Bioorganic & Medicinal Chemistry最新文献

{"title":"Ligustrazine as a multitarget scaffold in drug design and discovery","authors":"Xueyang Jiang ,&nbsp;Siyi Li ,&nbsp;Ning Wang ,&nbsp;Jiaming Li","doi":"10.1016/j.bmc.2025.118110","DOIUrl":"10.1016/j.bmc.2025.118110","url":null,"abstract":"<div><div>Ligustrazine has gained significant attention for its unique structural role in natural medicinal chemistry and its potential in drug discovery and development. The ligustrazine structure has been recognized as a clinical drug for treating cardiovascular and cerebrovascular diseases, especially in the design of neuroprotective agents. Recently, ligustrazine-based anti-tumor agents have also been reported. This knowledge can undoubtedly be applied to design multi-target-directed ligands, a highly relevant strategy for the complex pathological conditions of multifactorial diseases. In this review, we first discuss the biological properties and clinical applications of ligustrazine, then focus on the rational design of ligustrazine-based multifunctional ligands.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118110"},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities","authors":"Yun-He Liu ,&nbsp;Zi-Yue Wang ,&nbsp;Yi-Fei Du ,&nbsp;Xuan-Han Liu ,&nbsp;Jin-Bo Niu ,&nbsp;Jian Song ,&nbsp;Cheng-Yun Jin ,&nbsp;Sai-Yang Zhang","doi":"10.1016/j.bmc.2025.118109","DOIUrl":"10.1016/j.bmc.2025.118109","url":null,"abstract":"<div><div>Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure–activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118109"},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 activity of human glutaminyl cyclase inhibitors against Alzheimer’s disease","authors":"Jingjing Li ,&nbsp;Keli Zong ,&nbsp;Chaochun Wei ,&nbsp;Qidi Zhong ,&nbsp;Hong Yan ,&nbsp;Juan Wang ,&nbsp;Xingzhou Li","doi":"10.1016/j.bmc.2025.118105","DOIUrl":"10.1016/j.bmc.2025.118105","url":null,"abstract":"<div><div>Human glutaminyl cyclase (hQC) has emerged as a critical target in Alzheimer’s disease (AD) due to its role in generating pyroglutamate-modified amyloid β (pE-Aβ). In this study, 13 compounds were designed as target compounds by fragment-based drug design (FBDD) and molecular docking, and subsequently assessed for drug-like properties and predicted inhibitory activities through ADMET analysis and Uni-QSAR modeling. Target compounds were synthesized via systematic multi-step approaches, with acceptable yields. The <em>in vitro</em> hQC enzyme inhibition assay revealed that all target compounds exhibited superior inhibitory activity compared to the reference compound <strong>PBD150</strong> (140.50 <span><math><mo>±</mo></math></span> 0.93 nM), with compounds <strong>A3</strong> (3.36 <span><math><mo>±</mo></math></span> 0.90 nM), <strong>A4</strong> (3.20 <span><math><mo>±</mo></math></span> 1.15 nM), <strong>B1</strong> (3.99 <span><math><mo>±</mo></math></span> 0.99 nM), and <strong>B2</strong> (3.64 <span><math><mo>±</mo></math></span> 0.98 nM) standing out for further investigation. Further, molecular dynamics (MD) simulations were conducted on compounds <strong>A3</strong>, <strong>A4</strong>, <strong>B1</strong>, and <strong>B2</strong>, revealing the stability and binding interactions of the compounds within the hQC active site over a 200 ns simulation period. Then, the results of binding free energy calculations validated the superior binding affinities of compounds <strong>A3</strong>, <strong>A4</strong>, <strong>B1</strong>, and <strong>B2</strong> than <strong>PBD150</strong>. These findings highlight <strong>A3</strong>, <strong>A4</strong>, <strong>B1</strong>, and <strong>B2</strong> as promising hQC inhibitors, offering insights for AD drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118105"},"PeriodicalIF":3.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid conjugated BimBH3 analogues with d‑amino acid substitution as PTPN1 inhibitors with enhanced activity, biostability and orally available potency for the treatment of diabetes","authors":"Liyan Gong ,&nbsp;Guozhen Dong ,&nbsp;Qianqian Zhang ,&nbsp;Yiying Shi ,&nbsp;Zongwen Gu ,&nbsp;Xianmin Yang ,&nbsp;Xiang Gao ,&nbsp;Yaning Zheng ,&nbsp;Chuanliang Zhang","doi":"10.1016/j.bmc.2025.118107","DOIUrl":"10.1016/j.bmc.2025.118107","url":null,"abstract":"<div><div>Protein tyrosine phosphatase non-receptor type 1 (PTPN1) is a crucial regulator of insulin and leptin signaling pathways, positioning it as a promising therapeutic target for the development of insulin sensitizers in the treatment of type 2 diabetes mellitus (T2DM). Our previous studies demonstrated that lipidated/acylated BimBH3 core peptide analogues function as potent PTPN1 inhibitors with potential for once-weekly hypoglycemic efficacy. Additionally, alanine scanning identified specific residues that could be modified without compromising inhibitory activity. In this study, we designed and synthesized 14 lipidated BimBH3 analogues incorporating <span>d</span>-amino acids through site-specific modifications to enhance peptide stability and activity. Among these, analogues D-1, D-9, D-10, D-11, D-12, and D-14 exhibited potent PTPN1 inhibitory activity, demonstrated significant resistance to proteolytic degradation, and showed good stability in mouse plasma. Notably, in glucose tolerance tests, subcutaneous administration of D-14 led to a significant 26.2 % reduction in blood glucose (AUC_0–120 min), while oral administration achieved a 15.4 % reduction (AUC_0–180 min), indicating promising oral bioavailability. Further analysis using molecular docking and kinetic studies confirmed the strong binding affinity of <span>d</span>-amino acid-containing BimBH3 analogues for PTPN1, supporting their potential for sustained hypoglycemic effects. Overall, our findings demonstrate that the dual modifications of <span>d</span>-amino acid substitution and lipid conjugation significantly enhance the inhibitory activity, bio-stability, and oral availability of BimBH3 analogues, highlighting their potential as novel, long-acting therapeutics for T2DM management.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118107"},"PeriodicalIF":3.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research progress of flavonoids targeting estrogen receptor in the treatment of breast cancer","authors":"Jianling Long ,&nbsp;Pengju Ye ,&nbsp;Weixi Yuan ,&nbsp;Qixian Yang ,&nbsp;Zhe Wang ,&nbsp;Hongxiang Xiao ,&nbsp;Zhizhong Xie ,&nbsp;Xiaoyong Lei ,&nbsp;Xiaoyan Yang ,&nbsp;Xiangping Deng ,&nbsp;Guotao Tang","doi":"10.1016/j.bmc.2025.118106","DOIUrl":"10.1016/j.bmc.2025.118106","url":null,"abstract":"<div><div>Breast cancer (BC) stands as the most prevalent malignancy among women. Targeting the estrogen receptor (ER) or ER pathway is one of the important approaches for ER⁺ BC treatment. As a class of phytoestrogens, flavonoids possess notable anti-tumor properties and hold immense potential in regulating ER signaling. In this review, we reported the recent advances in both <em>in vitro</em> and <em>in vivo</em> studies of flavonoids and their synthetic derivatives targeting the ER signaling pathway, including the target and mechanism of action of these molecules, as well as their structure–activity relationship. Based on the available literature, the beneficial effects of flavonoids as ER targeting agents are promising but they require further <em>in vitro</em> and <em>in vivo</em> studies to enable its translation from bench to bedside. This review will provide valuable guidance and insights for the future development of drugs targeting the ER pathway.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118106"},"PeriodicalIF":3.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 pyrazole derivatives as potential SARS-CoV-2 Mpro inhibitors: An integrated approach merging combinatorial chemistry, molecular docking, and deep learning","authors":"Arthur Antunes Ferrarezi ,&nbsp;João Vítor Perez de Souza ,&nbsp;Bernard Maigret ,&nbsp;Érika Seki Kioshima ,&nbsp;Sidnei Moura ,&nbsp;Arildo José Braz de Oliveira ,&nbsp;Fernanda Andreia Rosa ,&nbsp;Regina Aparecida Correia Gonçalves","doi":"10.1016/j.bmc.2025.118095","DOIUrl":"10.1016/j.bmc.2025.118095","url":null,"abstract":"<div><div>The global impact of SARS-CoV-2 has highlighted the urgent need for novel antiviral therapies. This study integrates combinatorial chemistry, molecular docking, and deep learning to design, evaluate and synthesize new pyrazole derivatives as potential inhibitors of the SARS-CoV-2 main protease (M^pro). A library of over 60,000 pyrazole-based structures was generated through scaffold decoration to enhance chemical diversity. Virtual screening employed molecular docking (ChemPLP scoring) and deep learning (DeepPurpose), with consensus ranking to identify top candidates. Binding free energy calculations refined the selection, revealing critical structural features such as tryptamine and <em>N</em>-phenyl fragments for M^pro binding. High-temperature solvent-free amidation allowed the synthesis of a selected derivative. Final compounds demonstrated favorable drug-likeness properties based on Lipinski’s and Veber’s rules. This work highlights the integration of computational and synthetic strategies to accelerate the discovery of M^pro inhibitors and provides a framework for future antiviral development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118095"},"PeriodicalIF":3.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 2-Phenyl Indole Analogues of OXi8006 as Colchicine Site Inhibitors of Tubulin Polymerization and Vascular Disrupting Agents","authors":"Rebecca Vairin ,&nbsp;Caleb Tamminga ,&nbsp;Zhe Shi ,&nbsp;Christian Borchardt ,&nbsp;Jayaram Jambulapati ,&nbsp;Ruoli Bai ,&nbsp;Hashini Wanniarachchi ,&nbsp;Lorena Bueno ,&nbsp;Ernest Hamel ,&nbsp;Ralph P. Mason ,&nbsp;Mary Lynn Trawick ,&nbsp;Kevin G. Pinney","doi":"10.1016/j.bmc.2024.117981","DOIUrl":"10.1016/j.bmc.2024.117981","url":null,"abstract":"<div><div>Inhibitors of tubulin polymerization represent a promising therapeutic approach for the treatment of solid tumors. Molecules that bind to the colchicine site are of interest as they can function with a dual mechanism of action as both potent antiproliferative agents and tumor-selective vascular disrupting agents (VDAs). One such example is a 2-aryl-3-aroyl-indole molecule (OXi8006) from our laboratory that demonstrates potent inhibition of tubulin polymerization and strong antiproliferative activity (cytotoxicity) against a variety of human cancer cell lines. A water-soluble prodrug OXi8007, synthesized from OXi8006, demonstrates <em>in vivo</em> disruption of tumor-associated microvessels in several tumor types (mouse models). The molecular framework of OXi8006 inspired a series of fourteen new 2-aryl-3-aroyl-indole analogues that incorporated various functional group modifications on both the indole core and the aroyl ring. Electron withdrawing and donating groups at the mono-substituted 3′ position and the di-substituted 3′,5′ positions were all accommodated while maintaining inhibition of tubulin polymerization (IC₅₀ &lt; 5 μM), with several analogues demonstrating activity comparable to OXi8006 and the benchmark natural product combretastatin A-4 (CA4). Preliminary structure–activity relationship (SAR) studies were further enhanced by molecular docking to predict possible colchicine site interactions. Two analogues (KGP366 and KGP369) previously synthesized in our laboratory were re-synthesized using a somewhat modified route to increase synthetic efficiency and were subsequently converted to their corresponding water-soluble phosphate prodrug salts to evaluate their efficacy as VDAs. Administration of the prodrug salt (KGP415) of KGP369 caused significant reduction in bioluminescence signal from an orthotopic kidney tumor (RENCA-luc) in BALB/c mice, indicative of VDA activity. Collectively, these new functionalized indole-based analogues have extended SAR knowledge related to the colchicine binding site, and the most biologically active analogues hold promise for continued development as pre-clinical candidates for cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 117981"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Charge-neutralized polyethylenimine-lipid nanoparticles for gene transfer to human embryonic stem cells","authors":"Guoqing Feng ,&nbsp;Yang Bai ,&nbsp;Pengyu Huang ,&nbsp;Yuan Liu ,&nbsp;Qingbin Yang ,&nbsp;Bowen Li ,&nbsp;Qing Yuan ,&nbsp;Niansong Qian ,&nbsp;Bin Zheng","doi":"10.1016/j.bmc.2024.118008","DOIUrl":"10.1016/j.bmc.2024.118008","url":null,"abstract":"<div><div>Gene delivery is fundamentally crucial for the genetic manipulation of stem cells. Here, we present a straightforward approach to create a library of charge-neutralized polyethylenimine (PEI)-lipid nanoparticles designed for stem cell transfection. These lipid nanoparticles were formulated using small, branched PEI and lipidic anhydrides. Remarkably, over 15% of the lipid nanoparticles demonstrated high transfection efficiency across various cell types, surpassing the efficiency of both Lipofectamine 2000 and FuGENE HD. A structure–activity analysis indicated that the length and ratio of hydrophobic alkyl substitutions were critical parameters for efficient gene delivery. Notably, the transfection efficiency was higher than that of the original cation PEI. Our optimized PEI-lipid system enabled highly effective plasmid DNA delivery and successfully co-transferred two plasmid DNAs into difficult-to-transfect human embryonic stem cells (hESCs), facilitating optogenetic manipulation within these cells.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118008"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential COX-2 inhibitors modulating NF-κB/MAPK signaling pathways: Design, synthesis and evaluation of anti-inflammatory activity of Pterostilbene-carboxylic acid derivatives with an oxime ether moiety","authors":"Peng Luo ,&nbsp;Taotao Chen ,&nbsp;Shaoling Huang ,&nbsp;Feng Peng ,&nbsp;Yunhou Huang ,&nbsp;Weigao Pan","doi":"10.1016/j.bmc.2024.118022","DOIUrl":"10.1016/j.bmc.2024.118022","url":null,"abstract":"<div><div>In this work, a series of novel Pterostilbene–oxime ether–carboxylic acid (<strong>POC</strong>) derivatives (<strong>d1–d10</strong>, <strong>e1–e10</strong> and <strong>1</strong>–<strong>13</strong>) were designed, synthesized, and characterized by spectroscopic techniques. In order to further determine the absolute configuration of these compounds, one of them, compound <strong>d3</strong>, was investigated by X-ray single crystal diffraction method. <strong>d3</strong> had a triclinic crystal with <em>P</em>-1 space group, and its <img>CH<img>CH<img> and <img>CH<img>N<img> was confirmed as <em>E</em> configuration. A strong hydrogen bond was formed between the hydrogen atom in <img>CH<img>CH<img> moiety and the nitrogen atom in <img>CH<img>N<img> moiety, which was a vital factor in the formation and stability of <em>E</em> configuration in the <img>CH<img>CH<img> and <img>CH<img>N<img>. The safety and anti-inflammatory activities of compounds (<strong>d1–d10</strong>, <strong>e1–e10</strong> and <strong>1</strong>–<strong>13</strong>) in vitro were evaluated. At 20 μM, compounds (<strong>d1–d10</strong>, <strong>e1–e10</strong> and <strong>1</strong>–<strong>13</strong> were non-toxic and exhibited weak to strong inhibitory effects on the LPS-induced NO release. Among them, five compounds (<strong>1</strong>, <strong>2</strong>, <strong>7</strong>, <strong>8</strong> and <strong>9</strong>) showed excellent anti-inflammatory effects with IC₅₀ (NO) values ranging from 9.87 to 19.78 μM, as well as strong COX-2 inhibitory abilities with IC₅₀ (COX-2) values ranging from 85.44 to 140.88 nM. Moreover, there was a rough positive correlation between their anti-inflammatory properties and the COX-2 inhibitory abilities. Compounds (<strong>1</strong>, <strong>2</strong>, <strong>7</strong>, <strong>8</strong> and <strong>9</strong>) smoothly docked with COX-2 protein (PDB ID: 5KIR) to form stable complexes with strong hydrogen bonds, with an affinity range of −8.3 to −9.9 kcal/mol. SAR indicated that the amidation of POC at R₂ position was more favorable for enhancing the compound’s biological actives than esterification. In addition, the 4-fluobenzyl substitution at R₂ position of the oxime ether moiety can obviously enhance the activity of above amide derivates. Introducing acyl groups (<img>CO(CH₂)_nCH₃, n = 2, 4 and 6) into <img>NH(CH₂)₃OH group to form ester chain is disadvantageous for activity enhancing, moreover, the longer the carbon chain, the poorer the activity. The strongest COX-2 inhibitor (IC₅₀ (COX-2) = 85.44 ± 3.88 nM), compound <strong>7</strong>, exerted as anti-inflammatory activities (IC₅₀ (NO) = 9.87 ± 1.38 μM) by down-regulating the expression of COX-2 and iNOS, and modulating NF-κB/MAPK signaling pathways.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118022"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and in vitro evaluation of novel compounds and discovery of a promising iodine-125 radioligand for purinergic P2X7 receptor (P2X7R)","authors":"Lin Qiu ,&nbsp;Jinzhi Wang ,&nbsp;Manju Tewari ,&nbsp;Derek T. Rensing ,&nbsp;Terrance M. Egan ,&nbsp;Joel S. Perlmutter ,&nbsp;Zhude Tu","doi":"10.1016/j.bmc.2024.118054","DOIUrl":"10.1016/j.bmc.2024.118054","url":null,"abstract":"<div><div>The purinergic P2X ligand-gated ion channel 7 receptor (P2X7R) plays a critical role in various inflammatory processes and other diseases. Fast determination of compounds P2X7R binding potency and discovery of a promise PET radiotracer for imaging P2X7R require a P2X7R suitable radioligand for radioactive competitive binding assay. Herein, we designed and synthesized thirteen new P2X7R ligands and determined the <em>in vitro</em> binding potency. The fluorescence screening assay identified the iodide compound <strong>1c</strong> with high potency and specificity toward P2X7R with an IC₅₀ of 0.25 ± 0.05 nM. Therefore, <strong>1c</strong> was ¹²⁵I-labeled to afford [¹²⁵I]<strong>1c</strong> with a good radiochemical yield (44 ± 12 %, n = 3) and high radiochemical purity (&gt;95 %). Radioligand saturation binding assay showed that [¹²⁵I]<strong>1c</strong> specifically bound to human P2X7R with high affinity (K_d = 1.68 nM and B_max = 94 fmol/mg). A radioactive high throughput binding assay using [¹²⁵I]<strong>1c</strong> for our new compounds demonstrated that the imidazole compounds <strong>1b</strong>, <strong>1c</strong>, and <strong>1d</strong> exhibited high inhibition for &gt;70 %, while the analogues of <strong>GSK314181A</strong> exhibited low inhibition for &lt;35 %. In addition, our radioligand competitive binding assays using [¹²⁵I]<strong>1c</strong> demonstrated that <strong>1b</strong>, <strong>1c</strong>, and <strong>1d</strong> have high potency with IC₅₀ values of 7.91 ± 0.22, 7.06 ± 1.68, and 7.16 ± 0.41 nM toward P2X7R, respectively.Together, compounds <strong>1b</strong>, <strong>1c</strong>, and <strong>1d</strong> are highly potent for P2X7R, and [¹²⁵I]<strong>1c</strong> has great potential to be a radioligand for screening P2X7R binding potency of the new compounds and investigating the P2X7R expression in animal models of human disease.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118054"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}