European Journal of Medicinal Chemistry最新文献

{"title":"In vitro and in vivo studies on antitumor potential of Ni(II) and Pd(II) complexes based on a series of thiourea-based ligands","authors":"Shivendra Kumar Pandey ,&nbsp;Swati Singh ,&nbsp;Pratima Chaudhary ,&nbsp;Avinash Chaudhary ,&nbsp;Ray J. Butcher ,&nbsp;Partha Pratim Manna ,&nbsp;Manoj Kumar Bharty","doi":"10.1016/j.ejmech.2025.118206","DOIUrl":"10.1016/j.ejmech.2025.118206","url":null,"abstract":"<div><div>Palladium (II) complexes have been investigated as prospective chemotherapeutic agents for cancer treatment. This study aims to synthesize and characterize three thiourea-based ligands with different substituents (-H (<strong>ThU1</strong>), -Cl (<strong>ThU2</strong>), –CH₃ (<strong>ThU3</strong>)) and their corresponding Ni(II) and Pd(II) complexes. The synthesized ligands and metal complexes are well characterized by FT-IR, NMR, ESI-MS, and SC-XRD studies. SC-XRD analysis of <strong>PdThU1</strong> and <strong>PdThU2</strong> confirmed square planar geometries around the palladium centre. The <em>in-vitro</em> antiproliferative activities of ligands and metal complexes against a metastatic and highly aggressive metastatic murine lymphoma (DL) and human B cell lymphoma (Raji) cancer cells suggest Pd(II) complexes have a much better cytotoxic response than thiourea ligands and Ni(II) complexes. Interestingly, Pd(II) complexes <strong>PdThU1</strong> (2.45 μM &amp; 5.19 μM) and <strong>PdThU2</strong> (4.7 μM &amp; 9.54 μM) showed significantly lower IC₅₀ values compared to cisplatin (34.96 &amp; 71.13 μM) against DL and Raji cancer cells, respectively. Further, direct cytotoxicity was studied using LDH release assay. The cell vialibity analysis of <strong>PdThU1</strong> and <strong>PdThU2</strong> against normal human lymphocytes and monocytes suggests their biocompatibility. Apoptosis induction was assessed using Annexin V-FITC/PI labelling and flow cytometry. <em>In vivo</em> investigations were performed on a BALB/c mouse DL tumour model to assess treatment effectiveness and biosafety. <em>In vivo</em> studies demonstrated that <strong>PdThU1</strong> and <strong>PdThU2</strong> significantly reduced tumour growth and prolonged survival, with minimal toxicity. Our data suggests that the Pd(II) complexes demonstrated significant antitumor effect against murine lymphoma both <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118206"},"PeriodicalIF":5.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141052","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":"Tubulin-based dual-target compounds and protein degraders for cancer therapy—An updated review (2021-present)","authors":"Shijia Li,&nbsp;Zhouyan Liu,&nbsp;Tong Li,&nbsp;Ziwei Tang,&nbsp;Yanyan Feng,&nbsp;Cheng Chen,&nbsp;Chenglei Gu,&nbsp;Jichao Chen","doi":"10.1016/j.ejmech.2025.118191","DOIUrl":"10.1016/j.ejmech.2025.118191","url":null,"abstract":"<div><div>Simultaneous regulation of microtubule dynamics and other carcinogenic target activity has been proven a viable approach to combat cancer. Over the past few decades, numerous tubulin-based dual-target compounds have successfully been developed with the capacity to enhance antitumor efficacy and surmount drug resistance as well as reduce side effects. This review provides an updated overview of tubulin-based dual-target compounds in the recent five years, emphasizing their target selection, design strategy, structure-activity relationship analysis, and anticancer properties. Moreover, emerging targeted protein degraders based on tubulin polymerization inhibitors are also summarized. Additionally, potential challenges and the corresponding remedies are proposed for the future development of tubulin-based dual-target compounds.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118191"},"PeriodicalIF":5.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134243","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":"Potential next generation targets for antibacterial agent's discovery and development","authors":"Pooja Gupta ,&nbsp;Pushplata Yadav ,&nbsp;Manjul Lata ,&nbsp;Shivani Chaudhary ,&nbsp;Vrushti Telang ,&nbsp;Raj Kishore ,&nbsp;Jai Kishan ,&nbsp;Kamini Goswami ,&nbsp;Jesu Arockiaraj ,&nbsp;L Ravithej Singh ,&nbsp;Anamika Sharma ,&nbsp;Mukesh Pasupuleti","doi":"10.1016/j.ejmech.2025.118188","DOIUrl":"10.1016/j.ejmech.2025.118188","url":null,"abstract":"<div><div>Inappropriate and excessive use of antimicrobials, in addition to evolutionary process, lead to the development of antimicrobial-resistant strains at an unprecedented accelerated rate, leading to global public health crisis. Antimicrobial resistantance is a global challenge that not only causes mortality and disability but also carries, affect all the countries regardless of wealth, health care infrastructure and socio-economic conditions leading to huge economic loss. Recent studies have indicated that we are moving back to the post-antibiotic era at a faster rate as our novel antibacterial armamentarium has almost reached zero. Unfortunately, lead molecules in the preclinical pipeline are unable to tackle drug-resistant bacteria as these are either derivative of clinically used antibiotics or against the target for which resistance development has already started. Currently, the need for development of new antimicrobials with novel mechanisms is pressing more than ever due to the impending global clinical crisis and no new antibacterial agent with novel target has been added in the last 10 years. Herein, we summarized 28 feasible unexplored targets for the development of novel antibacterial agents. As antimicrobial resistance is a universal problem, this review lists novel molecules that are reported to have antibacterial activity and their potential sites in the past five years so that researchers can start on building those scaffolds to develop safe, effective and affordable drugs. Furthermore, we provide an overview of the key gaps, issues and approaches that need to be revisited is presented. This review emphasis strategy that help in harmonization of procedures and also to reduce the attrition rate in the next generation antibacterial drug development process.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118188"},"PeriodicalIF":5.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134245","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":"Photooxidation of biomolecules in cancer cells with a viscosity-dependent fluorescent Rhodamine derivative decorated with a naphthoimidazole rotor","authors":"Zhuo-Liang Zhou,&nbsp;Ming-Hao Hu","doi":"10.1016/j.ejmech.2025.118200","DOIUrl":"10.1016/j.ejmech.2025.118200","url":null,"abstract":"<div><div>This study presented the development of <strong>LD5</strong>, a novel viscosity-responsive Rhodamine derivative decorated with a naphthoimidazole rotor, as a dual-functional theranostic agent for cancer treatment. <strong>LD5</strong> exhibited viscosity-dependent fluorescence activation under yellow-light excitation (550 nm), enabling precise mitochondrial labeling in tumor cells. Simultaneously, <strong>LD5</strong> demonstrated potent photodynamic activity under blue-light irradiation (450 nm) via Type I mechanism. <strong>LD5</strong> was then proved to induce oxidative damage to critical biomolecules including GSH and NADH, trigger DNA damage, and thereby cause cell cycle arrest as well as apoptosis. The compound effectively inhibited 2D and 3D cancer cell models while maintaining the potential for real-time monitoring tumors. This work advances PDT by overcoming hypoxia limitations through Type I process and establishes a new paradigm for developing microenvironment-responsive theranostic agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118200"},"PeriodicalIF":5.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134515","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":"Bufalin targeting METTL17 inhibits the occurrence and metastasis of oral cancer through JAK1/STAT3 signaling pathway","authors":"Huhu Zhang ,&nbsp;Fulin Sun ,&nbsp;Xiaoyan Ding ,&nbsp;Xiaolei Dong ,&nbsp;Fanghao Yang ,&nbsp;Ruolan Chen ,&nbsp;Xiaoze Zhang ,&nbsp;Ziyuan Wen ,&nbsp;Mohan Su ,&nbsp;Chunjuan Yu ,&nbsp;Yiming Wang ,&nbsp;Lina Yang ,&nbsp;Bing Li","doi":"10.1016/j.ejmech.2025.118197","DOIUrl":"10.1016/j.ejmech.2025.118197","url":null,"abstract":"<div><div>Oral cancer (OC) is a malignant tumor that arises at the mucosal tissues of the oral cavity and is commonly treated with surgical resection. Bufalin is one of the most potent anticancer monomers extracted from <em>bufonis venenum</em> and has been shown to have anticancer effects against a wide range of cancers, including lung cancer, gastric cancer and hepatocellular carcinomas. However, there are fewer studies on the role of bufalin in OC and a lack of clear targets. Moreover, bufalin is more difficult to apply clinically due to its cardiac glycoside effects. Notably, oral cancer is a facial tumor, and bufalin acts first in the oral tissues and does not need to go through the blood circulation to reach the heart, which greatly mitigates the risk and overcomes the major limitation. The effects of bufalin on the proliferation and migration of oral cancer cells were detected by CCK-8 assay, wound healing assay, transwell assay and Western blot. Potential direct interacting proteins of bufalin were screened by human proteomic microarray, and the binding sites were predicted using molecular docking technology. In <em>vitro</em> and <em>vivo</em> biological experiments were performed to verify the role of bufalin direct interacting protein and the mechanism by which bufalin targets this protein to inhibit OC metastasis. The results showed that bufalin inhibited the proliferation and migration of OC cell lines from Cal-27, HN30 and SCC-15 cultured in <em>vitro</em>. METTL17, a direct-interacting protein of bufalin, has several potential binding sites with bufalin. METTL17 is highly expressed in OC and promotes OC occurrence and development in <em>vitro</em> and <em>vivo</em> through activation of the JAK1/STAT3 signaling pathway. Bufalin reversed the promotional effect of METTL17 on OC by down-regulating METTL17 expression. These results provide a new rationale for bufalin as a promising drug for the treatment of OC and avoid the difficulty that bufalin has a strong cardiac glycosides effect on the heart through the bloodstream.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118197"},"PeriodicalIF":5.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127956","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, anticancer evaluation, biological screening, and computational study of novel 6,7-dimethoxyquinazoline derivatives as VEGFR-2 inhibitors and apoptotic inducers","authors":"Mostafa M.A. Aref ,&nbsp;Abdallah E. Abdallah ,&nbsp;Mohammed A. Dahab ,&nbsp;Abeer A. Mohamed ,&nbsp;Ismail Celik ,&nbsp;Wafa A. Bawazir ,&nbsp;Ahd A. Mansoure ,&nbsp;Aisha Taib Alnami ,&nbsp;Mennatullah N. Abdelhamed ,&nbsp;Mohamed Ayman El-Zahabi","doi":"10.1016/j.ejmech.2025.118187","DOIUrl":"10.1016/j.ejmech.2025.118187","url":null,"abstract":"<div><div>Novel quinazoline analogs were designed, synthesized, and evaluated for their activities as potential anticancer agents. The compounds bearing a 4-substituted-6,7-dimethoxyquinazoline scaffold underwent <em>in vitro</em> cytotoxicity screening against 60 cancer cell lines under the National Cancer Institute (NCI) protocol, for all the novel synthesized compounds at 10 μM concentration. Notably, the initial single-concentration screening revealed that compounds <strong>9a-d</strong> exhibited the most potent growth inhibition percentage (GI%) on most of the screened nine panels of cancer, with a mean range of (50.23–189.98 %). The most potent compounds, <strong>9a-c</strong>, continued to be tested at concentrations of 0.01, 0.1, 1, 10, and 100 μM to identify the GI₅₀, TGI, and LC₅₀ values and evaluate the compounds' efficacy and selectivity. Compound <strong>9a</strong> generally demonstrated broad-spectrum potent growth inhibitory activity (GI₅₀) reaching to nanomolar level (GI₅₀ = 10 nM) against leukemia CCRF-CEM and colon COLO-205 cells. Compound <strong>9b</strong> exhibited a leukemia subpanel midpoint inhibitory value (MIDb) of 0.56 μM, with a selectivity ratio (SR) of 9.15 against leukemia cell lines. Additionally, <strong>9b</strong> induced apoptosis and caused cell cycle arrest at the G1 phase in leukemia CCRF-CEM cells. The RT-PCR results showed that <strong>9b</strong> increased the levels of proapoptotic mediators, Bax, caspase-3, and p53, with values of 8.91, 6.15, and 4.95 fold change, respectively, in addition to the decreased level of anti-apoptotic protein Bcl-2 to 0.372 fold change in the treated CCRF-CEM leukemia cells. Compound <strong>9b</strong> was docked to VEGFR-2 (ΔG = −14.1 kcal/mol), suggesting strong interactions within the VEGFR2 active site, comparable to the reference ligand sorafenib (ΔG = −14.8 kcal/mol). The molecular dynamic (MD) simulation (200ns) confirmed the docking results by demonstrating that compound <strong>9b</strong> retained stable interactions inside the VEGFR-2 active site throughout the trajectory. Moreover, the MTT viability test for compounds <strong>9a</strong>, <strong>9b</strong>, and <strong>9c</strong> demonstrated less cytotoxicity against normal fibroblast cells (WI38), revealing enhanced safety profiles with IC₅₀ values of 28.04, 219.79, and 43.77 μM, respectively, compared to Sorafenib (IC₅₀ = 26 μM). Enzyme inhibition assays revealed that compounds <strong>9a-c</strong> effectively inhibited EGFR and VEGFR-2, confirming the multi-targeting potential of this series of compounds.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118187"},"PeriodicalIF":5.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127954","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 characterization of novel phenyl carboxamide-selenium analogs: Identification of a potent DHODH inhibitor as a potential anticancer agent","authors":"Cristina Morán-Serradilla ,&nbsp;Carmen Sanmartín ,&nbsp;Asif Raza ,&nbsp;Amandeep Singh ,&nbsp;César Aliaga ,&nbsp;Daniel Plano ,&nbsp;Arun K. Sharma","doi":"10.1016/j.ejmech.2025.118193","DOIUrl":"10.1016/j.ejmech.2025.118193","url":null,"abstract":"<div><div>Despite continued research efforts, cancer remains a growing public health problem. Herein, we have designed four different libraries of compounds by rationally introducing select Se moieties into the phenyl carboxamide backbone and characterized them <em>in vitro</em> to assess their antiproliferative activities. The identified lead compounds, <strong>A1</strong> and <strong>C3</strong>, displayed a discerning cytotoxicity against a panel of 60 cancer cell lines in the DTP of the NCI. Their ability to induce apoptosis and ROS and modulate the cell cycle was assessed in MDA-MB-231 breast cancer cells. In addition, both <strong>A1</strong> and <strong>C3</strong> inhibited tumor growth with no evident toxicity signs in a syngeneic breast cancer mouse model. Notably, in concordance with the COMPARE analysis, compound <strong>A1</strong> was found to act at the level of the <em>de novo</em> pyrimidine biosynthetic pathway by inhibiting <em>in vitro</em> the cellular dihydroorotate dehydrogenase (DHODH), which was also supported by the molecular modeling studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118193"},"PeriodicalIF":5.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127957","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 and synthesis of novel cyclin-dependent kinase 4/6(CDK4/6) and histone deacetylase (HDAC) dual inhibitors: In vitro and in vivo anticancer activity","authors":"Bongsu Kim ,&nbsp;Chandra kantha ,&nbsp;Wonku Kang ,&nbsp;Jayaprakash Neerasa ,&nbsp;Hunsuk Chung","doi":"10.1016/j.ejmech.2025.118192","DOIUrl":"10.1016/j.ejmech.2025.118192","url":null,"abstract":"<div><div>Resistance to CDK4/6 inhibitors in certain tumors arises from the upregulation of cyclin D1 and the downregulation of the cell cycle regulator p21. Conversely, HDAC inhibitors can counteract this resistance by upregulating acetyl-histone H3 and p21 expression levels. To address this challenge, we developed a series of novel dual-targeting inhibitors that simultaneously inhibit CDK4/6 and HDAC1. Among these, selected compounds <strong>MFDCH016</strong>, <strong>MFDCH022</strong> and <strong>MFDCH025</strong> potently inhibited CDK4 and HDAC1/6 at nM levels, inducing apoptosis and cell cycle arrest in G2/M and G₀/G₁ phase and promote apoptosis in MCF-7 cells. This effect was mediated through the modulation of the HDAC-p21-CDK signalling pathway, as evidenced by increased acetyl-H3 and p21 levels. Compound <strong>MFDCH016</strong> demonstrated significant anti-tumor activity in breast cancer cell line and in MCF-7 xenograft model without apparent toxicity. More importantly <strong>MFDCH016</strong> show highly selective against CDK4 over CDK2 compare to standard drug Palbociclib. Our data demonstrated that compound <strong>MFDCH016</strong> as a single agent could be novel dual-targeting CDK4/6-HDAC inhibitor could be a promising drug candidate for cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118192"},"PeriodicalIF":5.9,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103723","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":"Research progress of TRK inhibitors and their structure-activity relationship","authors":"Yao-Yao Ye ,&nbsp;Ruo-Xuan Xu ,&nbsp;Wen Zhang ,&nbsp;Guo-Wu Rao ,&nbsp;Quan Zheng","doi":"10.1016/j.ejmech.2025.118183","DOIUrl":"10.1016/j.ejmech.2025.118183","url":null,"abstract":"<div><div>Neurotrophic tyrosine receptor kinase (NTRK) is a member of the transmembrane receptor tyrosine kinase family. The TRK protein preserves the survival and regular operation of nerve cells and is intimately linked to cell division, proliferation, metabolism, and apoptosis. Any fusion mutations in the <em>NTRK</em> gene with other genes will result in aberrant TRK protein, which causes aberrant cell division and promotes the development of malignancies. As <em>NTRK</em> is the first identified cancer-independent and druggable gene, it is undoubtedly one of the most important anti-cancer targets in the world. However, <em>NTRK</em> gene fusions occur in less than 1 % of solid tumors but are very common in rare tumors, suggesting that early diagnosis is difficult. At the same time, due to the mechanism of targeted or off-target drug resistance, patients become resistant to TRK inhibitors after treatment, and the efficacy is greatly reduced, so it is necessary to conduct further research to overcome the drug resistance problem. In order to provide a theoretical foundation for the development of safer and more effective inhibitors against this target and to expand the range of treatment options available to patients with <em>NTRK</em> gene fusion, this article reviews the mechanism and characteristics of gene fusions, as well as the research status of marketed and investigational targeted therapy drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118183"},"PeriodicalIF":5.9,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103630","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":"Quinazoline-based dual-target inhibitors disrupt influenza virus RNP complex: Rational design, synthesis and mechanistic validation of potent anti-influenza agents","authors":"Chao Zhang ,&nbsp;Xu-Hui Huang ,&nbsp;Zhe Wang ,&nbsp;Tai Li ,&nbsp;Jing Zhao ,&nbsp;Jun-Jie Xiang ,&nbsp;Jian Feng ,&nbsp;Gu-Zhou Chen ,&nbsp;Pang-Chui Shaw ,&nbsp;Chun Hu","doi":"10.1016/j.ejmech.2025.118185","DOIUrl":"10.1016/j.ejmech.2025.118185","url":null,"abstract":"<div><div>In this study, we report the rational design and synthesis of 34 novel quinazoline analogs targeting the influenza virus ribonucleoprotein (RNP) complex. These compounds, categorized into four structural classes, were evaluated for anti-influenza activity. Lead compounds <strong>26</strong> and <strong>30</strong> demonstrated potent antiviral efficacy against A/WSN/33(H1N1), with EC₅₀ values of 5.09 ± 0.21 μM and 3.63 ± 0.06 μM, respectively, and high selectivity indices (SI &gt; 19.7 and &gt; 27.5). Surface plasmon resonance (SPR) experiments confirmed dual binding to nucleoprotein (NP; <em>K</em>_D = 6.72 μM for <strong>26</strong>, 10.1 μM for <strong>30</strong>) and the PA C-terminal domain (PAc; <em>K</em>_D = 3.94 μM for <strong>26</strong>, 0.857 μM for <strong>30</strong>), key components of the viral RNP complex. Molecular docking and dynamics simulations revealed critical interactions: disruption of the NP Glu339-Arg416 salt bridge (essential for oligomerization) and binding to the PA-PB1 interface (residues Lys643, Glu623, Trp706), destabilizing polymerase assembly. RNP inhibition assays further validated suppression of viral transcription/replication (56.8–68.5 % inhibition at 12.5 μM). Despite favorable potency, solubility optimization remains necessary for improved drug-like properties. By integrating static docking poses with MD-derived dynamic correlations (DCCM), principal component analysis (PCA), and FEL-quantified energy basins, this study revealed transient yet mechanistically vital ligand-protein interaction nodes. This study establishes quinazoline-based dual-targeting inhibitors as promising anti-influenza agents, providing a foundation for further development against resistant strains.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118185"},"PeriodicalIF":5.9,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093650","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}