European Journal of Medicinal Chemistry最新文献

{"title":"4,5-Diazafluorene derivatives and their silver(I) complexes: Synthesis and biological evaluation as antiproliferative agents","authors":"Leonardo Sandin-Mazzondo, Angela Trejo, Mariachiara Mammone, Maria Grazia Perrone, Marialessandra Contino, Sandra Rico-Martínez, Concepción Alonso, Camino Bartolomé","doi":"10.1016/j.ejmech.2025.117680","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117680","url":null,"abstract":"This work is focused on the synthesis and biological evaluation of 4,5-diazafluorene bipyridines and their silver(I) complexes. These 4,5-diazafluorene derivatives have two aromatic R groups at the C9 position (R = 4-C₆H₄X, X = H, <strong>3</strong>; Me, <strong>4</strong>; NH₂, <strong>5</strong>; OH, <strong>6</strong>; OMe, <strong>7</strong>; Br, <strong>8</strong>; F, <strong>11</strong>; Cl, <strong>12</strong>; I, <strong>13</strong>; R = 3-Me-4-NH₂-C₆H₃, <strong>9</strong>; 3,5-Me₂-4-NH₂-C₆H₂, <strong>10</strong>). Their synthesis was carried out from a direct S_EAr from 4,5-diazafluoren-9-one and the corresponding aryl compound or <em>via</em> the diazonium salt strategy. These compounds were used as ligands to synthesize [Ag(N-N)₂]NO₃ complexes (<strong>3Ag</strong>-<strong>13Ag</strong>). The stability of these complexes in DMSO solution was studied showing that no dissociation was observed over 48 h. All compounds were characterized by NMR (¹H and ¹³C) and MS. The crystal structures of three complexes were determined by single-crystal X-ray diffraction revealing different coordination geometries in solid state. The cytotoxicity study of the compounds was analyzed in lung carcinoma (A-549), cervical carcinoma (HeLa), melanoma (HBT70) cancerous cell lines and in non-malignant lung fibroblasts (MRC-5) and normal human dermal fibroblasts (HDFn) cell lines. Only ligands <strong>3</strong>, <strong>7</strong>, <strong>11</strong>, and <strong>13</strong> exhibited antiproliferative activity. On the other hand, most of the complexes were active suggesting a positive impact when silver is incorporated into the molecule. The selectivity index towards cancerous cells was calculated. Values from 3 to more than 16 were obtained suggesting that these silver complexes are promising molecules for future anticancer treatments. Drug-likeness and ADME properties were <em>in silico</em> calculated for the ligands. The Pgp interaction and <em>P</em>_app were experimentally evaluated. Regarding their action, ROS production does not appear to be the main mechanism by which these complexes exert their cytotoxicity, nor do they appear to be DNA intercalators or DNA covalent binders.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866789","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":"Re-styling an old scaffold: ebsulfur analogs with improved activity and selectivity against the infective stage of trypanosomes","authors":"Cristina Quiroga, Marcelo Incerti, Diego Benítez, Martin Luzardo, Eduardo Manta, Alejandro Leyva, Margot Paulino, Marcelo A. Comini, Andrea Medeiros","doi":"10.1016/j.ejmech.2025.117675","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117675","url":null,"abstract":"Several species of trypanosomatids cause fatal and disabling diseases in humans and livestock animals. The current chemotherapy is limited and new drug candidates with improved efficacy and safety are needed. The benziso-thiazolone (e.g. Ebsulfur, EbS) and -selenazolone (e.g. Ebselen, EbSe) have been extensively investigated for their promising action towards transmissible and non-transmissible diseases.Here, we synthetized 23 benzisothiazolones and tested their anti-trypanosomatid activity against the clinically relevant stages of three major trypanosomatid species (<em>Trypanosoma brucei brucei</em>, <em>Trypanosoma cruzi</em> and <em>Leishmania infantum</em>). Several compounds presented nM or low μM activity and, at least a two-digit selectivity against <em>Trypanosoma</em> sp. but most proved inactive towards <em>L. infantum</em>. Structure-activity relationship analysis reveals that the chemotype of the top hits consisted of phenyl and benzyl rings occupying the <em>N</em>² position of the benzisothiazolone scaffold and harboring polar substituents in the <em>para</em> position. Most compounds from these two clusters induced a rapid redox imbalance in the intracellular pool of low molecular weight thiols. None of the hits, but EbSe and EbS, affected Trypanothione synthetase activity (the enzyme producing the major low molecular weight thiol of trypanosomatids). However, at large enzyme:compound ratios, some inhibited irreversibly (and covalently) Trypanothione reductase (the enzyme maintaining trypanothione in a reduced state). Some hits exerted a minor effect on the rate of glucose consumption. Preliminary assessment of therapeutic efficacy in a murine infection model of acute African trypanosomiasis, the top candidate could not reduce parasite burden (monitored by <em>in vivo</em> imaging) but extended animal survival.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862702","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 evaluation of novel 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives as potent antitumor agents","authors":"Ju Liu, Junfeng Gao, Rui Jing, Siyu Lin, Yunpeng Zhou, Zhicheng Zhang, Enhui Han, Fanqi Jin, Yunlei Hou, Chunyan Li, Ye Chen, Jiwei Shen, Shi Ding","doi":"10.1016/j.ejmech.2025.117671","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117671","url":null,"abstract":"A series of 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives were designed, synthesized and evaluated for their in vitro inhibitory activities against PI3Kα and antiproliferative activities against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cancer cell lines. Inhibitory activities against PI3Kα evaluation indicated that some compounds showed excellent PI3Kα activity in vitro, and IC₅₀ values of eight compounds (<strong>17c</strong>, <strong>17e</strong>, <strong>17f</strong>, <strong>17h</strong>, <strong>17l</strong>, <strong>17m</strong>, <strong>17o</strong>, <strong>17p</strong>) were less than 100 nM. The most promising compound <strong>17f</strong> (PI3Kα: IC₅₀ = 0.039 μM) showed remarkable antiproliferative against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cell lines with IC₅₀ values of 3.48 μM, 1.06 μM, 2.21μM and 0.93 μM, respectively. Furthermore, <strong>17f</strong> effectively reduced p-PI3K protein expression and inhibited the activation of downstream signaling AKT and mTOR proteins in MDA-MB-453 cells. In addition, <strong>17f</strong> induced cell apoptosis by down-regulating the expression levels of anti-apoptotic proteins Bcl-XL and Bcl-2 and up-regulating the expression of anti-apoptotic protein BAX, and in MDA-MB-453 cells. All these results indicated the potential of compound <strong>17f</strong> to develop as potent anticancer agent.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"47 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858199","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":"Exploring Indole-Dihydropyrimidinone Derivatives: Design, Synthesis, Biological Assessment, SAR Analysis, and Evaluation of Mode of Action in Experimental Visceral Leishmaniasis","authors":"Garvita Mishra, Arvind Kumar Jaiswal, Ajay Kishor Kushawaha, Abhishek Kumar, Hemlata Bhatt, Alisha Ansari, Amol Chhatrapati Bisen, Rupa Hansda, Sristi Agrawal, Payel Acharjee, Rajdeep Guha, Rabi Sankar Bhatta, Bidyut Purkait, Koneni V. Sashidhara","doi":"10.1016/j.ejmech.2025.117667","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117667","url":null,"abstract":"The emergence of drug resistance and the non-availability of vaccines encouraged us to identify novel chemical scaffolds as new anti-leishmanial agents. In doing so, a series of thirty-four indole-dihydropyrimidinone hybrid compounds were synthesized using the Biginelli multicomponent reaction. These synthesized compounds were tested against <em>L. donovani in vitro</em> and <em>in vivo</em> in experimental golden hamster model of visceral leishmaniasis. Compounds <strong>4f</strong> and <strong>4m</strong> were found to have promising anti-leishmanial properties against intracellular amastigotes (IC₅₀ <strong>4.54</strong> &amp; <strong>5.05</strong> μM, respectively) with minimal cytotoxicity against J774.1 macrophage. <strong>4f</strong> and <strong>4m</strong> were tested <em>in vivo</em>, and only 4f effectively cleared the parasite burden (&gt;65%) in infected golden hamsters. Mode of action studies discloses that <strong>4f</strong> induces oxidative stress-mediated mitochondrial dysfunction and impairment of ATP production and triggers apoptosis. SAR and PK studies revealed that compound <strong>4f</strong> (indole-dihydropyrimidinone hybrid) may be used as a lead for developing future chemotherapeutic options for VL.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"108 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862704","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 structure-activity relationship of 5,7- dimethylbenzo[d]thiazoles as novel Kv7.2/7.3 activators with antiepileptic effects","authors":"Denggao Zhang, Wei Xiang, Jie Liu, Wei Li, Zhen Qiao, KeWei Wang, Liming Shao","doi":"10.1016/j.ejmech.2025.117660","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117660","url":null,"abstract":"The activation of neuronal Kv7 channels has emerged as an important therapeutic strategy for epilepsy due to their role in regulating neuronal excitability. Retigabine (RTG), a Kv7.2/7.3 channel activator, was previously approved for epilepsy treatment but was withdrawn in 2017 its side effects of ophthalmological and dermatological pigmentation. Despite this setback, Kv7.2/7.3 channel remains a promising target for the development of antiepileptic drugs (AEDs). Previous studies have attributed the toxic metabolic quinone/azaquinone diimines and associated blue discoloration of RTG to its electron-rich tri-amine aromatic scaffold. A common strategy to mitigate this toxicity involves removing the <em>ortho-</em>aniline moiety of RTG. In this study, we designed and synthesized a series of compounds based on dimethylbenzene heterocyclic scaffolds as Kv7.2/7.3 activators. Among them, compound <strong>2c</strong> demonstrated improved efficacy in Rb⁺ efflux assays and exhibited comparable activity in whole-cell patch clamp recordings on Kv7.2/7.3 channels. Moreover, compound <strong>2c</strong> was effective in both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (<em>sc-</em>PTZ) mouse models, with ED₅₀ values of 4.02 mg/kg and 43.17 mg/kg, respectively. The LD₅₀ value of <strong>2c</strong> in acute toxicity experiments was 340.35 mg/kg (95% CI: 293.68–394.45) in mice. Additionally, <strong>2c</strong> exhibited locomotor impairment with at TD₅₀ of 48.93 mg/kg in an open field test and 49.25 mg/kg in a rotarod test. Compound <strong>2c</strong> also demonstrated reasonable pharmacokinetic (PK) properties and blood-brain barrier (BBB) penetration, along with good photostability. Site-directed mutagenesis, combined with molecular docking, confirmed that <strong>2c</strong> interacted with key residues (W236, F305, and L299) in the Kv7.2 channel. Our findings suggest that compound <strong>2c</strong> is a promising lead compound with a novel scaffold as a Kv7.2/7.3 activator for the management of epilepsy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"219 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858230","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":"Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment","authors":"Barbora Svobodova ,&nbsp;Zuzana Moravcova ,&nbsp;Anna Misiachna ,&nbsp;Gabriela Novakova ,&nbsp;Ales Marek ,&nbsp;Vladimir Finger ,&nbsp;Jitka Odvarkova ,&nbsp;Jaroslav Pejchal ,&nbsp;Jana Zdarova Karasova ,&nbsp;Jakub Netolicky ,&nbsp;Marek Ladislav ,&nbsp;Martina Hrabinova ,&nbsp;Ales Sorf ,&nbsp;Lubica Muckova ,&nbsp;Lenka Fikejzlova ,&nbsp;Marketa Benkova ,&nbsp;Martin Novak ,&nbsp;Lukas Prchal ,&nbsp;Jan Capek ,&nbsp;Jiri Handl ,&nbsp;Jan Korabecny","doi":"10.1016/j.ejmech.2025.117678","DOIUrl":"10.1016/j.ejmech.2025.117678","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and <em>N</em>-methyl-<span>d</span>-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, <em>in silico</em> screening predicted favorable CNS permeability and oral bioavailability. Subsequent <em>in vitro</em> evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives <strong>5i</strong> and <strong>5m</strong> displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound <strong>5e</strong>, whereas <strong>5i</strong> and <strong>5m</strong> underwent rapid metabolism. Notably, compound <strong>7</strong> showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound <strong>5m</strong> exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through <em>in vitro</em> PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound <strong>5m</strong> advanced to <em>in vivo</em> pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound <strong>5m</strong> as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117678"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862703","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":"Structural optimization and pharmacological evaluation of diphenyl amine esters as anti-hepatocellular carcinoma agents by targeting TAR RNA-binding protein 2","authors":"Ruihan Zhang ,&nbsp;Zhao Wu ,&nbsp;Hairong Wang ,&nbsp;Minghui Ji ,&nbsp;Tianze Shen ,&nbsp;Linhan Yang ,&nbsp;Yiming Li ,&nbsp;Jialing Yu ,&nbsp;Yinqiao Huang ,&nbsp;Lingyu Li ,&nbsp;Zihan Xu ,&nbsp;Yuwen Sheng ,&nbsp;Xiaoli Li ,&nbsp;Fei Wang ,&nbsp;Weilie Xiao","doi":"10.1016/j.ejmech.2025.117676","DOIUrl":"10.1016/j.ejmech.2025.117676","url":null,"abstract":"<div><div>Hepatocellular Carcinoma (HCC), a leading cause of cancer-related death in the world, urgently requires novel therapeutic strategies and drug targets. The TRBP-Dicer complex plays a critical role in miRNA biosynthesis, which can be regulated by small molecules to exert anti-cancer effects. This study presented the structural modification of the natural product (−)-Gomisin M1(GM), resulting in the synthesis of 37 derivatives with a diphenyl amine ester scaffold. Several of these derivatives exhibited enhanced modulation of miRNA biogenesis compared to GM. Notably, derivative <strong>13j</strong> displayed improved binding affinity to TRBP and greater efficacy in modulating miRNA biosynthesis, as well as anti-HCC activity <em>in vitro</em> and <em>in vivo</em>. Further investigation revealed that <strong>13j</strong> induced apoptosis and pyroptosis while inhibiting the epithelial-to-mesenchymal transition process in HCC cells. In terms of druggability, <strong>13j</strong> possesses favorable drug-likeness and a promising safety profile. These findings provide a promising scaffold with potent activity and low toxicity, offering a foundation for the development of miRNA-based therapeutic strategies for HCC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117676"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862706","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 the first-in-class FABP/PPAR multiple modulator for the treatment of metabolic dysfunction-associated steatohepatitis","authors":"Ya Chen ,&nbsp;Zibin Liao ,&nbsp;Jianming Mao ,&nbsp;Wenxin Wang ,&nbsp;Yuxia Liu ,&nbsp;Wei Dai ,&nbsp;Zheng Wen ,&nbsp;Sishi Liu ,&nbsp;Yayi Chen ,&nbsp;Yiming Ma ,&nbsp;Xiaoying Wang ,&nbsp;Zheng Li","doi":"10.1016/j.ejmech.2025.117635","DOIUrl":"10.1016/j.ejmech.2025.117635","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic syndrome, and the development of new drugs is urgently needed. Fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid absorption, metabolism and inflammation. Considering the synergistic effect of FABP and PPAR in the regulation of MASH pathophysiology, the development of FABP/PPAR multiple modulators might be a promising anti-MASH strategy. Herein, the first-in-class FABP/PPAR multiple modulators were designed by hybrid resveratrol and PPARs agonist Elafibranor. Among them, the compound <strong>27</strong> was identified as the optimal FABP/PPAR multiple modulator (FABP1 IC₅₀ = 0.65 μM, FABP4 IC₅₀ = 1.08 μM, PPARα EC₅₀ = 9.19 μM, PPARγ EC₅₀ = 2.20 μM, PPARδ EC₅₀ = 1.58 μM). Further MST assay confirmed the direct interaction of compound <strong>27</strong> and FABP1, providing a robust validation of its target specificity. In MASH mice, compound <strong>27</strong> exhibited a better therapeutic effect than clinical candidate obeticholic acid in ameliorating multiple pathological features of MASH. This study reported the successful discovery of the first-in-class FABP/PPAR multiple modulators, which provided preliminary evidence that such multi-target agents have broad medical prospects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117635"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858203","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 hydrazide-based PI3K/HDAC dual inhibitors with enhanced pro-apoptotic activity in lymphoma cells","authors":"Baogeng Hou, Geng Jia, Zhongqiang Li, Yuqi Jiang, Yuxin Chen, Xiaoyang Li","doi":"10.1016/j.ejmech.2025.117658","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117658","url":null,"abstract":"PI3K and HDAC are concurrently upregulated in a variety of cancers, and simultaneous inhibition of PI3K and HDAC may synergistically inhibit tumor proliferation and induce apoptosis, providing a rationale for the study of dual-target PI3K/HDAC inhibitors. In this study, we rationally designed and synthesized a series of novel PI3K/HDAC dual-target inhibitors by combining the morpholino-triazine pharmacophore of PI3K inhibitor ZSTK474 with the hydrazide moiety of HDAC1-3 selective inhibitor <strong>11h</strong>. Representative compound <strong>31f</strong> possessed both PI3K (IC₅₀ = 2.5-80.5 nM for PI3Kα, β, γ, and δ) and HDAC1-3 inhibitory activities (IC₅₀ = 1.9-75.5 nM for HDAC1-3). <strong>31f</strong> showed potent antiproliferative activity against a variety of tumor cell lines. Meanwhile, we designed and synthesized tool molecule <strong>39a</strong>, a HDAC inhibitor structurally similar to <strong>31f</strong>. In the mantle cell lymphoma Jeko-1 cell line, <strong>31f</strong> showed significantly greater efficacy than the single inhibitors in inducing apoptosis. In conclusion, this study provided insights into the development of novel hydrazide-based dual HDAC/PI3K inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858204","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":"Marine natural products as potential anti-Pseudomonas aeruginosa agents: challenges and advances","authors":"Liu-Xia Lv, Jun-Na Yin, Yi-Lin Sun, Mei-Yan Wei, Wen-Qing Jiang, Yu-Cheng Gu, Xiao-Ping Yang, Chang-Lun Shao","doi":"10.1016/j.ejmech.2025.117670","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117670","url":null,"abstract":"Antimicrobial resistance (AMR) has become a pressing need to address in the major global public health challenges, posing a serious threat to human health. <em>Pseudomonas aeruginosa</em> (PA) is one of the most concerning Gram-negative pathogens and is typically treated with broad-spectrum antibiotics. PA exhibits resistance to multiple antibiotics, multifactorial virulence, and dynamic hyperadaptation, which results in a particularly formidable challenge in eliminating PA from patients. The problem of drug resistance is becoming increasingly serious, and the development of new antibiotics is extremely lagging behind, resulting in no drug with a new structure and mechanism being approved for the treatment of infections caused by drug-resistant Gram-negative bacteria over the past half-century. Consequently, the development of new antibiotics is of utmost urgency and importance. Marine natural products (MNPs) have become an important source for developing new antibiotics due to their unique properties. So far, 44 potential molecules with significant anti-PA activity have been isolated from marine organisms, of which 19 have been reported as quorum-sensing system inhibitors (QSIs) with potential for further development. In this review, we provide a comprehensive summary of the current status of drug resistance, pathogenic mechanisms, and resistance mechanisms associated with PA infections. We also highlight the challenges and opportunities presented by MNPs in the development of anti-PA drugs, and offer recommendations to accelerate the antibiotic development process, thereby providing valuable insights for the study and exploitation of novel antibiotics.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858209","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}