European Journal of Medicinal Chemistry最新文献

{"title":"Novel benzenesulfonamide derivatives linked to diaryl pyrazole tail as potential carbonic anhydrase II/VII inhibitors with anti-epileptic activity","authors":"Wael A.A. Fadaly ,&nbsp;Mohamed T.M. Nemr ,&nbsp;Abeer M. Abd El-Hameed ,&nbsp;Simone Giovannuzzi ,&nbsp;Mahmoud Abdelrahman Alkabbani ,&nbsp;Mohamed M. Hefina ,&nbsp;Alessio Nocentini ,&nbsp;Mamdouh F.A. Mohamed ,&nbsp;Claudiu T. Supuran ,&nbsp;Wagdy M. Eldehna ,&nbsp;Taha H. Zidan","doi":"10.1016/j.ejmech.2025.117619","DOIUrl":"10.1016/j.ejmech.2025.117619","url":null,"abstract":"<div><div>Two new series of 1,2,3-triazole benzenesulfonamide derivatives <strong>16a-f</strong> and imino-thiazolidinone benzenesulfonamide derivatives <strong>19a-f</strong> with diaryl pyrazole tail were synthesized as carbonic anhydrase (CA) <strong>II</strong>, <strong>VII</strong> inhibitors and assessed for antiepileptic activity. All compounds were tested <em>in vitro</em> for their inhibition activity against the human (h) carbonic anhydrase I, II, and VII isoforms. Among these series, compounds <strong>16b, 16d, 19b,</strong> and <strong>19d</strong> exhibited exceptional inhibitory activity against hCA II, with K_i 10.9–47.1 nM, and hCA VII, with K_i 8.4–23.6 nM, while the two series did not show significant activity against hCA I. Furthermore, <strong>16b, 16d, 19b</strong>, and <strong>19d</strong> were tested against <em>in vivo</em> pilocarpine-induced seizure model, and they showed excellent neuroprotective activity; they delayed seizure onset, reduced seizure severity, and improved survival rates compared to the pilocarpine group, which highlighted their efficacy in regulating neuronal excitability through CA inhibition and chloride homeostasis. Also, hippocampal levels of KCC2 and mTOR were analyzed, as these markers are critical in regulating neuronal excitability and are closely linked to epilepsy. Noteworthy, Compounds <strong>16d</strong> and <strong>19b</strong> surpassed the standard anti-convulsant valproic acid in key parameters, underscoring their superior efficacy. In addition, they do not show any significant neurotoxic effects or alterations in liver and kidney function. Moreover, the results of <em>in vitro</em> cytotoxicity of compounds <strong>16d</strong> and <strong>19b</strong> against Vero cells indicate their safety at the doses given (IC₅₀ = 59.7, 71.9 μM respectively) compared to acetazolamide (IC₅₀ = 32.3 μM). Finally, molecular docking of sulfonamide derivatives with hCA II (PDB code: 2h4h) and hCA VII (PDB code: 3ml5) was performed.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117619"},"PeriodicalIF":6.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806575","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 biological evaluation of novel triarylmethane analogues as HIV-1 entry inhibitors","authors":"Ruiying Liang ,&nbsp;Jianjun Guo ,&nbsp;Shuolan Gu ,&nbsp;Yang Wu ,&nbsp;Shanshan Huo ,&nbsp;Juan Wang ,&nbsp;Fang Huang ,&nbsp;Shibo Jiang ,&nbsp;Dou Dou ,&nbsp;Fei Yu","doi":"10.1016/j.ejmech.2025.117574","DOIUrl":"10.1016/j.ejmech.2025.117574","url":null,"abstract":"<div><div>Small molecule-based entry inhibitors (EIs) may be promising to reduce human immunodeficiency virus (HIV) infection. Taking our recently described HIV entry inhibitor, <strong>ADS-J21</strong>, as prototype, a new series of triarylmethane analogues have been designed and synthesized. Among them, compound <strong>L14</strong> emerged as the most promising showing significant antiviral activity against HIV-1_IIIB infection (IC₅₀: 0.39 μM) and low cytotoxicity (CC₅₀: 210.03 μM, SI: 537.1). <strong>L14</strong> also exhibit cell-cell fusion inhibition activity and antiviral activity against both HIV-1 T20-resistant and primary strains, with potency in the submicromolar range. Mechanistically, <strong>L14</strong> interacts by hydrogen bonding and π-π stacking with Lys35, Gln38 and Trp32 residues present in the gp41 NHR pocket. Additionally, <strong>L14</strong> did not show significant toxicity in acute and subacute toxicity studies performed on healthy Kunming mice. The oral bioavailability of <strong>L14</strong> in Sprague Dawley (SD) rats is about 7.0 %. Therefore, compound <strong>L14</strong> holds promise as a novel HIV-1 small-molecule entry inhibitor although a further ten-fold improvement in activity is needed for further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117574"},"PeriodicalIF":6.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791371","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 antimicrobial evaluation of novel quaternary quinolone derivatives with low toxicity and anti-biofilm activity","authors":"Ye Qu ,&nbsp;Chen Gao ,&nbsp;Ruirui Li ,&nbsp;Yuequan Wu ,&nbsp;Hongtao Kong ,&nbsp;Yuanbo Li ,&nbsp;Daran Li ,&nbsp;Maxwell Ampomah-Wireko ,&nbsp;Ya-Na Wang ,&nbsp;En Zhang","doi":"10.1016/j.ejmech.2025.117591","DOIUrl":"10.1016/j.ejmech.2025.117591","url":null,"abstract":"<div><div>To overcome the increasing global drug resistance, the development of novel antimicrobial drugs is a top priority in the fight against multidrug resistant (MDR) and persistent bacteria. In this work, we report the synthesis of novel single quaternary quinolone antibacterial agents. The majority of the tested compounds exhibited significant antimicrobial efficacy against Gram-negative pathogens (<em>E. coli</em> and <em>S. maltophilia</em>). Notably, the selected compound (<strong>4e)</strong> was highly inhibitory with a MIC value of 0.25 μg/mL against <em>E. coli</em>. Additionally, compound <strong>4e</strong> demonstrated excellent stability in complex biological fluids with low hemolytic activity (HC₅₀ &gt; 1280 μg/mL) and a significantly lower propensity to induce bacterial resistance. Encouragingly, <strong>4e</strong> showed not only rapid bactericidal activity and inhibition of bacterial biofilms, but also low toxicity to erythrocytes and RAW 264.7 cells compared to the clinical drug ciprofloxacin. Mechanism studies have found that compound <strong>4e</strong> has a relatively weak destructive effect on the cell membrane of <em>E. coli</em>.</div><div>However, it can effectively inhibit the activity of glutathione (GSH), promote the massive accumulation of intracellular reactive oxygen species (ROS), and then disrupt the antioxidant defense system of bacteria, achieving a bactericidal effect. In addition, compound <strong>4e</strong> has a certain binding effect with bacterial DNA.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787467","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":"Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies","authors":"Dóra Laczi ,&nbsp;Sofia Schönbauer Huamán ,&nbsp;Taylah Andrews-Clark ,&nbsp;Stephen M. Laidlaw ,&nbsp;Eidarus Salah ,&nbsp;Leo Dumjahn ,&nbsp;Petra Lukacik ,&nbsp;Hani Choudhry ,&nbsp;Martin A. Walsh ,&nbsp;Miles W. Carroll ,&nbsp;Christopher J. Schofield ,&nbsp;Lennart Brewitz","doi":"10.1016/j.ejmech.2025.117603","DOIUrl":"10.1016/j.ejmech.2025.117603","url":null,"abstract":"<div><div>Nirmatrelvir is a substrate-related inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (M^pro) that is clinically used in combination with ritonavir to treat COVID-19. Derivatives of nirmatrelvir, modified at the substrate P2-equivalent position, have been developed to fine-tune inhibitor properties and are now in clinical use. We report the synthesis of nirmatrelvir derivatives with a (<em>R</em>)-4,4-dimethyl-4-silaproline (silaproline) group at the P2-equivalent position. Mass spectrometry (MS)-based assays demonstrate that silaproline-bearing nirmatrelvir derivatives efficiently inhibit isolated recombinant M^pro, albeit with reduced potency compared to nirmatrelvir. Investigations with SARS-CoV-2 infected VeroE6 cells reveal that the silaproline-bearing inhibitors with a CF₃ group at the P4-equivalent position inhibit viral progression, implying that incorporating silicon atoms into M^pro inhibitors can yield <em>in vivo</em> active inhibitors with appropriate optimization. MS and crystallographic studies show that the nucleophilic active site cysteine residue of M^pro (Cys145) reacts with the nitrile group of the silaproline-bearing inhibitors. Substituting the electrophilic nitrile group for a non-activated terminal alkyne shifts the inhibition mode from reversible covalent inhibition to irreversible covalent inhibition. One of the two prochiral silaproline methyl groups occupies space in the S2 pocket that is unoccupied in M^pro:nirmatrelvir complex structures, highlighting the value of sila-derivatives in structure-activity-relationship (SAR) studies. The combined results highlight the potential of silicon-containing molecules for inhibition of M^pro and, by implication, other nucleophilic cysteine enzymes.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117603"},"PeriodicalIF":6.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798236","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":"The synthesis, photophysical and biological properties of 5,10,15,20-tetra(4-substituted phenyl)tetrabenzoporphyrin derivatives","authors":"Ying Jiang ,&nbsp;Hong-Yu Liang ,&nbsp;Yi-Jia Yan ,&nbsp;Igor D. Romanishkin ,&nbsp;Gennady A. Meerovich ,&nbsp;Igor V. Reshetov ,&nbsp;Xing-Ping Zhou ,&nbsp;Zhi-Long Chen","doi":"10.1016/j.ejmech.2025.117612","DOIUrl":"10.1016/j.ejmech.2025.117612","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) had garnered considerable focus owing to its high photoactivation efficacy and low systemic toxicity. The performance of PDT heavily relied on the behavior of photosensitizers. In this study, a series of new 5,10,15,20-tetra(4-substituted phenyl)tetrabenzoporphyrin derivatives were prepared and their antitumor effects <em>in vitro</em> and <em>in vivo</em> were evaluated. These new compounds presented an absorption peak at ∼700 nm within the phototherapeutic window (600–760 nm). Their effective ROS generation capacities were predominantly verified via the type II mechanism during the irradiation process. <em>In vitro</em> experiments displayed that all compounds exhibited notable phototoxicity with low dark toxicity (IC₅₀ &gt; 76 μM) toward Eca-109 cells. Among them, <strong>VI</strong> showed obvious photoactivation with a cell survival rate reduction to 7 % at a concentration of 10 μM after exposure to 650 nm laser light (12 J/cm²). <em>In vivo</em> studies revealed that <strong>VI</strong> had significant antitumor effects with inhibition rate up to 94 %. Subcellular experiments demonstrated that <strong>VI</strong> distributed mainly in mitochondria, lysosomes and partially in endoplasmic reticulum. Thus, compound <strong>VI</strong>, which possessed long-wavelength and multi-wavelength absorption capabilities, high photocytotoxicity and low dark toxicity to tumor, would emerge as a promising photosensitizer for individual photo-diagnosis and photodynamic therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117612"},"PeriodicalIF":6.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798134","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 bioevaluation of novel hydrazide derivatives as enhancers of immunotherapy and DNA-damage response in antitumor therapy","authors":"Zhihao Hu ,&nbsp;Shuqing Li ,&nbsp;Wanyi Pan,&nbsp;Haiyan Wu,&nbsp;Xiaopeng Peng","doi":"10.1016/j.ejmech.2025.117601","DOIUrl":"10.1016/j.ejmech.2025.117601","url":null,"abstract":"<div><div>We have designed and synthesized a series of novel hydrazide-based HDAC3 inhibitors, with the representative compound <strong>8ae</strong> demonstrating potent HDAC3 inhibitory activity, having an IC₅₀ value of 311 nM (with a selectivity index SI greater than 32 over other HDACs). Compound <strong>8ae</strong> also exhibited significant anti-proliferative activity against five types of cancer cells, with an average inhibitory rate IC₅₀ value of 5.036 μM, and was capable of inhibiting the migration, invasion, and wound healing activities of B16–F10 cells. Further studies revealed that <strong>8ae</strong> effectively modulates the expression of Ac-H3 within tumor cells and can degrade PD-L1 in tumor cells through the lysosome pathway mediated by cathepsin B (CTSB). Notably, <strong>8ae</strong> also possesses favorable pharmacokinetic properties. In <em>in vivo</em> experiments, the combination of <strong>8ae</strong> with the PD-L1 inhibitor NP-19 activated the immune system in melanoma-bearing mice, leading to an enhanced anti-tumor immune response (TGI = 65 %). When combined with olaparib, <strong>8ae</strong> significantly enhanced tumor suppressive activity (TGI = 88 %) in a breast cancer mouse model and displayed a favorable safety profile. Collectively, <strong>8ae</strong> is a promising HDAC3 inhibitor that warrants further exploration in cancer therapeutic strategies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117601"},"PeriodicalIF":6.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798131","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":"Proof of concept study for developing 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors to treat Parkinson's disease complicating depression","authors":"Xuan Chen ,&nbsp;Mengxiao Zhu ,&nbsp;Qingyuan Shi ,&nbsp;Zhenquan Huang ,&nbsp;Junjie Zhu ,&nbsp;Pingping Sun ,&nbsp;Hongzhen Zhang ,&nbsp;Lili Yang ,&nbsp;Xun Chen ,&nbsp;Yu Zhang ,&nbsp;Lili Feng ,&nbsp;Katsuhisa Horimoto ,&nbsp;Fei Li ,&nbsp;Feng Han ,&nbsp;Dongyin Chen","doi":"10.1016/j.ejmech.2025.117597","DOIUrl":"10.1016/j.ejmech.2025.117597","url":null,"abstract":"<div><div>Depressive symptoms are the most common neuropsychiatric disorders at all stages of Parkinson's disease (PD). Imbalances of the kynurenine pathway of tryptophan metabolism have been closely linked to the pathogenesis of PD and depression. Herein, we designed and synthesized a series of 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors; among them, compound <strong>CZ-17</strong> manifested moderate inhibitory activities to IDO1 and TDO with IC₅₀ values of 0.33 and 1.78 μM, respectively. <strong>CZ-17</strong> inhibited the kynurenine pathway of tryptophan degradation at the cellular level, and remarkably reduced the kynurenine/tryptophan ratio. <strong>CZ-17</strong> displayed directly neuroprotective effect in corticosterone-induced PC12 neural cell injury model. <em>In vivo</em> experiments demonstrated that <strong>CZ-17</strong> significantly increased dopamine and serotonin levels, improved MPTP-induced motor disability and rescued LPS-induced depressive behavior in zebrafish model. Acute toxicity tests of <strong>CZ-17</strong> in zebrafish embryos showed no toxicity within the effective dose range. Additionally, <strong>CZ-17</strong> displayed the potential to cross the BBB <em>via</em> passive diffusion according to ADMET prediction and Caco-2 permeability assay. Thus, <strong>CZ-17</strong> may be a promising drug candidate for PD complicating depression.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117597"},"PeriodicalIF":6.0,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784756","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":"Corrigendum to “Design, synthesis and evaluation of carbamate-bridged amino acid prodrugs of cycloicaritin with improved antitumor activity, aqueous solubility and phase II metabolic stability” [Eur. J. Med. Chem. 276 (2024) 116646]","authors":"Weiping Wang, Jiaqi Fan, Fengxiao Li, Shuo Gan, Jiaming Zhang, Yanfang Wang, Yingchao Li, Wenchao Li, Zhonggui He, Huaiwei Ding, Yongbing Sun, Tianhong Zhang, Qikun Jiang","doi":"10.1016/j.ejmech.2025.117594","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117594","url":null,"abstract":"The authors regret an error in Acknowledgments. The corrected version is provided below:","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"89 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790073","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":"A deep learning model for structure-based bioactivity optimization and its application in the bioactivity optimization of a SARS-CoV-2 main protease inhibitor","authors":"Zhenyu Yang ,&nbsp;Kai Wang ,&nbsp;Guo Zhang ,&nbsp;Yuanyuan Jiang ,&nbsp;Rui Zeng ,&nbsp;Jingxin Qiao ,&nbsp;Yueyue Li ,&nbsp;Xinyue Deng ,&nbsp;Ziyi Xia ,&nbsp;Rui Yao ,&nbsp;Xiaoxi Zeng ,&nbsp;Liyun Zhang ,&nbsp;Yi Zhao ,&nbsp;Jian Lei ,&nbsp;Runsheng Chen","doi":"10.1016/j.ejmech.2025.117602","DOIUrl":"10.1016/j.ejmech.2025.117602","url":null,"abstract":"<div><div>Bioactivity optimization is a crucial and technical task in the early stages of drug discovery, traditionally carried out through iterative substituent optimization, a process that is often both time-consuming and expensive. To address this challenge, we present Pocket-StrMod, a deep-learning model tailored for structure-based bioactivity optimization. Pocket-StrMod employs an autoregressive flow-based architecture, optimizing molecules within a specific protein binding pocket while explicitly incorporating chemical expertise. It synchronously optimizes all substituents by generating atoms and covalent bonds at designated sites within a molecular scaffold nestled inside a protein pocket. We applied this model to optimize the bioactivity of <strong>Hit1</strong>, an inhibitor of the SARS-CoV-2 main protease (M^pro) with initially poor bioactivity (IC₅₀ : 34.56 μM). Following two rounds of optimization, six compounds were selected for synthesis and bioactivity testing. This led to the discovery of <strong>C5</strong>, a potent compound with an IC₅₀ value of 33.6 nM, marking a remarkable 1028-fold improvement over <strong>Hit1</strong>. Furthermore, <strong>C5</strong> demonstrated promising in vitro antiviral activity against SARS-CoV-2. Collectively, these findings underscore the great potential of deep learning in facilitating rapid and cost-effective bioactivity optimization in the early phases of drug development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117602"},"PeriodicalIF":6.0,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784757","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 and exploration of disubstituted [1,2,5]oxadiazolo- [3,4-b]pyrazines as novel C-C chemokine receptor type 5 signaling inhibitors targeting the intracellular allosteric binding pocket","authors":"Margaux Billen ,&nbsp;Sten Reynders ,&nbsp;Sandra Claes ,&nbsp;Silke Kleinboelting ,&nbsp;Jef Rozenski ,&nbsp;Radu-George Bulai ,&nbsp;Edoardo Rocca ,&nbsp;Natalie Z.M. Homer ,&nbsp;Scott P. Webster ,&nbsp;Tim P. Kaminski ,&nbsp;Eveline Lescrinier ,&nbsp;Dominique Schols ,&nbsp;Peter Verwilst","doi":"10.1016/j.ejmech.2025.117600","DOIUrl":"10.1016/j.ejmech.2025.117600","url":null,"abstract":"<div><div>The C-C chemokine receptor type 5 is a G protein-coupled receptor expressed on various immune cells, playing a crucial role in inflammation and chemotaxis. Beyond its physiological functions, C-C chemokine receptor type 5 is implicated in numerous diseases, including cardiovascular, central nervous system, immune system, and infectious diseases, as well as in the progression of cancer. The therapeutic potential of C-C chemokine receptor type 5 inhibition has been demonstrated by antagonists targeting the extracellular domain, notably maraviroc, a Food and Drug Administration-approved Human Immunodeficiency Virus entry inhibitor. However, challenges such as suboptimal pharmacokinetics and efficacy necessitate new antagonists with unique modes of action. Recent advancements in G protein-coupled receptor structural characterization have identified a novel intracellular allosteric binding site in chemokine receptors. This study introduces a series of disubstituted [1,2,5]oxadiazolo-[3,4-<em>b</em>]pyrazines targeting the intracellular allosteric binding pocket of C-C chemokine receptor type 5. Among these, compound <strong>3ad</strong> emerged as a promising C-C chemokine receptor type 5-selective allosteric antagonist with an half-maximal inhibitory concentration of 1.09 μM and an almost 30-fold selectivity over C-C chemokine receptor type 2. Molecular dynamics simulations and a competition assay with a Gα_q11 mimetic were used to confirm the intracellular binding mode of these compounds. This novel class of C-C chemokine receptor type 5-selective intracellular antagonists offers a foundation for developing molecular tools and therapeutic agents, potentially overcoming the limitations of current extracellular C-C chemokine receptor type 5 antagonists.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117600"},"PeriodicalIF":6.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776196","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}