Bioorganic & Medicinal Chemistry最新文献

{"title":"New phenylpiperazine-thiazolidine-2,4-dione hybrids targeting MAO inhibition: Synthesis, biological evaluation, kinetic study and in silico insights","authors":"Lamiaa O. El-Halaby ,&nbsp;Mohammad M. Al-Sanea ,&nbsp;Abdullah A. Elgazar ,&nbsp;Samar S. Tawfik ,&nbsp;Abdelrahman Hamdi ,&nbsp;Wafaa A. Ewes","doi":"10.1016/j.bmc.2025.118123","DOIUrl":"10.1016/j.bmc.2025.118123","url":null,"abstract":"<div><div>Monoamine oxidase inhibitors are promising drug targets for many neurological diseases such as depression, Alzheimer’s disease, and Parkinson’s disease. The current study developed new hybrid compounds by merging phenyl piperazines, and 2,4-thiazolidinedione moieties based on their reported MAO inhibitory activities. The newly synthesized derivatives were screened for their MAOs inhibitory activity using <em>in-vitro</em> fluorometric assay. Most newly synthesized compounds elicited strong inhibitory activity against both <em>h</em>MAO isozymes. Hybrids <strong>4a</strong> and <strong>4c</strong> were the most potent <em>h</em>MAO-A inhibitors with IC₅₀ values of 0.194 and 0.188 µM, respectively, compared to toloxatone as reference (IC₅₀ = 1.080 µM), meanwhile, compound <strong>4g</strong> exhibited the most potent inhibitory activity against MAO-B with an IC₅₀ value of 0.330 µM. The kinetic study of compound <strong>4c</strong> revealed that it exhibited a mixed inhibition mode with a K_i value of 3.4 nM. Compound <strong>4c</strong> was evaluated against the normal SH-SY5Y cell line and found to be non-cytotoxic at its active inhibition concentration. ADME profiles of the most active hybrids <strong>4a</strong>, <strong>4c</strong>, <strong>4j</strong>, and <strong>4k</strong> revealed that they could serve as successful drug candidates showing good CNS penetration. Molecular docking simulations were executed for the most active motifs <strong>4a</strong> and <strong>4c</strong> to demonstrate the binding pattern with the target proteins explaining their potential inhibitory activity. Lastly, this study will significantly contribute to developing novel safe, effective medications for treating various neurological disorders in the foreseeable future.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118123"},"PeriodicalIF":3.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464862","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 in vitro validation of bivalent binders of SARS-CoV-2 spike protein: Obeticholic, betulinic and glycyrrhetinic acids as building blocks","authors":"Martina Pedrini ,&nbsp;Luca Pozzi ,&nbsp;Francesca Sacchi ,&nbsp;Andrea Citarella ,&nbsp;Valerio Fasano ,&nbsp;Pierfausto Seneci ,&nbsp;Stefano Pieraccini ,&nbsp;Lorenzo Ruberto ,&nbsp;Helena Perez Peña ,&nbsp;Alfredo Garzino-Demo ,&nbsp;Adriana Vitiello ,&nbsp;Leonardo Sernicola ,&nbsp;Alessandra Borsetti ,&nbsp;Arianna Calistri ,&nbsp;Cristina Parolin ,&nbsp;Daniele Passarella","doi":"10.1016/j.bmc.2025.118124","DOIUrl":"10.1016/j.bmc.2025.118124","url":null,"abstract":"<div><div>SARS-CoV-2 is the virus responsible for the COVID-19 pandemic, which caused over 6.7 million deaths worldwide. The Spike protein plays a crucial role in the infection process, mediating the binding of the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2), and its subsequent entry into target cells. Previous studies identified, through virtual screening, several natural products capable of binding to two distinct pockets of the Spike protein: triterpenoids binding to pocket 1 and bile acid derivatives binding to pocket 5. Building on these findings, our study advances the field by developing bivalent compounds <strong>1–4</strong> that through a spacer combine a triterpenoid (betulinic acid or glycyrrhetinic acid) with a semisynthetic bile acid derivative (obeticholic acid). These bivalent compounds are designed to simultaneously bind both pockets of the Spike protein, offering significant advantages over single molecules or the combination of the two natural products. <em>In vitro</em> cell assays using pseudotyped recombinant lentiviral particles with selected SARS-CoV-2 Spike proteins demonstrated that <strong>1</strong> and <strong>2</strong> exhibit enhanced activity in reducing viral entry into target cells compared to individual natural products, thus highlighting their potential as superior antiviral agents with reduced side effects.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118124"},"PeriodicalIF":3.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479794","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}

{"title":"Structure-activity relationship studies and pharmacological evaluation of 4-phenylthiazoles as dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors","authors":"Cassandra Yuan ,&nbsp;Amanda Tsang ,&nbsp;Manuel Berumen ,&nbsp;Adriana Rodriguez ,&nbsp;Faye Yun ,&nbsp;Anesa Mesic ,&nbsp;Annie Olivares ,&nbsp;Lissette Dubon ,&nbsp;Allen Nguyen ,&nbsp;Lucy Pavana ,&nbsp;Madison Mercado ,&nbsp;Gabrielle Gorostiza ,&nbsp;Christophe Morisseau ,&nbsp;Bruce D. Hammock ,&nbsp;Ram Kandasamy ,&nbsp;Stevan Pecic","doi":"10.1016/j.bmc.2025.118112","DOIUrl":"10.1016/j.bmc.2025.118112","url":null,"abstract":"<div><div>Forty-two 4-phenylthiazole analogs, organized in two libraries <strong>4a-u</strong> and <strong>6a-u</strong>, were prepared and biologically evaluated in human fatty acid amide hydrolase (FAAH), and human, rat and mouse soluble epoxide hydrolase (sEH) inhibition assays. This structure–activity relationship (SAR) study explores the impact of electronic and steric changes on the molecule’s potency and binding affinity to better understand the structural features important for dual sEH/FAAH inhibition which will guide the development of novel treatments for pain and inflammation. Our SAR revealed that electron-donating groups on the aromatic ring of the 4-phenylthiazole moiety are particularly well tolerated by both enzymes when placed at the ortho, meta and para positions; however, the overall 3D shape of the molecule is very important for the potent FAAH inhibition, suggesting more restricted size of the FAAH binding pocket compared to sEH binding pocket. Two selected dual inhibitors, <strong>4p</strong> and <strong>4s</strong>, were tested in the rat liver microsomes stability assays and evaluated <em>in vivo</em> in the formalin test. Systemic administration of <strong>4p</strong> and <strong>4s</strong> via intraperitoneal injection decreased nociceptive behavior (i.e., licking of the injected paw) in male rats, and this effect was dose-dependent for both compounds. Two doses, 1 and 3 mg/kg of <strong>4p</strong>, decreased nociceptive behavior to a similar extent to that of 30 mg/kg ketoprofen, a traditional nonsteroidal anti-inflammatory drug. However, only 3 mg/kg of <strong>4s</strong> decreased nociceptive behavior compared to vehicle-treated animals, and this effect was comparable to ketoprofen-treated animals. Taken together, these findings reveal the antinociceptive potential of 4-phenylthiazole-based dual FAAH and sEH inhibitors and suggest pharmacodynamic differences within this class of inhibitors despite similar potencies <em>in vitro</em>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118112"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445264","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}

{"title":"Discovery of niclosamide as a p300/transcription factor protein–protein interaction inhibitor","authors":"Dhina Fitriastuti ,&nbsp;Kazuki Miura ,&nbsp;Satoshi Okada ,&nbsp;Hiroyuki Hirano ,&nbsp;Hiroyuki Osada ,&nbsp;Hiroyuki Nakamura","doi":"10.1016/j.bmc.2025.118114","DOIUrl":"10.1016/j.bmc.2025.118114","url":null,"abstract":"<div><div>Protein-protein interactions (PPIs) are crucial in various biological processes and are attractive targets for drug discovery. In this study, we identified niclosamide (<strong>9</strong>) as a novel inhibitor of the hypoxia-inducible factor 1α (HIF-1α)/p300 PPI from the RIKEN NPDepo compound library using a fluorescence anisotropy-based screening method. We synthesized niclosamide azide (<strong>10</strong>) as a photoaffinity labelling probe to identify the p300 binding site of compound <strong>9</strong> and elucidated the binding mode using photoaffinity labelling experiments and molecular docking simulations. Furthermore, we demonstrated that compound <strong>9</strong> inhibited not only HIF-1α/p300 PPI but also p300-transcription factor PPIs, including interaction with p53 and STAT3, thereby suppressing the expression of BAX and c-MYC, respectively.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118114"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438086","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":"Optimizing biofilm inhibitors: Balancing activity and toxicity in 2N-aminated 5-aryl-2-aminoimidazoles","authors":"Lynn Maetens ,&nbsp;Banibrata Maiti ,&nbsp;Freya Cools ,&nbsp;Stefan Verheye ,&nbsp;Dirk Daelemans ,&nbsp;Leentje Persoons ,&nbsp;Liesbet Temmerman ,&nbsp;Amanda Kieswetter ,&nbsp;Erik V. Van der Eycken ,&nbsp;Guglielmo A. Coppola ,&nbsp;Thijs Vackier ,&nbsp;Hans P. Steenackers","doi":"10.1016/j.bmc.2025.118115","DOIUrl":"10.1016/j.bmc.2025.118115","url":null,"abstract":"<div><div>To evaluate the effect of amination on biofilm inhibition against <em>Escherichia coli</em>, <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus,</em> representative compounds of two previously described 5-aryl-2-aminoimidazole (5-Ar-2-AI) classes were aminated by installing an amino group at the end of the substituted <em>n</em>-alkyl chain. Amination led to an improvement in activity for one of the two classes, the 2<em>N</em>-substituted 5-Ar-2-AI class. Based on these findings, a more extensive library of 2<em>N</em>-substituted-aminated 5-Ar-2-AIs was synthesized having different <em>n</em>-alkyl and halogen substitutions on the 2<em>N</em>-position and the 4(5)-phenyl ring, respectively. Compounds were evaluated for their biofilm inhibitory activity against <em>E. coli</em>, <em>P. aeruginosa</em>, <em>S. aureus</em>, <em>Staphylococcus epidermidis</em> and MRSA. Additionally, their toxicity was tested on eight continuous cell lines, peripheral blood mononuclear cells and <em>Caenorhabditis elegans,</em> along with their genotoxicity on Capan-1. Halogenation and elongation of the <em>n</em>-alkyl substituent showed a positive effect on biofilm inhibitory activity, but also increased toxicity. Compromising between activity and toxicity, a non-halogenated 2<em>N</em>-substituted-aminated 5-Ar-2-AI compound with an intermediate <em>n</em>-heptyl substitution demonstrated promising broad-spectrum biofilm inhibition, making it a suitable candidate for further research in anti-infectious medical applications.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118115"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479915","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 novel PROTACs compounds with good ERα degradation ability","authors":"Xueqian Yang ,&nbsp;Xiangnan Zheng ,&nbsp;Cheng Liu ,&nbsp;Jiaqing Zheng ,&nbsp;Xu Dong ,&nbsp;Wengang Ren ,&nbsp;Tao Zhang ,&nbsp;Hongxiang Lou ,&nbsp;Peihong Fan","doi":"10.1016/j.bmc.2025.118111","DOIUrl":"10.1016/j.bmc.2025.118111","url":null,"abstract":"<div><div>A series of ER-PROTACs compounds were designed, synthesized and tested for their ability to degrade estrogen receptor proteins and exhibit Human breast cancer cells (MCF-7) inhibition activity. Molecular docking simulations were performed using Discovery studio. Among these compounds, <strong>QDE-003-W</strong> had the highest estrogen receptor protein degradation ability and cellular activity, with a DC₅₀ value of 95 nM, for estrogen receptor protein degradation and an IC₅₀ value of 30.2 nM for cellular activity. Furthermore, the molecular docking study revealed that the biological activity of <strong>QDE-003-W</strong> depended on its suitable linker length, which gave us some reference significance for the study of ER-PROTACs. And compared with fulvestrant, <strong>QDE-003-W</strong> exhibited more favorable pharmacokinetic (PK) characteristics. No significant adverse side effects were observed under the administration protocol, which indicates that the tested mice had excellent tolerance to both the administration method and the dosage. Such favorable PK characteristics and safety features further enhance the prospects of QDE-003-W as a viable candidate for subsequent preclinical and clinical development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118111"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579835","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":"Chemical modification for improving drug-like molecular properties of climacostol, a natural resorcinolic lipid","authors":"Gabriele Lupidi ,&nbsp;Elisabetta Catalani ,&nbsp;Federico Buonanno ,&nbsp;Dario Gentili ,&nbsp;Simone Giorgi ,&nbsp;Vishnuprasad Ponnarassery Aravindakshan ,&nbsp;Serena Gabrielli ,&nbsp;Kashi Brunetti ,&nbsp;Anna Maria Fausto ,&nbsp;Simona Picchietti ,&nbsp;Claudio Ortenzi ,&nbsp;Enrico Marcantoni ,&nbsp;Davide Cervia","doi":"10.1016/j.bmc.2025.118113","DOIUrl":"10.1016/j.bmc.2025.118113","url":null,"abstract":"<div><div>Small organic molecules are compounds that are manufactured through chemical synthesis. One of the key advantages of small molecules is that they have a low molecular weight and simple chemical structures. This allows more predictability to their pharmacokinetics and pharmacodynamics, which means that dosing is simpler. To use small molecules as a useful tool to address human health issues, the collaboration between disciplines, especially chemistry and biology, is essential. In recent years in our laboratories, we have demonstrated that climacostol, a 5-alkenyl resorcinolic produced by eukaryotic microorganisms as secondary metabolite and obtained by our synthetic strategy too, it shows important biological and pharmacological activities. These ones are highly dependent on the 5-alkenyl chain, and chemical modifications to the resorcinolic moiety can be exploited to achieve higher toxicity against pathogen microbes and protists than climacostol. In this study, we have designed and made a synthetic strategy for a new analogue of climacostol (<strong>AN3</strong>), and evaluated how the new hydroxyl group at position four in the aromatic ring influences its biological effects on prokaryotic and free-living protists and on non-target cells/organisms, especially with regard to cytotoxic properties.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118113"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419680","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, biological evaluation, and mechanism of action of new pyrazines as anticancer agents in vitro and in vivo","authors":"Jin-Xia Lan ,&nbsp;Le-Jun Huang ,&nbsp;Si-Shuang Kang ,&nbsp;Hao-Huang ,&nbsp;Sheng-Lan Liu ,&nbsp;Wei Dai ,&nbsp;Xin-Liang Xu ,&nbsp;Jin-Yang Wang ,&nbsp;Guang-Zhao Shu ,&nbsp;Wen Hou","doi":"10.1016/j.bmc.2025.118108","DOIUrl":"10.1016/j.bmc.2025.118108","url":null,"abstract":"<div><div>Cancer is the second leading cause of mortality worldwide. The development of innovative antitumor pharmaceuticals is urgently needed to alter this circumstance. <em>N</em>-heterocycles, pyrazines for example are prevalent pharmacophores in the architecture of anticancer medicines. This research involved the design and synthesis of seventy-seven new pyrazine derivatives, followed by an evaluation of their anticancer activity <em>in vitro</em> and <em>in vivo</em>. Several new pyrazines exhibiting remarkable antiproliferative activity and selectivity were identified. The links between structure and function were analyzed, and the mechanisms of action were examined. Our mechanistic investigations indicated that these chemicals triggered mitochondria-associated apoptosis in cancer cells. Moreover, they suppressed the phosphorylation of STAT3, concomitant with the down-regulation of BcL-2, BcL-XL, c-Myc, XIAP, GLI1, TAZ, MCL1, JAK1, JAK2 and up-regulation of Bax, p21. Furthermore, the lead compounds <strong>B-11</strong> and <strong>C-27</strong> demonstrated significant anticancer activity <em>in vivo</em> in the SKOV3 xenograft nude mouse model. Our research establishes a basis for the identification of pyrazines as JAK/STAT3 inhibition based anticancer lead compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118108"},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419583","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":"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}