ferroptosis. Notably, in the acetaminophen-induced acute liver injury model, <strong>13l</strong> showed an excellent therapeutic effect. Overall, this compound reported here could be a promising lead compound for drug discovery targeting ferroptosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117042"},"PeriodicalIF":6.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into tryptamine psychedelics: The role of hydroxyl indole ring site in 5-HT2A receptor activation and psychedelic-like activity","authors":"Miyuan Zhang ,&nbsp;Yuefeng Yang ,&nbsp;Zhishuai Yang ,&nbsp;Xin Wen ,&nbsp;Cong Zhang ,&nbsp;Peng Xiao ,&nbsp;Yibo Wang ,&nbsp;Jinpeng Sun ,&nbsp;Hongshuang Wang ,&nbsp;Xiaohui Wang","doi":"10.1016/j.ejmech.2024.117049","DOIUrl":"10.1016/j.ejmech.2024.117049","url":null,"abstract":"<div><div>Recent advancements in the study of mushroom-derived tryptamines, particularly psilocybin and its metabolite psilocin, highlight their unique psychedelic properties and potential therapeutic applications, especially for mental health conditions like depression. This study examines how the position of the hydroxyl group on the indole ring affects the 5-HT_2A receptor activity and psychedelic-like effects of psilocin analogs. Chemically synthesized psilocin (<strong>1</strong>) and its analogs bufotenine (<strong>2</strong>), 6-OH-DMT (<strong>3</strong>), and 7-OH-DMT (<strong>4</strong>) were assessed for 5-HT_2A receptor agonistic activity using the Gα_q-Gγ dissociation bioluminescence resonance energy transfer (BRET) assay and for psychedelic-like effects through the head-twitch response assay. Results show that compounds with hydroxyl group at the 4th and 5th positions exhibit significantly higher 5-HT_2A agonistic and psychedelic-like activities than those with hydroxyl group at the 6th and 7th positions. Funnel metadynamics simulations revealed that psilocin (<strong>1</strong>) and bufotenine (<strong>2</strong>) have lower binding free energies, correlating with experimental data. Analysis of the simulation trajectories reveals that the formation of a hydrogen bond with residue L229 is crucial for guiding psilocin (<strong>1</strong>) and bufotenine (<strong>2</strong>) into the 5-HT_2AR binding site. In contrast, analogs <strong>3</strong> and <strong>4</strong>, which lack this interaction, fail to be directed into the orthosteric site. Furthermore, psilocin (<strong>1</strong>) and bufotenine (<strong>2</strong>) establish a stable salt bridge and hydrogen bond with residue D155. These interactions are more stable compared to those formed by ligands <strong>3</strong> and <strong>4</strong>, contributing to the latter's poor 5-HT_2AR activities. These findings underscore the critical role of the hydroxyl group position on the indole ring in modulating 5-HT_2A receptor activity and the corresponding psychedelic-like effects, offering valuable insights for the development of targeted therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117049"},"PeriodicalIF":6.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of selective sigma-1 receptor ligands with antiallodynic activity: A focus on piperidine and piperazine scaffolds","authors":"Giuseppe Cosentino ,&nbsp;Maria Dichiara ,&nbsp;Francesca Alessandra Ambrosio ,&nbsp;Claudia Giovanna Leotta ,&nbsp;Giosuè Costa ,&nbsp;Francesca Procopio ,&nbsp;Giuliana Costanzo ,&nbsp;Alessandro Raffa ,&nbsp;Antonia Artacho-Cordón ,&nbsp;M. Carmen Ruiz-Cantero ,&nbsp;Lorella Pasquinucci ,&nbsp;Agostino Marrazzo ,&nbsp;Giovanni Mario Pitari ,&nbsp;Enrique J. Cobos ,&nbsp;Stefano Alcaro ,&nbsp;Emanuele Amata","doi":"10.1016/j.ejmech.2024.117037","DOIUrl":"10.1016/j.ejmech.2024.117037","url":null,"abstract":"<div><div>The design and synthesis of a series of piperidine and piperazine-based derivatives as selective sigma receptor (SR) ligands associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose features. The most promising compounds were subjected to <em>in vitro</em> toxicity testing and subsequently screened for <em>in vivo</em> analgesic properties. Compounds <strong>12a</strong> (AD353) and <strong>12c</strong> (AD408) exhibited negligible <em>in vitro</em> cellular toxicity and high potency both in a model of capsaicin-induced allodynia and in PGE2-induced mechanical hyperalgesia. Functional activity experiments showed that S1R antagonism is needed for the effects of these compounds, since the effect was reversed by PRE-084 or absent in KO mice. In addition, <strong>12a</strong> exhibited a favorable pharmacokinetic profile, confirming its therapeutic value in treating allodynic conditions. Moreover, a computational model was developed in order to help the understanding about the mechanism of action of most active compounds.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117037"},"PeriodicalIF":6.0,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and preclinical evaluation of diarylamine derivative as Tau-PET radiotracer for Alzheimer's Disease","authors":"Tianqing Liu ,&nbsp;Chao Ren ,&nbsp;Wantong Guo ,&nbsp;Xiaojun Zhang ,&nbsp;Yuying Li ,&nbsp;Yan Wang ,&nbsp;Qilei Zhang ,&nbsp;Baian Chen ,&nbsp;Jiapei Dai ,&nbsp;Xiao-xin Yan ,&nbsp;Jinming Zhang ,&nbsp;Li Huo ,&nbsp;Mengchao Cui","doi":"10.1016/j.ejmech.2024.117046","DOIUrl":"10.1016/j.ejmech.2024.117046","url":null,"abstract":"<div><div>The presence of aggregated Tau in the brain is a dominant pathological hallmark of Tauopathies, particularly in Alzheimer's disease (AD). Therefore, developing ligands that can specifically and sensitively bind to Tau aggregates is essential for diagnosing and monitoring therapeutic interventions. In this study, we further investigated the structural optimization of the diarylamine skeleton, which exhibited promising binding characteristics and biological properties. We supplementarily explored the effects of the number and position of nitrogen atoms, types of heteroatoms and aromatic moieties, and radioactive positions on affinity for Tau. Through a structure-activity relationship (SAR) analysis based on ¹²⁵I-labeled diarylamine derivatives, [¹²⁵I]<strong>A6</strong> was identified as a lead compound due to its desirable binding properties and ability to penetrate the brain, making it suitable for conversion into a¹⁸F-labeled PET tracer. Satisfactorily, [¹⁸F]<strong>FA1</strong> fulfilled critical requirements as a Tau radiotracer, demonstrating high specificity and selectivity for Tau, a clean off-target profile against Aβ plaques and monoamine oxidase B (MAO-B), and favorable <em>in vivo</em> brain kinetics, as confirmed by dynamic PET studies in rodents and non-human primates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117046"},"PeriodicalIF":6.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors","authors":"Daniel Stopper ,&nbsp;Susanna Buntrock ,&nbsp;Kathrin Tan ,&nbsp;Lais Pessanha de Carvalho ,&nbsp;Linda Schäker-Hübner ,&nbsp;Jana Held ,&nbsp;Matthias U. Kassack ,&nbsp;Finn K. Hansen","doi":"10.1016/j.ejmech.2024.117045","DOIUrl":"10.1016/j.ejmech.2024.117045","url":null,"abstract":"<div><div>In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the <em>Plasmodium falciparum</em> strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound <strong>18b</strong> of the type C series as the most potent. It demonstrated low nanomolar IC₅₀ values (IC₅₀ (3D7) = 0.023 μM; IC₅₀ (Dd2) = 0.047 μM) and high parasite selectivity (SI^{MRC−5/<em>Pf</em>3D7} &gt; 2174). HDAC inhibition assays confirmed substantial inhibition of the <em>P. falciparum</em> enzyme <em>Pf</em>HDAC1 (IC₅₀ = 0.037 μM) as well as of human HDAC1 (IC₅₀ = 0.021 μM) and HDAC6 (IC₅₀ = 0.25 μM). Docking studies suggested distinct binding modes of <strong>18b</strong> in <em>P. falciparum</em> and human HDAC1. Additionally, the <em>in vitro</em> anticancer activity was evaluated in Cal27 (head-neck carcinoma), HepG2 (hepatocellular carcinoma), A2780 (ovarian carcinoma), and U87 (glioblastoma) cell lines. Compounds <strong>9b</strong>, <strong>9d</strong>, and <strong>13f</strong> showed potent antiproliferative activity and caspase 3/7 activation, in contrast to <strong>18b</strong>. Furthermore, these compounds caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified the HDAC inhibitor <strong>18b</strong> with selective antiplasmodial and <strong>9b</strong>, <strong>9d</strong>, and <strong>13f</strong> with selective anticancer activities, providing valuable hits for further drug development efforts aimed at creating derivatives with reduced cytotoxicity against non-cancer cells compared to quisinostat.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117045"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation cancer therapeutics: PROTACs and the role of heterocyclic warheads in targeting resistance","authors":"Ebna Azizal Omar ,&nbsp;R. Rajesh ,&nbsp;Pronoy Kanti Das ,&nbsp;Rohit Pal ,&nbsp;Gurubasavaraja Swamy Purawarga Matada ,&nbsp;Lalmohan Maji","doi":"10.1016/j.ejmech.2024.117034","DOIUrl":"10.1016/j.ejmech.2024.117034","url":null,"abstract":"<div><div>One of the major obstacles to sustained cancer treatment effectiveness is the development of medication resistance. Current therapies that block proteins associated with cancer progression often lose their efficacy due to acquired drug resistance, which is frequently driven by mutated or overexpressed protein targets. Proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic strategy by hijacking the cell's ubiquitin-proteasome system to degrade disease-causing proteins, presenting several potential advantages. Over the past few years, PROTACs have been developed to target various cancer-related proteins, offering new treatment options for patients with previously untreatable malignancies and serving as a foundation for next-generation therapeutics. One of the notable benefits of PROTACs is their ability to overcome certain resistance mechanisms that limit the effectiveness of conventional targeted therapies, as shown in several recent studies. Additionally, research teams are investigating how PROTACs can selectively degrade mutant proteins responsible for resistance to first-line cancer therapies. In the pursuit of novel and effective treatments, this review highlights recent advancements in the development of PROTACs aimed at overcoming cancer resistance. When it comes to drug design, heterocyclic scaffolds often serve as a foundational framework, offering opportunities for modification and optimization of novel molecules. Researchers are similarly exploring various heterocyclic derivatives as “warheads” in the design of PROTACs has been instrumental in pushing the boundaries of targeted protein degradation. As warheads, these heterocyclic compounds are responsible for recognizing and binding to the target protein, which ultimately leads to its degradation via the ubiquitin-proteasome system. This study aims to provide a comprehensive overview of cutting-edge strategies in PROTAC design, offering detailed insights into key concepts and methodologies for creating effective PROTACs. Special emphasis is placed on structure-based rational design, the development of novel warheads, and their critical in influencing biological activity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117034"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design and synthesis of novel N-benzylindole-based epalrestat analogs as selective aldose reductase inhibitors: An unexpected discovery of a new glucose-lowering agent (AK-4) acting as a mitochondrial uncoupler","authors":"Antonios Kousaxidis ,&nbsp;Paolo Paoli ,&nbsp;Lucia Kovacikova ,&nbsp;Massimo Genovese ,&nbsp;Alice Santi ,&nbsp;Milan Stefek ,&nbsp;Anthi Petrou ,&nbsp;Ioannis Nicolaou","doi":"10.1016/j.ejmech.2024.117035","DOIUrl":"10.1016/j.ejmech.2024.117035","url":null,"abstract":"<div><div>Diabetes mellitus is one of the most frequent metabolic diseases associated with hyperglycemia. Although antidiabetic drugs reduce hyperglycemia, diabetic patients suffer from abnormal fluctuations in blood glucose levels leading to the onset of long-term complications. Aldose reductase inhibitors are considered a promising strategy for regulating the occurrence of diabetic-specific comorbidities. So far, epalrestat is the only drug being approved in Asian countries. In this paper, we ground our research in discovering novel epalrestat analogs that prevent chronic complications and normalize hyperglycemia. Herein, we describe the rational design and synthesis of four novel 4-thiazolidinone acetic acid derivatives (<strong>AK-1-4</strong>) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. <strong>AK-1-4</strong> were also tested against human recombinant protein tyrosine phosphatase 1B as a key target in insulin sensitization and towards the closely related T-cell-derived enzyme. Docking analyses suggested possible binding modes on examined targets. The promising inhibitory profile of <strong>AK-4</strong> sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under <em>ex vivo</em> conditions. We further investigated the ability of <strong>AK-4</strong> to target mitochondria acting as an uncoupling agent and impairing mitochondrial membrane potential. Herein, we report for the first time a new glucose-lowering agent (<strong>AK-4</strong>) that can combine alleviation for chronic diabetic complications without off-target adverse effects and antihyperglycemic efficacy through controlled mitochondrial uncoupling activity. Pharmacokinetic and toxicity studies <em>in silico</em> revealed optimal properties of <strong>AK-4</strong> for oral administration without potential side effects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117035"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors","authors":"Arun K. Ghosh ,&nbsp;Yueyi Chen ,&nbsp;Ranjith Kumar Gadi ,&nbsp;Amol Sonawane ,&nbsp;Sandali Piladuwa Gamage ,&nbsp;JohnJ.G. Tesmer","doi":"10.1016/j.ejmech.2024.117024","DOIUrl":"10.1016/j.ejmech.2024.117024","url":null,"abstract":"<div><div>G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117024"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and pharmacodynamic evaluation of 2-aminoindole derivatives against influenza A virus in vitro/vivo","authors":"Zhongmou Zhang ,&nbsp;Nanfang Wang ,&nbsp;Jiejie Lu ,&nbsp;Ying Qu ,&nbsp;Yihui Song ,&nbsp;Xinyu Yang ,&nbsp;Zhanyong Wei ,&nbsp;Qi Zhang ,&nbsp;Piet Herdewijn ,&nbsp;Junbiao Chang ,&nbsp;Xiao-Na Wang ,&nbsp;Zhenya Wang","doi":"10.1016/j.ejmech.2024.117044","DOIUrl":"10.1016/j.ejmech.2024.117044","url":null,"abstract":"<div><div>Influenza virus is a kind of respiratory pathogen with high morbidity and mortality, which still threatens human health. Existing anti-influenza drugs have various limitations, such as the inability to alleviate body injury and side effects. There remains an urgent need to develop a novel antiviral drug to efficiently inhibit viral infection while avoiding body injury. A series of 2-aminoindole derivatives were synthesized via the TMSOTf-catalyzed reactions of <em>N</em>-arylynamides with sulfilimines and evaluated for their anti-influenza virus activity. The experimental results showed that 2-aminoindole <strong>3h</strong> had significant antiviral activity (EC₅₀ = 8.37 ± 0.65 μM) and the lowest cytotoxicity (CC₅₀ = 669.26 ± 11.42 μM) <em>in vitro</em>. 2-Aminoindole <strong>3h</strong> could inhibit viral replication by effectively binding to RNA-dependent RNA polymerase (RdRp), and could also directly target host cells to inhibit cytokine storms and apoptosis induced by viral infection, thereby improving host cell survival rate. In addition, viral load and organ injury in the lung tissue of infected mice were effectively reduced by 2-aminoindole <strong>3h</strong> with satisfactory biosafety. These findings highlight the potential of a valuable therapeutic option against influenza infection while also laying the foundation for further research and development in this area.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117044"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}