European Journal of Medicinal Chemistry最新文献

{"title":"Discovery of a first-in-class protein arginine methyltransferase 1 (PRMT1) degrader for nonenzymatic functions studies","authors":"Chenning Ma ,&nbsp;Hanyin Sun ,&nbsp;Chang Shen ,&nbsp;Xinyu Li ,&nbsp;Yudao Shen","doi":"10.1016/j.ejmech.2025.117625","DOIUrl":"10.1016/j.ejmech.2025.117625","url":null,"abstract":"<div><div>Among the type I Protein Arginine Methyltransferases (PRMTs), PRMT1 plays a predominant part in catalyzing asymmetric dimethylation of arginine residues on histone or nonhistone substrates. PRMT1 level is abnormally elevated in numerous cancer cell types and inflammation diseases. Compared to the enzymatic functions of PRMT1, its nonenzymatic functions are shortly investigated in diseases. Previous study has confirmed that the stability of orphan receptor TR3, a binding partner of PRMT1, is closely regulated by PRMT1, but the effect is independent of PRMT1's methyltransferase activity, but depends on the physical binding of PRMT1. To date, multiple inhibitors targeting methyltransferase enzymatic activity of PRMT1 are developed, but all of them lack selectivity for PRMT1. Among them, only GSK3368715 advanced to clinical trials but was discontinued in phase I due to inadequate efficacy and thrombosis toxicity. Currently, small molecule degraders are gaining significant attention due to their advantages in efficacy and selectivity in therapeutic applications. Presumably, a potent and selective PRMT1 degrader could serve as a valuable alternative in the treatment of PRMT1-driven diseases and act as an instrumental tool in uncovering additional nonenzymatic functions of PRMT1. To date, however, the development of a PRMT1 degrader remains a challenge, with no such agents reported. In this study, we present the design, synthesis and characterization of CM112 (compound <strong>12</strong>), a first-in-class PRMT1 degrader, designed by tethering adamantane to MS023, a type I PRMTs pan inhibitor, via a 5-PEG linker. CM112 demonstrates a concentration- and time-dependent ability to induce PRMT1 degradation in various solid cancer cell lines. Additionally, CM112 shows high selectivity for PRMT1 degradation, without causing degradation of other type I PRMTs (PRMT3/4/6), although it retains potent inhibitory effects on their enzymatic activity. Pharmacokinetics studies indicated that CM112 possesses favorable bioavailability in mice. Notably, as anticipated, CM112 could target PRMT1's nonenzymatic function by downregulating the stability of the orphan receptor TR3, an effect not observed with the PRMT1 inhibitor MS023, that is in consistence with the previous findings. Taken together, CM112 represents a valuable tool for elucidating the unknown, methyltransferase-independent roles of PRMT1 in disease progression and pave the way for developing more potent and drug like PRMT1 degraders in future.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117625"},"PeriodicalIF":6.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831537","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":"Advancing N,N′-disubstituted diamines in antimalarial drug development: Structure-activity relationships and mechanistic studies","authors":"Alejandro I. Recio-Balsells ,&nbsp;Esteban Panozzo-Zénere ,&nbsp;Renzo Carlucci ,&nbsp;Nirupa Chaurasia ,&nbsp;Ashan Manhas ,&nbsp;Mercedes Bacelo Fioressi ,&nbsp;Georgina N. Montagna ,&nbsp;Gustavo Arrizabalaga ,&nbsp;Shabana I. Khan ,&nbsp;Babu L. Tekwani ,&nbsp;Niti Kumar ,&nbsp;Guillermo R. Labadie","doi":"10.1016/j.ejmech.2025.117630","DOIUrl":"10.1016/j.ejmech.2025.117630","url":null,"abstract":"<div><div>Previously we reported the synthesis of thirty <em>N</em>,<em>N</em>′-disubstituted diamines, several of which exhibited potent activity against apicomplexan parasites, including <em>Plasmodium falciparum</em> and <em>Toxoplasma gondii</em>. Building on this, we expanded the series with fifty-four new compounds, which were evaluated against the same parasites. These analogs were synthesized via a one-pot reductive amination of aliphatic diamines with various aromatic aldehydes. The new library showed great potential, with several compounds achieving a pIC₅₀ greater than 6.0 against <em>P. falciparum</em> and with an acceptable selectivity index range (SI ≥ 10). Additionally, some compounds exhibited activity against <em>T. gondii</em>, although no clear correlation in activity was observed between the two apicomplexan parasites which survive in different intracellular niches. A comprehensive structure-activity relationship (SAR) analysis was performed, encompassing both the previously reported collection and the new analogs. Furthermore, selected hits were tested against resistant <em>P. falciparum</em> strains, demonstrating comparable activity to that observed with sensitive strains. To gain insights into the mechanism of action, we examined morphological changes in the parasite for selected hits, observing distinct alterations that suggested diverse mechanisms across the compounds. Finally, we evaluated the <em>in</em> <em>vivo</em> activity of three selected hits, though substantial parasite clearance was not observed. This outcome highlights the opportunity to optimize SAR to enhance permeability, solubility, and bioavailability, or it may suggest a parasitostatic rather than parasiticidal mechanism of action. In conclusion, this work highlights the potential of <em>N</em>,<em>N</em>′-disubstituted diamines in antimalarial drug discovery. Future efforts will focus on improving <em>in vivo</em> efficacy and further elucidating the mechanism of action.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117630"},"PeriodicalIF":6.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831523","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":"The Groebke–Blackburn–Bienaymé (GBB) reaction: A powerful tool for generating diverse heterocyclic scaffold libraries in anticancer drug discovery","authors":"Khizra Khan ,&nbsp;Rashid Ali ,&nbsp;Shahnaaz Khatoon ,&nbsp;Amzad Khan ,&nbsp;Promod Kumar ,&nbsp;Shakir Ahamad ,&nbsp;Mohammad Saquib ,&nbsp;Mohd Kamil Hussain","doi":"10.1016/j.ejmech.2025.117629","DOIUrl":"10.1016/j.ejmech.2025.117629","url":null,"abstract":"<div><div>The Groebke–Blackburn–Bienaymé (GBB) reaction is a versatile multi-component (MCR) synthetic methodology that has transformed anticancer drug discovery by enabling the rapid and efficient generation of diverse heterocyclic scaffolds. These scaffolds, such as imidazo[1,2-<em>a</em>]pyridines, imidazo[1,2-<em>a</em>]pyrimidines, and their derivatives, are highly valuable moieties for targeting critical cancer pathways. The modular nature of the GBB reaction, coupled with post-reaction modifications, allows the design of compounds with tailored structures and enhanced pharmacological properties. GBB-derived compounds exhibit broad anticancer potential by modulating diverse molecular targets. These include protein kinases (e.g. Rock2, Gsk3β, B-Raf), microtubule dynamics via tubulin inhibition, and G-quadruplex DNA stabilization in oncogene promoters (e.g., c-MYC, BCL2), disrupting key mechanisms of tumour progression. Moreover, they target epigenetic regulators such as HDACs, CBP/P300 bromodomains, and BET bromodomains, affecting transcriptional regulation and chromatin remodeling. Immune checkpoints (e.g., PD-1/PD-L1), enzymes such as autotaxin, TDP1, and Hsp90, as well as apoptotic regulators (e.g., Bcl-2, BAG3), are also effectively inhibited. More importantly, these compounds address challenging targets, including KRAS G12C mutations and the menin–MLL interaction, offering solutions to previously “undruggable” pathways. The unparalleled efficiency of GBB reaction and its ability to generate structurally diverse, bioactive compounds spanning multiple oncogenic mechanisms highlights its central role in advancing anticancer drug discovery and its transformative impact on therapeutic innovation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117629"},"PeriodicalIF":6.0,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824841","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":"Topoisomerase II-targeting anticancer clinical candidates and drugs: A critical analysis, unravelling molecular medicinal insights and promising research roadmap","authors":"Ayan Acharya ,&nbsp;Nibedita Roy ,&nbsp;Vaishnavi Newaskar,&nbsp;Abhishek Rai,&nbsp;Abhrajyoti Ghosh,&nbsp;Mithilesh Nagpure,&nbsp;Santosh Kumar Giri,&nbsp;Gautam Sahni,&nbsp;Sankar K. Guchhait","doi":"10.1016/j.ejmech.2025.117611","DOIUrl":"10.1016/j.ejmech.2025.117611","url":null,"abstract":"<div><div>In recent years, the USFDA-approved drug molecules are being frequently analyzed to provide perspectives and strategies for novel therapeutic discovery and development. Some of the remarkable analyses include physicochemical properties of drugs relevant to oral bioavailability, frequent presence of drug relevant-structural motifs, natural products as sources of new drugs, and synthetic approaches to new drugs. In this review article, for the first time, we present a structure-function analysis of human topoisomerase II (hTopo II) inhibitors those are currently clinically used or under clinical trials for anticancer treatment. The case studies and a critical molecular medicinal insight for their therapeutic development have been presented. The review illustrates various key aspects: the hTopo II inhibitors’ molecular modulations, common pharmacophores, interactions at molecular level crucial for inhibition of enzyme at its various stages of catalytic function, and network polypharmacology of Topo II with different targets. Numerous toxicophore motifs have been identified, which provide important alerts while designing and discovering novel therapeutic agents. A range of innovative approaches including property-focused strategies, ADCs, and Click Activated Protodrugs Against Cancer (CAPAC) that have addressed challenges faced in the hTopo II-based therapeutic development have been discussed. The analysis with perspectives represents a valuable educational and research resource that will encourage hTopo II-inhibition and its network polypharmacology based drug discovery studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117611"},"PeriodicalIF":6.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819713","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 discovery of cinnamoyl amide derivatives as potent NagZ inhibitors with antibacterial activity","authors":"Jian Fu ,&nbsp;Qingqing Wang ,&nbsp;Huixiao Fu ,&nbsp;Dan Wang ,&nbsp;Aurélie Mayard ,&nbsp;Weidong Pan ,&nbsp;Stéphane P. Vincent","doi":"10.1016/j.ejmech.2025.117622","DOIUrl":"10.1016/j.ejmech.2025.117622","url":null,"abstract":"<div><div>β-<em>N</em>-acetylglucosaminidase (NagZ) plays an important role in the bacterial cell wall biosynthetic pathway. Inhibiting its activity could potentially impede bacterial growth. We report a study on the design and synthesis of cinnamoyl amides derived from rosmarinic acid (RA), and their enzymatic, antibacterial activity against NagZ and <em>Pseudomonas aeruginosa</em> respectively. <em>In vitro</em> enzyme activity determination showed that the best synthetic RA analogues displayed higher inhibitory activity than that of parent RA, in the same range than the most potent NagZ inhibitors reported so far. Remarkably, compounds <strong>11h</strong> and <strong>Br-6</strong> displayed interesting binding affinity values with <em>K</em>_i<em>=</em>3.3 ± 0.5 and 3.5 ± 1.0 μM, respectively. Docking simulations evidenced significant binding interactions of cinnamoyl amide derivatives with the active site of NagZ. Moreover, kinetic evaluations indicated these compounds displayed competitive behavior. Additionally, MICs of <strong>11h</strong> and <strong>Br-6</strong> combined with two β-Lactam antibiotics (imipenem and ceftazidime) were evaluated against <em>P. aeruginosa</em> by microdilution checkerboard assay, establishing that antibacterial agents show synergistic effects. <em>In vivo</em> antibacterial efficacy assay using a full-thickness skin defect model with <em>P. aeruginosa</em> infection confirmed these observations.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117622"},"PeriodicalIF":6.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819715","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 a deuterated TNF-α small molecule modulator for potential treatment of ulcerative colitis","authors":"Tong Song ,&nbsp;Mengxiao Zhuang ,&nbsp;Zhi Ying Dorothy Wong ,&nbsp;Ge Xu ,&nbsp;Mei-Lin Tang ,&nbsp;Buyu Kou ,&nbsp;Xun Sun","doi":"10.1016/j.ejmech.2025.117616","DOIUrl":"10.1016/j.ejmech.2025.117616","url":null,"abstract":"<div><div>Tumor necrosis factor-alpha (TNF-α) is an important target for the treatment of inflammatory diseases. Targeting TNF-α inhibition, such as antibody drug infliximab and adalimumab, has emerged as an effective therapeutic strategy for managing the most difficult-to-treat chronic ulcerative colitis (UC). So far, there are no small molecule TNF-α inhibitors available on the market for the treatment of UC. Previously, we reported an indanone analogue <strong>(<em>R</em>)-STU104</strong> showed considerable inhibitory activity on TNF-α production in both acute and chronic mouse models of UC with a favorable safety profile. However, further development potential of this compound was greatly limited due to its poor metabolic stability in human liver microsomes and suboptimal pharmacokinetic profiles in mice. Herein, we discovered a deuterated TNF-α small molecule modulator <strong>(<em>R</em>)-104-6D-01</strong>, which demonstrated promising clinical potential for the treatment of UC. This new compound exhibited enhanced oral bioavailability and exposure in pharmacokinetic studies, as well as superior anti-UC efficacy in a DSS-induced mouse UC model, compared with <strong>(<em>R</em>)-STU104</strong> at a dosage of 30 mg/kg/d. Collectively, <strong>(<em>R</em>)-104-6D-01</strong> proves to be a promising candidate of potential use in treating UC as an oral TNF-α small molecule modulator.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117616"},"PeriodicalIF":6.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819716","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 nonsteroidal steroid sulfatase inhibitors containing glutamic acid unit","authors":"Olga Ciupak ,&nbsp;Sebastian Demkowicz ,&nbsp;Janusz Rachon ,&nbsp;Karol Biernacki ,&nbsp;Paweł Czubak ,&nbsp;Aleksandra Martyna ,&nbsp;Maciej Masłyk ,&nbsp;Konrad Kubiński ,&nbsp;Magdalena Datta ,&nbsp;Janusz Rak ,&nbsp;Mateusz Daśko","doi":"10.1016/j.ejmech.2025.117627","DOIUrl":"10.1016/j.ejmech.2025.117627","url":null,"abstract":"<div><div>In the present work, we designed and successfully synthesized novel steroid sulfatase (STS) inhibitors based on coumarin, tyramine, triazole, and flavone cores with an additional glutamic acid residue in the structure. The molecular modeling studies revealed that designed derivatives have potential to bind to the molecular target active site, at least theoretically. The biological activity of synthesized compounds was evaluated under a two-step procedure including enzymatic assay and cellular studies using human choriocarcinoma JEG-3 cells. Among the synthesized compounds, the derivative <strong>54E</strong> was the most active in both enzymatic and cellular experiments. This result agreed with the molecular modeling data, which indicated that derivative <strong>54E</strong> demonstrates the highest affinity to the STS active site. In the enzymatic assay, the remaining STS activity values of 12.97, 17.58, and 20.52 % were observed at 10, 1, and 0.1 μM concentrations of compound <strong>54E</strong>, respectively. The IC₅₀ value of 22 nM determined in an experiment with JEG-3 cells for compound <strong>54E</strong> was close to the IC₅₀ value determined for the reference STS inhibitor <em>Irosustat</em> (2.7 nM). During the evaluation of the uptake mechanism of the compound <strong>54E</strong>, we found that organic anion transporting polypeptides (OATPs) may be responsible for its internalization into the cells. Furthermore, the incubation of zebrafish larvae with the compound <strong>54E</strong> revealed no detectable toxic effects <em>in vivo</em> indicating that the compound <strong>54E</strong> is a very promising candidate for further preclinical investigations.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117627"},"PeriodicalIF":6.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819710","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":"Redesigning oxazolidinones as carbonic anhydrase inhibitors against vancomycin-resistant enterococci","authors":"Andrea Ammara ,&nbsp;Simone Giovannuzzi ,&nbsp;Alessandro Bonardi ,&nbsp;Nader S. Abutaleb ,&nbsp;Ahmed A. Abouelkhair ,&nbsp;Daniel P. Flaherty ,&nbsp;Mohamed N. Seleem ,&nbsp;Clemente Capasso ,&nbsp;Paola Gratteri ,&nbsp;Alessio Nocentini ,&nbsp;Claudiu T. Supuran","doi":"10.1016/j.ejmech.2025.117620","DOIUrl":"10.1016/j.ejmech.2025.117620","url":null,"abstract":"<div><div>The rise of vancomycin-resistant enterococci (VRE) as a leading cause of hospital-acquired infections underscores the urgent need for new treatment strategies. In fact, resistance has developed not only to vancomycin but also to other clinically used agents, such as daptomycin and linezolid. We propose a novel drug design approach merging tedizolid, a second-generation oxazolidinone used as an unapproved salvage therapy in clinical settings, with carbonic anhydrase inhibitors (CAIs) recently validated as functioning decolonization agents. These sulfonamide derivatives showed potent inhibition of the carbonic anhydrases from <em>Enterococcus faecium</em>, with <em>K</em>_I values in the range of 14.6–598 nM and 63.2–798 nM against EfCAα and EfCAγ. Computational simulations elucidated the binding mode of these dual-action antibiotics to the peptidyl transferase center (PTC) of the 50S ribosome subunit and bacterial CAs. A subset of six derivatives showed potent PTC-related anti-enterococcal effects against multidrug-resistant <em>E. faecalis</em> and <em>E. faecium</em> strains with some compounds outperforming both the oxazolidinone and CA inhibitor drugs (MIC values in the range 1–4 μg/mL).</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117620"},"PeriodicalIF":6.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822943","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":"1,5-Disubstituted 1,2,3-triazoles: Molecular scaffolds for medicinal chemistry and biomolecular mimetics","authors":"Kunj B. Mishra","doi":"10.1016/j.ejmech.2025.117614","DOIUrl":"10.1016/j.ejmech.2025.117614","url":null,"abstract":"<div><div>Ruthenium (II) catalyzed click chemistry enable the highly efficient and selective synthesis of 1,5-disubstituted 1,2,3-triazoles. This method provides exclusive formation of the desired 1,5-regioisomer. In the past twenty years, these reactions have become a valuable tool in organic synthesis. Similar to 1,4-regioisomer of 1,2,3-triazole, 1,5-disubstituted 1,2,3-triazole functions as biocompatible linkers and biologically active scaffolds. This review focuses on the synthesis and medicinal chemistry significance of these triazoles as versatile building blocks. Notably, they serve as bioisosteres of the <em>cis</em>-amide bond, conferring enhanced stability and mimicking constrained amino acids, making them crucial for peptidomimetic development. Hence, we are discussing their application in the development of peptidomimetics. 1,5-Disbstituted 1,2,3- triazoles mimic <em>cis</em>-amide bond in the peptides, altering their conformation and biological activity. Furthermore, we have discussed its application to create novel bioactive molecules, including mimics of natural products, nucleosides, nucleotides, glycoconjugates, and protein-protein interaction inhibitors. This review highlights their substantial potential in drug discovery, and provides a valuable resource for future research in this field.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"291 ","pages":"Article 117614"},"PeriodicalIF":6.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819717","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 N-substituted nipecotamide derivatives as multifunctional agents for epilepsy treatment","authors":"Wei Li, Lijun Hong, Linrui Li, Yu Yuan, Yi Ding, Jiang Zhu, Chao Wang, Zhongcheng Cao, Xin Tian","doi":"10.1016/j.ejmech.2025.117613","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117613","url":null,"abstract":"To discover novel multi-functional antiepileptic agents, nipecotamide was hybridized with salicylaldehyde, paeonol, vanillin and cinnamaldehyde to generate a series of <em>N</em>-substituted nipecotamide derivatives. Biological screening revealed that compound <strong>11c</strong> exhibited remarkable scavenging activities against ABTS (2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) ) radical (scavenging IC₅₀: 92.0 μM), DPPH (1,1-Diphenyl-2-picrylhydrazyl) radical (scavenging IC₅₀: 70.9 μM), and superoxide anion radical (inhibition percentage: 48.4%). Additionally, electrophysiological results showed that compound <strong>11c</strong> demonstrated potent inhibitory effects on abnormal electrical discharges. Furthermore, compound <strong>11c</strong> displayed the capacity to relieve H₂O₂-induced oxidative damage and LPS-induced neuroinflammation at the cellular level. Besides, compound <strong>11c</strong> could cross the blood-brain barrier, alleviate the symptoms of epilepsy induced by pentylenetetrazole and pilocarpine effectively, and mitigate oxidative damage caused by sodium nitrite in mice. Therefore, compound <strong>11c</strong> possesses symptomatic-treatment and disease-modification properties for epilepsy. These results highlighted that compound <strong>11c</strong> was a highly promising candidate for further development as an antiepileptic agent.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"90 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819714","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}