European Journal of Medicinal Chemistry最新文献

{"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":"<h2>Section snippets</h2><section><section><section><h2>Structural expanding design logic of SHP2 allosteric inhibitors and chemistry</h2><strong>Structural feature of the allosteric site of SHP2:</strong> Upon binding to the allosteric inhibitors, SHP2 adopts an autoinhibited conformation, analogous to its apo-state.<sup>2</sup> As illustrated in Figure 3a, binding of SHP099 enables N-SH2 domain to sterically block the PTP catalytic cleft,<sup>11</sup> 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</section></section></section><section><section><h2>Conclusions</h2>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 <em>J</em>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 <strong>B1</strong> and <strong>B8</strong>, novel allosteric SHP2 inhibitors</section></section><section><section><section><h2>Compound synthesis and characterization</h2>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 (<em>J</em>) provided in Hertz (Hz).</section></section></section><section><section><h2>CRediT authorship contribution statement</h2><strong>Chenxiao Shan:</strong> Data curation. <strong>Rui Han:</strong> Investigation. <strong>Feimeng Duan:</strong> Investigation. <strong>Luyao Wang:</strong> Investigation. <strong>Haozhe Li:</strong> Investigation. <strong>Menghui Liu:</strong> Methodology, Formal analysis, Investigation, Data curation. <strong>BO WANG:</strong> Supervision, Formal analysis, Conceptualization, Writing – original draft, Data curation, Writing – review & editing, Investigation. <strong>Shuyun Wu:</strong> Formal analysis, Investigation, Data curation. <strong>Wei Li:</strong> Writing – review & editing, Supervision. <strong>Maoqian Zhang:</strong> Methodology, Formal</section></section><section><section><h2>Uncited reference</h2>(23); (25); (26).</section></section><section><section><h2>Declaration of competing interest</h2>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.</section></section><section><section><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":"SGLT2 inhibitors in translational medicine: A paradigm shift for diabetes and heart health","authors":"Ritu Soni,&nbsp;Dipti Pal,&nbsp;Ajay Kumar Gupta,&nbsp;Achal Mishra,&nbsp;Yogesh Vaishnav,&nbsp;Sanmati Kumar Jain","doi":"10.1016/j.ejmech.2025.117977","DOIUrl":"10.1016/j.ejmech.2025.117977","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 117977"},"PeriodicalIF":6.0,"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":"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 ,&nbsp;Nan Wang ,&nbsp;De-Yi Luo ,&nbsp;Yong-Sheng Hou ,&nbsp;Qiu-Yang Li ,&nbsp;Tian Chai ,&nbsp;Yi-Dan Zheng ,&nbsp;Xing-Sheng Bu ,&nbsp;En-Jie Zhu ,&nbsp;Xiao-Feng Shi ,&nbsp;Xian-Hua Meng ,&nbsp;Xing-Rong Wang ,&nbsp;Jun-Li Yang","doi":"10.1016/j.ejmech.2025.117982","DOIUrl":"10.1016/j.ejmech.2025.117982","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117982"},"PeriodicalIF":6.0,"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":"Uncoupling toxic NO signaling: Progress, challenges, and therapeutic promise of disrupting the PSD-95/nNOS protein–protein interaction","authors":"Emadeldin M. Kamel ,&nbsp;Ahmed A. Allam ,&nbsp;Hassan A. Rudayni ,&nbsp;Noha A. Ahmed ,&nbsp;Faris F. Aba Alkhayl ,&nbsp;Al Mokhtar Lamsabhi","doi":"10.1016/j.ejmech.2025.117994","DOIUrl":"10.1016/j.ejmech.2025.117994","url":null,"abstract":"<div><div>The interaction between postsynaptic density-95 (PSD-95) and neuronal nitric-oxide synthase (nNOS) forms a signaling hub that couples N-methyl-<span>d</span>-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.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 117994"},"PeriodicalIF":6.0,"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":"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 ,&nbsp;Yue-Zhi Lee ,&nbsp;Hsing-Yu Hsu,&nbsp;Shiow-Ju Lee","doi":"10.1016/j.ejmech.2025.117985","DOIUrl":"10.1016/j.ejmech.2025.117985","url":null,"abstract":"<div><div>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 peptidylcitrulline 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 3760-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.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 117985"},"PeriodicalIF":6.0,"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}

{"title":"Quantum Mechanics-Driven Structure-Activity Relationship Study of PEX5-PEX14 Protein-Protein Interaction Inhibitors Based On a Dibenzo[b,e]azepin-6(6H)-one Scaffold","authors":"Michał Nowacki, Filipe Menezes, Emilia Pykacz, Mateusz Popiołek, Valeria Napolitano, Chethan K. Krishna, Vishal C. Kalel, Ralf Erdmann, Tony Fröhlich, Oliver Plettenburg, Michael Sattler, Grzegorz M. Popowicz, Maciej Dawidowski","doi":"10.1016/j.ejmech.2025.117979","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117979","url":null,"abstract":"Targeting protein-protein interactions (PPIs) is a promising strategy in drug development. However, despite the considerable progress in the field, targeting PPIs with small molecules remains challenging, requiring novel strategies in inhibitor design and subsequent structure-activity relationship (SAR) studies. We have recently identified the PEX5-PEX14 PPI as a novel therapeutic target against diseases related to <em>Trypanosoma</em> infections and discovered small-molecule inhibitors against PEX14 using structure-based drug discovery (SBDD). The current study demonstrates that combining SBDD with quantum mechanical (QM) energy decomposition and deconvolution analysis (EDDA) provides an in-depth understanding of SAR in the newly developed PPI inhibitors class. We obtained diverse dibenzo[<em>b</em>,<em>e</em>]azepin-6(6<em>H</em>)-one PEX14 inhibitors, which resulted from redesigning the central scaffold of one of the previous compound lines and follow-up modifications. The diversification strategy yielded compounds obtained by multicomponent reactions (MCRs), from which the Kabachnik-Fields reaction products were the most potent tricyclic PEX5-PEX14 PPI inhibitors obtained so far. Overall, the activities of the compounds measured with biophysical assays aligned with the QM-derived compound binding energies. Hence, using an advanced computational approach, our results pave an alternative way for SAR rationalization of compounds against PPI targets.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"662 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652557","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":"Tissue factor derived β-hairpin peptides that bind and inhibit FVII activity","authors":"Angela Oliver, Emanuela Iaccarino, Arianna Migliorini, Samuele Di Cristofano, Lucia Falcigno, Gabriella D’Auria, Maria Cantile, Raffaele Ronca, Riccardo Sanna, Domenico Raimondo, Annamaria Sandomenico, Menotti Ruvo","doi":"10.1016/j.ejmech.2025.117987","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117987","url":null,"abstract":"The formation of the Tissue Factor(TF):Factor VII(FVII) complex is a pivotal event that initiates coagulation; targeting this early step allows for the prevention of the subsequent cascade amplification driven by positive feedback loops. For this reason, the TF:FVII complex is attracting increasing interest as a potential therapeutic target for regulating the coagulation cascade in a specific and timely manner. In order to generate TF-mimics capable of inhibiting this protein-protein interaction, we have designed four small cyclic peptides that simulate a TF region containing the two antiparallel β-strands: 106-110 (RVFSY) and 123-128 (EPLYEN). These strands are known to interact with FVII at well-known hot spots surrounding residues 365-369. With the aim of obtaining structures as similar as possible to the corresponding region of TF and therefore able to interact better with FVII, the four combinations of proline-proline dipeptides resulting from the four permutations of D-Pro and L-Pro have been introduced between the two strands. These strands have been connected on the opposite side by a disulphide bond in order to stabilise the resulting structures and also make them more resistant to protease action. The two cyclopeptides with the D-Pro-L-Pro and D-Pro-D-Pro moieties adopt β-hairpin-like conformations that recapitulate the structure of the two strands, as demonstrated by CD, NMR and molecular simulation studies. They also bind FVII and inhibit its activity in a Factor X-generating chromogenic assay. The other two peptides are significantly more disordered and are inactive in the same tests. Overall, the data validate the peptide design and confirm the region 365-369 of FVII as a target site for the design of coagulation inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological activity of 2-aroylbenzofuran-3-ols and 2-aroylbenzofuran derivatives: A new route towards hMAO-B inhibition","authors":"Paolo Guglielmi ,&nbsp;Michele Coluccia ,&nbsp;Guya Diletta Marconi ,&nbsp;Francesco Ortuso ,&nbsp;Francesca Procopio ,&nbsp;Simone Carradori ,&nbsp;Jacopo Pizzicannella ,&nbsp;Francesca Arrighi ,&nbsp;Anna Troiani ,&nbsp;Chiara Salvitti ,&nbsp;Fernanda Borges ,&nbsp;Daniel Chavarria ,&nbsp;Paola Chimenti ,&nbsp;Daniela Secci ,&nbsp;Francesca Diomede","doi":"10.1016/j.ejmech.2025.117983","DOIUrl":"10.1016/j.ejmech.2025.117983","url":null,"abstract":"<div><div>The crucial role of human monoamine oxidases (<em>h</em>MAOs), particularly the B isoform, in the pathogenesis of neurodegenerative diseases has been extensively studied. Alongside numerous other factors, the clinical use of <em>h</em>MAO-B inhibitors to alleviate symptoms of Parkinson's disease is well-established. In order to develop novel <em>h</em>MAO-B inhibitors as potential candidates for the treatment of these conditions, we have designed and synthesized two libraries of compounds based on the 2-aroylbenzofuran-3-ol and the 2-aroylbenzofuran scaffolds. The <em>h</em>MAO inhibitory activity and selectivity of these compounds was thoroughly investigated. In general, the 2-aroylbenzofuran-3-ols were unable to inhibit <em>h</em>MAO isoforms. In contrast, 2-aroylbenzofuran derivatives acted as potent and selective <em>h</em>MAO-B inhibitors, showing IC₅₀ values within the nanomolar range and as low as 8.2 nM. The best compounds exhibited broad safety ranges in human gingival fibroblasts (hGFs) and SH-SY5Y neuroblastoma cells. A preliminary evaluation of the compounds' neuroprotective effects was conducted through the co-exposure of the cells to the neurotoxic agent 6-hydroxydopamine (6-OHDA) and the synthesized compounds, whose activity was comparable to that of (<em>R</em>)-(−)-deprenyl, the reference <em>h</em>MAO-B inhibitors. The characterization of the compounds was enriched with the <em>in silico</em> prediction of the drug-likeness of the most active compounds among the 2-aroyl benzofurans using the free web tool SwissADME. All compounds were predicted to have high gastrointestinal absorption and to permeate the blood-brain barrier and molecular modelling studies provided insights into the molecular mechanisms responsible for the high <em>h</em>MAO-B inhibitory potency and selectivity of 2-aroylbenzofurans.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117983"},"PeriodicalIF":6.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652560","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}