European Journal of Medicinal Chemistry最新文献

{"title":"Design, Synthesis, and Biological Evaluation of Chalcone Derivatives as Selective Monoamine Oxidase-B Inhibitors with Potential Neuroprotective Effects","authors":"Giorgio Facchetti, Sara Marchese, Valentina Coccè, Luisa Doneda, Giulio Alessandri, Francesca Paino, Augusto Pessina, Luca Pinzi, Giulio Rastelli, Claudia Binda, Michael S. Christodoulou, Isabella Rimoldi","doi":"10.1016/j.ejmech.2025.117990","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117990","url":null,"abstract":"A series of chalcone derivatives was synthesized via Claisen–Schmidt condensation and further modified through selective reductions and amide couplings to explore their potential as monoamine oxidase B (MAO-B) inhibitors. Screening against recombinant human MAO-B identified compounds <strong>4a</strong>, <strong>4b</strong>, <strong>4e</strong>, and <strong>5a</strong> as potent inhibitors, showing submicromolar inhibition constants (<em>K</em>_<em>i</em>). Structure–activity relationship (SAR) analysis emphasized the relevance of a planar α,β-unsaturated carbonyl and specific aromatic substitutions for activity. Crystallographic studies showed conserved binding modes in the MAO-B active site, while computational analyses confirmed favorable interactions and conformational flexibility of compound <strong>5a</strong>. Cytotoxicity assays in normal and cancer cell lines indicated minimal toxicity for <strong>5a</strong>. Notably, <strong>5a</strong> also exhibited neuroprotective effects in SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA), a model of Parkinson’s disease. These findings demonstrated the importance of structural fine-tuning within the chalcone scaffold to achieve MAO-B selectivity and identify compound <strong>5a</strong> as a promising, non-toxic candidate for neurodegenerative disease treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"194 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677756","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":"Further Exploring the Tolerant Region II: Identification of 2,4,5-Trisubstituted Pyrimidines as HIV-1 Reverse Transcriptase Allosteric Inhibitors with Desirable Antiviral Activities and Reduced Cytotoxicity","authors":"Zhenzhen Zhou, Lin Zheng, Wenbo Jiang, Wenbo Zhang, Fabao Zhao, Zhening Liang, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Dongwei Kang, Xinyong Liu","doi":"10.1016/j.ejmech.2025.117992","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117992","url":null,"abstract":"Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by further exploring the potential tolerant region II within NNIBP. Most compounds were identified with potent inhibitory activity against HIV-1 wild-type (WT) strain with lower cytotoxicity. Among them, <strong>14l</strong> exhibited the most outstanding antiviral activity (EC₅₀ = 6.50-52.9 nM) against WT and a panel of mutant HIV-1 strains with much-reduced cytotoxicity (CC₅₀ = 228 <em>μ</em>M) and higher selectivity index (SI = 31434) than that of the lead <strong>36a</strong> (CC₅₀ = 45.6 <em>μ</em>M; SI = 20550). Furthermore, the detailed molecular modeling studies revealed that the 3-thienyl substituent of <strong>14l</strong> engages in multiple stable contacts with conserved residues within tolerant region II, providing a structural basis for the observed potent antiviral efficacy and enhanced anti-resistance profile. These findings collectively position <strong>14l</strong> as a promising candidate for subsequent development as a novel lead compound.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"664 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677760","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":"Harnessing cell cycle intervention and evading P-glycoprotein efflux: natural product-inspired C2-aminophenyl chromones as dual modulators against multidrug-resistant cancer","authors":"Yi-Han Chang, I-Ting Wu, Po-Yu Chien, Ching-Hui Su, Yu-Hsun Chen, Chin-Chuan Hung, Hsin-Yi Hung","doi":"10.1016/j.ejmech.2025.117978","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117978","url":null,"abstract":"The resilience of cancer cells to current anti-neoplastic agents remains a significant challenge in oncology, underscoring the pressing requirement for novel candidates to overcome multidrug-resistant (MDR) malignancies. Building on the C2-functionalized chromone scaffold, herein, a structure-activity relationship (SAR) investigation centered on the C2-atomic bridge identified C2-aminophenyl chromone as a privileged scaffold for tumoricidal compounds. Within this chemotype, <strong>12m</strong> and <strong>12n</strong> emerged as promising candidates, exhibiting potent anti-proliferative activity against not only drug-sensitive KB cells (IC₅₀ = 0.78 μM and 0.42 μM, respectively) but also MDR KBvin cells (IC₅₀ = 0.69 μM and 0.43 μM, respectively). Mechanistic investigations revealed that both molecules effectively triggered apoptosis and hampered cell cycle transition at the G2/M stage, marked by the upregulation of cyclin B1 and cyclin A2. Moreover, <strong>12m</strong> and <strong>12n</strong> demonstrated collateral sensitivity and chemosynerstic interactions in MDR cancer cells, significantly suppressing P-glycoprotein (P-gp) expression while bypassing P-gp-mediated efflux. <em>In vivo</em> evaluations using a zebrafish xenograft model further validated their therapeutic potential in terms of KBvin tumor growth without eliciting acute toxicity at 1.0 μM. Harnessing chemoresensitizing properties, these molecules further reduced KBvin tumor burden in zebrafish when co-administered with paclitaxel. To encapsulate, the C2-aminophenyl chromone scaffold represents a novel chemical framework for the development of dual-functional anti-neoplastic agents targeting MDR cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"115 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677806","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":"SGLT2 inhibitors in translational medicine: A paradigm shift for diabetes and heart health","authors":"Ritu Soni, Dipti Pal, Ajay Kumar Gupta, Achal Mishra, Yogesh Vishnav, Sanmati Kumar Jain","doi":"10.1016/j.ejmech.2025.117977","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117977","url":null,"abstract":"Diabetes mellitus (DM) is a major contributor to a number of catastrophic health disorders, including heart attacks, strokes, kidney failure, blindness, and lower limb amputations. In 2023, DM was recognized by the World Health Organization (WHO) as a major cause of death. Diabetes is becoming more and more common, and any family member could be impacted. Due to the limited availability of current antidiabetic drugs, the urgent need for new active pharmaceutical ingredients becomes clear. In recent decades, sodium-glucose cotransporter-2 (SGLT2) has drawn interest as a key target for type 2 diabetes treatment. This is attributed to its innovative mechanism of action, which works independently of the insulin signalling pathway.Gliflozines, which mainly function as SGLT2 inhibitors, are a significant class of drugs used to treat type II diabetes. Several gliflozines have received approval from regulatory bodies like the FDA, EMA, and PMDA, and other compounds are presently undergoing advanced research and development. Phlorizin, a naturally occurring O-glucoside, serves as a starting compound from which various derivatives have been synthesized, including O-glucoside, C-glucoside, and N-glucoside derivatives. In addition to providing insights into the chemical modifications that increase the potency of SGLT2 inhibitors and their analogues, the review emphasizes the structure-activity relationship of these drugs.The collaborative efforts of researchers in the ongoing synthesis and development of SGLT2 inhibitors, as well as the progress achieved in the field so far, are also highlighted.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"143 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677805","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":"Structure-Guided Expansion Strategy Unveils Potent Allosteric SHP2 Inhibitors with Synergistic Efficacy Against AML through MCL-1 Co-Targeting","authors":"Maoqian Zhang, Shuyun Wu, Menghui Liu, Haozhe Li, Luyao Wang, Feimeng Duan, Rui Han, Chenxiao Shan, Zequn Jiang, Junzhuo Liao, Yongmin Zhang, Wei Li, Bo Wang","doi":"10.1016/j.ejmech.2025.117988","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117988","url":null,"abstract":"&lt;h2&gt;Section snippets&lt;/h2&gt;&lt;section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Structural expanding design logic of SHP2 allosteric inhibitors and chemistry&lt;/h2&gt;&lt;strong&gt;Structural feature of the allosteric site of SHP2:&lt;/strong&gt; Upon binding to the allosteric inhibitors, SHP2 adopts an autoinhibited conformation, analogous to its apo-state.&lt;sup&gt;2&lt;/sup&gt; As illustrated in Figure 3a, binding of SHP099 enables N-SH2 domain to sterically block the PTP catalytic cleft,&lt;sup&gt;11&lt;/sup&gt; while SHP099 itself occupies a tunnel-shaped cavity formed at the interface of N-SH2, C-SH2, and PTP domains. Key interactions include hydrogen bonds between the pyrazine N1 and Arg111, the 2-amino group of the&lt;/section&gt;&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Conclusions&lt;/h2&gt;Despite recent developmental challenges, SHP2 has emerged as a compelling therapeutic target in oncology, with several clinical candidates demonstrating promise in solid tumors. Notably, the ongoing phase III trial of &lt;em&gt;J&lt;/em&gt;AB-3312 combined with the KRAS inhibitor Glecirasib for non-small cell lung cancer (NCT06416410) underscores the clinical relevance of SHP2 inhibition. In this study, we leveraged a structure-guided expansion strategy to develop &lt;strong&gt;B1&lt;/strong&gt; and &lt;strong&gt;B8&lt;/strong&gt;, novel allosteric SHP2 inhibitors&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Compound synthesis and characterization&lt;/h2&gt;All chemicals and solvents were obtained from commercial suppliers and utilized as received unless specified. Nuclear magnetic resonance (NMR) spectra were acquired using a Bruker AV-500 MHz or 400 MHz spectrometer. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as the internal standard (δ = 0). Signal multiplicities are denoted as singlet (s), doublet (d), triplet (t), or multiplet (m), with coupling constants (&lt;em&gt;J&lt;/em&gt;) provided in Hertz (Hz).&lt;/section&gt;&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;CRediT authorship contribution statement&lt;/h2&gt;&lt;strong&gt;Chenxiao Shan:&lt;/strong&gt; Data curation. &lt;strong&gt;Rui Han:&lt;/strong&gt; Investigation. &lt;strong&gt;Feimeng Duan:&lt;/strong&gt; Investigation. &lt;strong&gt;Luyao Wang:&lt;/strong&gt; Investigation. &lt;strong&gt;Haozhe Li:&lt;/strong&gt; Investigation. &lt;strong&gt;Menghui Liu:&lt;/strong&gt; Methodology, Formal analysis, Investigation, Data curation. &lt;strong&gt;BO WANG:&lt;/strong&gt; Supervision, Formal analysis, Conceptualization, Writing – original draft, Data curation, Writing – review &amp; editing, Investigation. &lt;strong&gt;Shuyun Wu:&lt;/strong&gt; Formal analysis, Investigation, Data curation. &lt;strong&gt;Wei Li:&lt;/strong&gt; Writing – review &amp; editing, Supervision. &lt;strong&gt;Maoqian Zhang:&lt;/strong&gt; Methodology, Formal&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Uncited reference&lt;/h2&gt;(23); (25); (26).&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Declaration of competing interest&lt;/h2&gt;The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;h2","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"98 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677813","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":"Uncoupling Toxic NO Signaling: Progress, Challenges, and Therapeutic Promise of Disrupting the PSD-95/nNOS Protein–Protein Interaction","authors":"Emadeldin M. Kamel, Ahmed A. Allam, Hassan A. Rudayni, Noha A. Ahmed, Faris F. Aba Alkhayl, Al Mokhtar Lamsabhi","doi":"10.1016/j.ejmech.2025.117994","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117994","url":null,"abstract":"The interaction between postsynaptic density-95 (PSD-95) and neuronal nitric-oxide synthase (nNOS) forms a signaling hub that couples N-methyl-D-aspartate receptor (NMDAR) calcium influx to bursts of neurotoxic nitric oxide. Disrupting this protein-protein interaction (PPI) offers a strategy to suppress pathological NO production while sparing normal synaptic transmission—an advantage unattainable with channel blockers or active-site nNOS inhibitors. Over the past two decades, cell-penetrant peptides such as nerinetide (Tat-NR2B9c) have validated the target from rodent stroke models to phase-III clinical trials, while bivalent constructs achieve low-nanomolar affinity and extended brain exposure. Parallel medicinal-chemistry campaigns have delivered multiple small-molecule scaffolds (IC87201, ZL006, SCR-4026, PCC-0105002) that cross the blood–brain barrier, disrupt the complex at low-micromolar concentrations, and demonstrate efficacy in ischemic stroke, neuropathic pain, and neuropsychiatric paradigms without the liabilities of NMDAR antagonists. A comprehensive assay cascade—from NMR and AlphaScreen to in-situ proximity ligation and in-vivo PLA—now links molecular binding to functional outcomes. Formulation advances (PEGylated liposomes, pH-responsive polymers) and non-invasive routes (intranasal, focused-ultrasound BBB opening) further enhance brain delivery. Remaining challenges include achieving sub-micromolar small-molecule potency, ensuring long-term circuit selectivity, and scaling complex peptide or nanocarrier manufacturing. Structural elucidation of ligand-bound complexes, covalent and bivalent chemistries, and AI-guided design promise to surmount these hurdles. Collectively, the evidence positions PSD-95/nNOS disruption as a versatile, clinically achievable approach for mitigating excitotoxic and nociceptive pathology and sets the stage for first-in-class therapies that uncouple toxic NO signaling without silencing healthy synapses.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel salidroside derivatives as potent hypoxia inducible factor 1α (HIF-1α) signaling inhibitors to treat high altitude cerebral edema","authors":"Shu-Yang Ni, Nan Wang, De-Yi Luo, Yong-Sheng Hou, Qiu-Yang Li, Tian Chai, Yi-Dan Zheng, Xing-Sheng Bu, En-Jie Zhu, Xiao-Feng Shi, Xian-Hua Meng, Xing-Rong Wang, Jun-Li Yang","doi":"10.1016/j.ejmech.2025.117982","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117982","url":null,"abstract":"High altitude cerebral edema (HACE) represents a potentially lethal manifestation of acute mountain sickness, associated with abnormal activation of hypoxia-inducible factor-1α (HIF-1α) and NF-κB inflammation pathway. Based on <em>ortho</em>-fluorophenyl pharmacophore and scaffold-hopping strategy, we designed and synthesized forty-three salidroside derivatives as HIF-1α inhibitors. Dual-luciferase reporter assay demonstrated that compound <strong>N41</strong> exhibited the strongest HIF-1α inhibitory activity in HEK293T cells with an IC₅₀ value of 2.02 ± 0.76 μM. Meanwhile, <strong>N41</strong> significantly suppressed the expression of inflammation factors of IL-6 and NO, as well as the accumulation of ROS without obvious cytotoxicity in C8-D1A cells. The <em>in vivo</em> study revealed that compound <strong>N41</strong> could reduce brain water content and oxidative stress level in MDA/SOD measurements. In immunofluorescence assay, <strong>N41</strong> suppressed inflammatory expression of IL-6, TNF-α, and blood-brain barrier permeability protein AQP-4. Furthermore, the western blotting assay and HE staining demonstrated that <strong>N41</strong> regulated the inflammation process in a dose-dependent manner to alleviate cerebral edema in the HACE mouse model. These findings highlighted that compound <strong>N41</strong> could effectively target HIF-1α/IKKα/NF-κB signaling pathway to mitigate pathological inflammation <em>in vivo</em>, providing a new strategy for anti-HACE drug research.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"95 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677807","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 “Development and structure-activity relationship of tacrine derivatives as highly potent CDK2/9 inhibitors for the treatment of cancer” [Eur. J. Med. Chem. 242 (2022): 114701]","authors":"Limeng Wu, Wenjie Liu, Yaoguang Huang, Chengze Zhu, Qun Ma, Qiong Wu, Liting Tian, Xiangling Feng, Mingyue Liu, Nan Wang, Xiangbo Xu, Xin Liu, Chang Xu, Jingsong Qiu, Zihua Xu, Wenwu Liu, Qingchun Zhao","doi":"10.1016/j.ejmech.2025.117984","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117984","url":null,"abstract":"The authors regret an error during the organization of <strong>Scheme 2</strong>. and <strong>Fig. 6</strong>. in this published article. The author's carelessness during the drawing process resulted in the loss of <em>N</em> atoms in the compound structure and errors in the images and numbering. The corrected Scheme 2. and Fig. 6 are shown here. This correction does not change the conclusions of the article in any way. We sincerely apologize for any inconvenience caused.<span><figure><span><img alt=\"Image 1\" height=\"219\" src=\"https://ars.els-cdn.com/content/image/1-s2.0-S0223523425007494-fx1.jpg\"/><ol><li><span><span>Download: <span>Download high-res image (177KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670131","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 evaluation of a novel class of spiro[chromene-2,2'-indoline] derivatives as potent inhibitors of peptidylarginine deiminase IV to treat rheumatoid arthritis","authors":"Cheng-Wei Yang, Yue-Zhi Lee, Hsing-Yu Hsu, Shiow-Ju Lee","doi":"10.1016/j.ejmech.2025.117985","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117985","url":null,"abstract":"Peptidylarginine deiminase isoform 4 (PADI4) is a potential therapeutic target for treatment of rheumatoid arthritis. Auto-antibodies induced by the dysregulated catalysis of peptidylarginine into peptidyl-citrulline by PADI4 can cause the onset and progression of rheumatoid arthritis. Herein, we report a novel class of spiro[chromene-2,2'-indoline] derivatives which were synthesized and optimized from a hit discovered by screening two libraries with 3,760-members of natural products and derivatives for PADI4 inhibitors. <em>In vitro</em>, our derivatives were proved capable of potently inhibiting PADI4 and diminishing cellular citrullination; <em>in vivo</em>, the representative compound <strong>7</strong>, 6,8-dimethoxy-1',3',3'-trimethylspiro[chromene-2,2'-indoline], effectively ameliorated the severity and pathologic progress of collagen type II antibody/LPS induced rheumatoid arthritis in a mouse model. This work establishes compound <strong>7</strong> and the related potent compounds worthy of further study and development to treat rheumatoid arthritis, and validates PADI4 as a therapeutic target for this purpose.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"128 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664601","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 Cinderella story in antimicrobials: CDPDP's perfect fit for multiple-pathway bacterial inhibition","authors":"S.S.U Hassan ,&nbsp;Naveed Ahmad ,&nbsp;Abdur Rehman ,&nbsp;Chengqian Pan ,&nbsp;Jiajia Wu ,&nbsp;Tao Li ,&nbsp;Shi-Kai Yan ,&nbsp;Huizi Jin","doi":"10.1016/j.ejmech.2025.117967","DOIUrl":"10.1016/j.ejmech.2025.117967","url":null,"abstract":"<div><div>The rapid rise of antibiotic resistance among bacterial pathogens threatens global health, rendering many existing drugs ineffective and creating an urgent demand for new therapeutic strategies. To the best of our knowledge, this is the first work reporting the detailed antibacterial mechanism of action of twelve targeted genes. Here, we evaluated the marine‐derived compound CDPDP for its antibacterial activity against <em>Staphylococcus aureus</em> (<em>S.A</em>.) and <em>Riemerella anatipestifer</em> (<em>R.A</em>.), demonstrating potent bactericidal effects (IC₅₀ = 300 μM for <em>S.A</em>.; 100 μM for <em>R.A</em>.). Scanning electron microscopy revealed pronounced morphological alterations in treated cells, including cell shrinkage, membrane blebbing, and wall irregularities. Comparative transcriptome analysis uncovered that CDPDP exerts its antibacterial activity in <em>S.A</em>. primarily through targeting DNA/nucleic acid‐binding genes—downregulating key replication and repair factors (<em>SSB, DnaN, RecF, MutS, PolA, LigA</em>)—while in <em>R.A</em>. it disrupts membrane integrity by suppressing genes involved in outer‐membrane biogenesis and protein translocation (<em>SecY, SecG, TatA, YajC, MurC, AccB</em>). Validation via qRT‐PCR consistently confirmed the RNA‐Seq differential expression patterns, verifying the downregulation of DNA-binding and membrane-associated genes in both pathogens after CDPDP treatment, and molecular docking identified crucial amino acid interactions mediating CDPDP binding (Arg1086/Thr1098 in <em>SSB</em>; Phe78/Ile82 in <em>SecY</em>). Molecular dynamics simulations further substantiated the stability of these interactions under physiological conditions. Additionally, in silico epoxidation and N‐dealkylation predictions reveal potential metabolic transformations that could influence CDPDP's bioactivity. Collectively, these findings unveil a dual antibacterial mechanism—DNA‐targeted lethality in Gram‐positives and membrane disruption in Gram‐negatives—demonstrating CDPDP's potential as a broad-spectrum, resistance-resilient antibiotic lead.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117967"},"PeriodicalIF":6.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652559","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}