European Journal of Medicinal Chemistry最新文献

{"title":"Design, Synthesis, and Biological Profiling of Novel Aryl-Spirocyclic Diamine Derivatives with Potential Antidepressant-like Properties","authors":"Jiefang Zheng, Yaxin Tian, Jiaxin Cheng, Zhengtao Hu, Junchi Zhang, Feipu Yang, Pengcheng Li, Zhijuan Jiang, Xudong Gong, Qiongqiong Hou, Guan Wang, Vivien Shen, Tianwen Hu, Zhijian Xu, Guanghui Tian, Weiliang Zhu, Yang He, Jingshan Shen","doi":"10.1016/j.ejmech.2025.118198","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118198","url":null,"abstract":"To meet the clinical need for therapeutic efficacy against cognitive impairment and pain comorbidities in depression, a rational drug design approach was used in the current study to synthesize a series of spirocyclic diamine derivatives. Among them, <strong>(<em>R</em>)-D24</strong> exhibited triple monoamine reuptake inhibitory activity (SERT, NET, and DAT), while <strong>D6</strong> and <strong>D17</strong> showed potent inhibitory activity against both SERT and 5-HT_3AR. <strong>D6</strong> and <strong>D17</strong> have acceptable systemic exposure and oral bioavailability in mice and low clearance in human liver microsomes. <strong>D6</strong> and <strong>D17</strong> exhibited favorable safety profiles in hepatic, renal, and hERG toxicity assays and showed potent antidepressant-like effects in the forced swim test, supporting their potential for further preclinical investigation. In addition, the compound-target interactions of the key compounds were analyzed through molecular docking. These results highlight the rationality of our design and provide new perspectives for the development of antidepressant drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183045","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":"Chiral pool synthesis of enantiomerically pure morphan derivatives with κ receptor affinity from (S)-perillaldehyde","authors":"Lea Flämig ,&nbsp;Thomas Schidelko ,&nbsp;Luca Blicker ,&nbsp;Katharina Hoffmann ,&nbsp;Constantin Daniliuc ,&nbsp;Dirk Schepmann ,&nbsp;Marcel Bermúdez ,&nbsp;Karin Loser ,&nbsp;Bernhard Wünsch","doi":"10.1016/j.ejmech.2025.118218","DOIUrl":"10.1016/j.ejmech.2025.118218","url":null,"abstract":"<div><div>Ethylenediamines represent a promising class of κ receptor agonists. Recently, the first ethylenediamine – morphan hybrid <strong>4</strong> with high κ receptor affinity, but poor selectivity over the σ₁ receptor was reported. Herein, the chiral pool synthesis of substituted morphans <strong>19</strong> and <strong>29</strong> is reported combining the morphan scaffold with the κ-pharmacophoric elements dichlorophenylacetamide and pyrrolidine. Starting from methyl (<em>S</em>)-perillate (<strong>12</strong>), a two-step sequence, <em>i.e</em>., epoxidation followed by reaction with benzylamine, provided enantiomerically pure morphan-8-carboxylate <strong>10a</strong>. Functional group modifications of the ester moiety and the benzylamine substructure of <strong>10a</strong> led to the pyrrolidinomethyl derivative <strong>19</strong>. Key step of the synthesis of pyrrolidine <strong>29</strong> was a Curtius rearrangement, in which the intermediate isocyanate was trapped with benzyl alcohol to obtain the carbamate <strong>27</strong>. The κ affinity of pyrrolidine <strong>29</strong> (<em>K</em>_i(κ) = 138 nM) was approximately 7-8-fold lower than the κ affinity of morphan <strong>4</strong> without further substituents. However, taking lipophilicity into account resulted in almost identical LLE values for <strong>4</strong> (LLE = 5.66) and <strong>29</strong> (LLE = 5.56). The additional OH moiety of <strong>29</strong> not only increased the polarity, but also the receptor selectivity, as <strong>29</strong> did no longer interact with σ₁ receptors. Docking studies demonstrated similar binding poses of <strong>4</strong> and <strong>29</strong> at the κ receptor. Moreover, the reduced affinity of <strong>29</strong> towards κ and σ₁ receptors could be explained. <em>In vitro,</em> <strong>29</strong> revealed high metabolic stability. Human peripheral blood mononuclear cells stimulated with lipopolysaccharide were used to show the anti-inflammatory and immunomodulatory effects of the κ receptor agonists <strong>4</strong> and <strong>29</strong>.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118218"},"PeriodicalIF":5.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153760","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":"Highly potent and selective degrader targeting ERα to improve the treatment outcomes of breast cancer","authors":"Xueting Bao ,&nbsp;Xunkai Yin ,&nbsp;Jinjing Xu ,&nbsp;ZhenZhen Zhu ,&nbsp;Wenyu Lu ,&nbsp;Yihui Cai ,&nbsp;Rupeng Dai ,&nbsp;Zhe Zheng ,&nbsp;Wenzhuo Xu ,&nbsp;Shulan Mei ,&nbsp;Songyun Xu ,&nbsp;Jie Li ,&nbsp;Nianguang Li ,&nbsp;Haohao Zhu ,&nbsp;Jianing Wang ,&nbsp;Jian Liu","doi":"10.1016/j.ejmech.2025.118199","DOIUrl":"10.1016/j.ejmech.2025.118199","url":null,"abstract":"<div><div>Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast cancer cases; therefore, it is considered a primary therapeutic target for breast cancer. Several therapeutic agents, including selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent <strong>ARV-471</strong> has been used to treat locally advanced or metastatic breast cancer in clinical trials. Herein, we designed, synthesized, and evaluated several novel ERα-PROTAC agents. After systematic structural optimization, compound <strong>A16</strong> was found to have excellent antiproliferative and ERα-inhibitory activities in the breast cancer cell line MCF-7. <strong>A16</strong> selectively degraded ERα (DC₅₀ = 3.78 nM) through the ubiquitin–proteasome pathway in a time- and concentration-dependent manner. It effectively attenuated drug resistance (MCF-7 Y537S cells; IC₅₀ = 1.3 nM), inhibited proliferation, and induced apoptosis in MCF-7 cells. In addition, it exhibited excellent antitumor effects (10 mg/kg/d intraperitoneal injection; total growth inhibition = 80.11 %) and a good safety profile in an MCF-7 xenograft model, highlighting its potential as a novel drug candidate for breast cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118199"},"PeriodicalIF":5.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183364","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":"Quinoline-5,8-dione CDC25 inhibitors: Potent anti-cancer agents in leukemia and patient-derived colorectal organoids","authors":"Iin Narwanti ,&nbsp;Zih-Yao Yu ,&nbsp;Bidyadhar Sethy ,&nbsp;Pei-Ling Zheng ,&nbsp;Li-Hsin Cheng ,&nbsp;Kelvin K. Tsai ,&nbsp;Sung-Bau Lee ,&nbsp;Jing-Ping Liou","doi":"10.1016/j.ejmech.2025.118215","DOIUrl":"10.1016/j.ejmech.2025.118215","url":null,"abstract":"<div><div>Cell division cycle 25 (CDC25) phosphatases are critical activators of cyclin-dependent kinases (CDKs) and guardians of genome integrity, making them attractive anticancer targets. Building on the quinoline-5,8-dione scaffold <strong>NSC663284</strong> (<strong>6a</strong>), we synthesized derivatives with diverse C-6/C-7 alkylamino side chains. Structure–activity studies identified <strong>D3a</strong>/<strong>D3b</strong> (2-(4-methylpiperidin-1-yl)ethylamino) and <strong>D11a</strong>/<strong>D11b</strong> (2-(dimethylamino)ethylamino) as the most potent, exhibiting low-submicromolar inhibition of CDC25. In cell-based assays, these compounds suppressed leukemia (IC₅₀ 0.21–1.22 μM) and colorectal cancer (IC₅₀ 0.13–1.50 μM) viability, with reduced toxicity in normal colonic epithelial cells. Mechanistically, these derivatives blocked CDC25-mediated CDK1 Tyr15 dephosphorylation, delayed G₂/M progression, and induced caspase-dependent apoptosis with DNA damage. Cytotoxic potency correlated with baseline CDC25C expression, confirming on-target activity. Notably, efficacy was validated in colorectal cancer patient-derived organoids, providing clinically relevant insights into patient-specific responses. Together, these findings define a new class of CDC25 inhibitors with potent and selective anticancer activity, advancing prospects for next-generation therapeutics in leukemia and colorectal cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118215"},"PeriodicalIF":5.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153765","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, SAR and Biophysical Mechanism of Action of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) Guanine-Adenine DNA Cross-Linking Agents","authors":"George Procopiou, Paul J.M. Jackson, Daniella di Mascio, Jennifer L. Auer, Paolo Andriollo, Ilona Pysz-Hosey, Julia Mantaj, Khondaker Miraz Rahman, Keith R. Fox, David E. Thurston","doi":"10.1016/j.ejmech.2025.118196","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118196","url":null,"abstract":"This study investigates the Structure–Activity Relationship (SAR) and biophysical mechanism of action of a series of novel Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) agents designed to alkylate adenine and guanine bases in the DNA minor groove. A library of 18 analogs was synthesized using a modular approach to vary linker length, rigidity and the CBI and PDD core structures. Structural modifications included alkyl, aromatic, heteroaromatic and sterically constrained linkers, as well as prodrug variants. Several compounds demonstrated potent <em>in vitro</em> cytotoxicity, with lead analogs achieving IC₅₀ values in the low picomolar range across multiple human tumor cell lines. Control compounds with inactivated electrophilic groups in either or both pharmacophores showed markedly reduced activity, confirming the necessity of dual alkylation for optimal cytotoxic potency. Fluorescence-based thermal denaturation (ΔT_m up to 34 °C) and gel-based assays were used to assess DNA binding and provide mechanistic insights into the DNA sequence requirements for mono-alkylation and interstrand cross-linking. The study also includes a scalable synthesis of a linker-payload construct suitable for Antibody–Drug Conjugate (ADC) applications based on these agents. Overall, these findings support the use of CBI-PDDs as a promising class of sequence-selective DNA cross-linking agents for targeted cancer therapies.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"90 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153763","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":"Locally constrained xylene-based cyclic mimetics of SOCS3 protein","authors":"Alessia Cugudda ,&nbsp;Sara La Manna ,&nbsp;Francesco Cozzolino ,&nbsp;Iogann Tolbatov ,&nbsp;Alessandro Marrone ,&nbsp;Daniela Marasco","doi":"10.1016/j.ejmech.2025.118210","DOIUrl":"10.1016/j.ejmech.2025.118210","url":null,"abstract":"<div><div>The development of SOCS3 peptidomimetics targeting the JAK2 signaling pathway presents a promising strategy for modulating cytokine-driven diseases. In this study, we designed four novel monocyclic analogues of a previously reported linear lead compound (KIRCONG chim PEG), introducing local conformational constraints via regioselective thioether cyclization of either the KIR (thio-monoleft) or CONG (thio-monoright) regions. Each variant was synthesized with one or two PEG moieties (PEG₁ or PEG₂) to modulate solubility and flexibility. Microscale Thermophoresis (MST) revealed that thio-monoright PEG₁ exhibited the highest affinity for the JAK2 catalytic domain, and inhibition assays further confirmed its superior ability to suppress JAK2 mediated phosphorylation. Circular dichroism (CD) and metadynamics simulations indicated enhanced structural organization and intramolecular hydrogen bonding in cyclic analogues, especially thio-monoright PEG₁, as supported by Natural Bond Orbital (NBO) and Second Order Perturbation Theory (SOPT) analyses. Conversely, PEG₂ analogues showed reduced activity and solubility, likely due to increased flexibility and aggregation arising from hydrophobic surface exposure, as demonstrated by fluorescence spectroscopy and solvent-accessibility calculations. Overall, thio-monoright PEG₁ represents a promising conformationally stabilized SOCS3 mimetic with improved bioactivity, providing a rational foundation for further optimization of JAK2 targeting peptide therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118210"},"PeriodicalIF":5.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141079","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":"HSP90 inhibitors in cancer immunotherapy: Therapeutic opportunities and challenges","authors":"Chao Zhang ,&nbsp;Wenying Nie ,&nbsp;Qiang Tu ,&nbsp;Youming Zhang ,&nbsp;Hongyu Zhao ,&nbsp;Chun Song","doi":"10.1016/j.ejmech.2025.118195","DOIUrl":"10.1016/j.ejmech.2025.118195","url":null,"abstract":"<div><div>Heat shock protein 90 (HSP90), a highly evolutionarily conserved molecular chaperone, plays critical roles in both physiological processes and disease pathogenesis, with particularly prominent involvement in cancer initiation and progression. Emerging evidence highlights the multifaceted functions of HSP90 within the tumor immune microenvironment, including mediation of immune evasion mechanisms, induction of tolerance/suppressive phenotypes, and facilitation of angiogenesis and metastatic dissemination. Notably, aberrant HSP90 accumulation (intracellularly and extracellularly) drives oncogenic signaling and promotes tumor survival and metastasis through immunomodulatory mechanisms. The pharmacological inhibition of HSP90 demonstrates dual therapeutic benefits: selective targeting of malignant cells and reprogramming of the immunosuppressive tumor niche, thereby exhibiting remarkable translational potential. In cancer immunotherapy, HSP90 inhibitors synergize with immune checkpoint blockade, chemotherapy, radiotherapy, and hyperthermia therapy by enhancing tumor immunogenicity and eliciting robust antitumor immune responses. Furthermore, the ongoing development of isoform-selective inhibitors and dual-targeting agents represents a paradigm shift toward precision therapies that maximize efficacy while minimizing off-target effects. This review systematically examines HSP90's structural biology, its multifaceted immunoregulatory roles in malignancies, and the clinical promise of HSP90-targeted combinatorial immunotherapies. We further discuss emerging research frontiers and translational challenges, providing a strategic framework for advancing next-generation cancer immunotherapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118195"},"PeriodicalIF":5.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153762","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":"Repurposing carboplatin-based Pt(IV)-deferoxamine conjugates for infection theranostics","authors":"Martin Kraihammer ,&nbsp;Hristo P. Varbanov ,&nbsp;Kateřina Dvořáková Bendová ,&nbsp;Miloš Petřík ,&nbsp;Annie Yap ,&nbsp;Giacomo Gariglio ,&nbsp;Hubertus Haas ,&nbsp;Clemens Decristoforo","doi":"10.1016/j.ejmech.2025.118216","DOIUrl":"10.1016/j.ejmech.2025.118216","url":null,"abstract":"<div><div>Recently, multifunctional platinum(IV) complexes designed as prodrugs for the anticancer drug carboplatin and the iron chelator deferoxamine (DFO), each featuring a DFO unit at one axial position and either hemisuccinate or acetate at the other, were developed. As these compounds contain DFO, they hold the potential to be radiolabelled with gallium-68 for molecular imaging and to be recognized by microorganisms, which can utilise DFO as a siderophore-based iron source being taken up by specific siderophore transporters (SITs). Combining this recognition mechanism with a cytotoxic carboplatin core, these compounds could potentially lead to specific antimicrobial activity, particularly against <em>Aspergillus fumigatus</em> (AFU), which causes systemic infections and expresses relevant SITs. The two complexes were radiolabelled with gallium-68 and evaluated for radiochemical purity and protein binding, exhibiting quantitative ⁶⁸Ga-labeling yields with high radiochemical purity and stability in human serum as well as low protein binding. <em>In vitro</em> uptake assays in AFU and AFU mutants lacking SITs were performed as well as MIC assays for assessment of antifungal activity in comparison to DFO and carboplatin alone. Complexes were also evaluated in <em>in vivo</em> assays including stability studies in healthy mice as well as biodistribution studies and PET imaging in a rat pulmonary aspergillosis model, revealing favourable pharmacokinetics with rapid distribution and a renal excretion pattern with pronounced accumulation in AFU infected lung tissue. However, rapid metabolism of the complexes was observed already 5 min p.i. in serum and urine samples. Overall, this study demonstrates the potential of carboplatin-based Pt(IV)-DFO conjugates for application in infection theranostics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118216"},"PeriodicalIF":5.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153768","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 and validation of LAGi-DEL: A nanomolar LAG-3 inhibitor that reverses immune suppression in tumor-immune co-culture models","authors":"Hossam Nada ,&nbsp;Laura Calvo-Barreiro ,&nbsp;Somaya A. Abdel-Rahman ,&nbsp;Moustafa T. Gabr","doi":"10.1016/j.ejmech.2025.118204","DOIUrl":"10.1016/j.ejmech.2025.118204","url":null,"abstract":"<div><div>Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor that drives T cell exhaustion and tumor immune evasion. While antibody-based LAG-3 inhibitors have entered clinical practice, their poor tumor penetration, high manufacturing costs, and prolonged half-lives limit dosing flexibility and can lead to extended immune-related toxicities. Potent small molecule LAG-3 inhibitors remain elusive, leaving a major gap in the immuno-oncology landscape. Here, we report the discovery of <strong>LAGi-DEL</strong>, the first nanomolar small molecule LAG-3 inhibitor, identified through screening a 4.2-billion compound DNA-encoded chemical library (DEL). <strong>LAGi-DEL</strong> binds directly to LAG-3 with a <em>K</em>_d of 97 nM (SPR) and 271 nM (MST) and disrupts the LAG-3/MHC-II interaction with an EC₅₀ of 138 nM, the highest potency reported for a small molecule against LAG-3. Molecular docking and dynamics simulations reveal that <strong>LAGi-DEL</strong> induces stabilizing conformational changes within the LAG-3 binding pocket. Functionally, <strong>LAGi-DEL</strong> restores T cell activation, elevates IFN-γ secretion, and promotes immune-mediated killing in acute myeloid leukemia and lung cancer co-culture models, matching the efficacy of the FDA-approved antibody relatlimab. Pharmacokinetic profiling shows favorable drug-like properties, including high solubility, acceptable permeability, robust metabolic and plasma stability, low cytotoxicity toward normal cells, and negligible hERG and CYP liabilities. These attributes, combined with broad functional activity and unprecedented potency, position <strong>LAGi-DEL</strong> as a promising scaffold for developing orally available LAG-3 inhibitors and as a blueprint for next-generation immune checkpoint therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118204"},"PeriodicalIF":5.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153767","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":"Development of 2,6,9-trisubstituted purines as neuroprotective agents targeting butyrylcholinesterase and cannabinoid CB2 receptor","authors":"Helena Kordinová ,&nbsp;Václav Mik ,&nbsp;Noemi Hemelíková ,&nbsp;Gabriel Gonzalez ,&nbsp;Šárka Štěpánková ,&nbsp;Veronika Górová ,&nbsp;Václav Bazgier ,&nbsp;Miroslav Kvasnica","doi":"10.1016/j.ejmech.2025.118217","DOIUrl":"10.1016/j.ejmech.2025.118217","url":null,"abstract":"<div><div>Neurodegenerative diseases (ND) are a diverse group of disorders characterized by the progressive loss of neurons, leading to severe cognitive and physical impairments. Parkinson's, Alzheimer's, and Huntington's diseases are among the most prominent examples, with their prevalence steadily increasing due to the aging global population. In 2009, approximately 50 million people worldwide were affected by ND, and current projections suggest this number will exceed 115 million by 2050. The development of ND is complex and multifactorial, influenced by genetic predispositions, environmental factors, aging, and cellular dysfunction. A significant challenge in addressing these diseases lies in the absence of curative treatments; existing therapies are limited to symptom management and enhancing quality of life.</div><div>We report the synthesis and biological evaluation of a series of 2,6,9-trisubstituted purine derivatives, some of which exhibited strong neuroprotective effects in cellular models of mitochondrial (3-nitropropionic acid-induced) and oxidative (glutamate-induced) stress. Also, several compounds functioned as selective butyrylcholinesterase (BChE) inhibitors and three of which showed CB2 receptor agonist activity, supporting their potential as multifunctional agents for neurodegenerative disorders. <em>In vitro</em> assays confirmed their protective effects across multiple cellular pathways, including reduction of apoptosis, oxidative stress, and mitochondrial permeability transition. Notably, compound <strong>3e</strong> emerged as the most effective derivative, combining strong BChE inhibition, CB2 receptor activation, and cytoprotective effects. These findings identify 2,6,9-trisubstituted purines as promising scaffolds for the development of multi-target-directed ligands in neurodegenerative disease therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118217"},"PeriodicalIF":5.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153766","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}