European Journal of Medicinal Chemistry最新文献

{"title":"Antiviral strategies based on targeted protein degradation: An overview of the literature and future outlook","authors":"Fan Zhou ,&nbsp;Dazhou Shi ,&nbsp;Baohu Li ,&nbsp;Mei Wang ,&nbsp;Shujing Xu ,&nbsp;Jinfei Yang ,&nbsp;Xu Deng ,&nbsp;Peng Zhan","doi":"10.1016/j.ejmech.2025.118208","DOIUrl":"10.1016/j.ejmech.2025.118208","url":null,"abstract":"<div><div>Viral infections persist as global threats, with traditional therapies limited by resistance and narrow targets. This review highlights targeted protein degradation (TPD) as a transformative antiviral strategy, covering proteolysis-targeting chimeras (PROTACs), hydrophobic tagging (HyT), and lysosome-targeting chimeras (LYTACs) against Influenza A virus (IAV), Human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and Hepatitis C virus (HCV). TPD's “event-driven” mechanism degrades “undruggable” viral/host proteins (e.g., PA, HDAC6) to bypass resistance. Key breakthroughs include PROTAC vaccines (10⁶-fold titer reduction) and liver-targeted degraders. It addresses pharmacokinetic/off-target challenges, proposing multi-target strategies and organ-specific delivery to redefine antiviral therapy from passive control to active eradication.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118208"},"PeriodicalIF":5.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188339","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":"Breaking barriers: Medicinal chemistry strategies and advanced in-silico approaches for overcoming the BBB and enhancing CNS penetration","authors":"Eneye D. Ajayi ,&nbsp;Mahmoud Elazazy ,&nbsp;Khaled Abouzid ,&nbsp;Hamed I. Ali","doi":"10.1016/j.ejmech.2025.118219","DOIUrl":"10.1016/j.ejmech.2025.118219","url":null,"abstract":"<div><div>Delivering small molecules to the brain and central nervous system (CNS) is greatly hindered by the restrictive blood-brain barrier (BBB), which selectively permits essential molecules while excluding toxic molecules. This selective permeability feature of the membrane also poses a challenge in delivering small molecules to the brain intended for therapeutic benefits. Pharmaceutical approaches such as designing a prodrug, conjugating with liposomes/immunoliposomes, and formulating as nanoparticles have been employed to increase BBB penetration. Despite these efforts, the challenge of suboptimal concentration reaching the brain persists. Modifying small molecules in the early stages of drug discovery is a promising strategy for designing drugs that can penetrate the BBB. To achieve this, it is essential to fine-tune physicochemical parameters to enhance permeability while carefully avoiding toxicity. In this review, we elucidate the most recent strategies for optimizing small molecules by adjusting molecular weight, lipophilicity, pKa, number of hydrogen bond donors, number of rotatable bonds, topological polar surface area, and the ratio of drug concentration in the brain to that in the blood (LogBB). This review will enable researchers to rapidly adopt a framework to overcome BBB challenges in CNS drug discovery by integrating empirical and computational strategies. The insights presented here aim to empower researchers to develop effective BBB-penetrable small molecules, advancing CNS therapeutics and improving the treatment of neurological disorders and brain metastasis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118219"},"PeriodicalIF":5.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195434","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":"Disarming superbugs: New frontiers in inhibiting NDM-1 and other clinically relevant metallo-β-lactamases","authors":"Pulkit Dhiman ,&nbsp;Amit Patwa ,&nbsp;Arya B. Narayanan ,&nbsp;Aayushi Saini ,&nbsp;Ankita Pundir ,&nbsp;Manoj D. Dhole ,&nbsp;Vinod D. Chaudhari","doi":"10.1016/j.ejmech.2025.118220","DOIUrl":"10.1016/j.ejmech.2025.118220","url":null,"abstract":"<div><div>The emergence and global spread of Metallo-β-lactamases (MBLs), particularly New Delhi Metallo-β-lactamase (NDM), Verona Integron-encoded Metallo-β-lactamase (VIM), and Imipenemase (IMP), pose a significant threat to the efficacy of β-lactam antibiotics, including carbapenems, often regarded as the last line of defence against multidrug-resistant bacterial infections. This review comprehensively analyzes recent advances in the development of MBL inhibitors (MBLIs), targeting NDM, VIM, and IMP enzymes with a special focus on NDM-1. The inhibitors are categorized based on key functional groups responsible for their activity, offering insight into the structure activity relationships (SAR) that govern their potency and selectivity. We highlight representative compounds with potent inhibition data (IC₅₀/K_i values), supported by molecular docking studies and where available co-crystal structures with target MBLs to elucidate their binding interactions. Synthetic approaches for these inhibitors are also discussed. This review aims to provide a detailed, functionally organized framework for ongoing efforts in designing potent, broad-spectrum MBL inhibitors capable of restoring the utility of β-lactam antibiotics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118220"},"PeriodicalIF":5.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183044","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":"Lipophilic integrated bioorthogonal self-catalyzed nitric oxide donor–platinum(IV) prodrugs for enhanced antitumor efficacy against esophageal cancer","authors":"Ziyu Qian ,&nbsp;Xun Yuan ,&nbsp;Qing Zhao ,&nbsp;Chi Zhang ,&nbsp;Jia Shao ,&nbsp;Lin Wang ,&nbsp;Haoyang Tang ,&nbsp;Zirui Su ,&nbsp;Mengshuang Huang ,&nbsp;Jiayi Xue ,&nbsp;Chen Zhang ,&nbsp;Huiqin Chen ,&nbsp;Ummatjon Gayrat Ugli Mustafaev ,&nbsp;Ziqi Pan ,&nbsp;Hui Ye ,&nbsp;Yihua Zhang ,&nbsp;Zhangjian Huang ,&nbsp;Shan Yang ,&nbsp;Jianbing Wu","doi":"10.1016/j.ejmech.2025.118221","DOIUrl":"10.1016/j.ejmech.2025.118221","url":null,"abstract":"<div><div>Esophageal cancer (EC) represents a globally prevalent malignancy with limited validated therapeutic targets, for which the cisplatin (CDDP)/5-fluorouracil (5-FU) combination remains the standard chemotherapy backbone. Nitric oxide (NO) and platinum(IV) complexes have attracted significant research interest in antitumor therapy. Previously designed integrated prodrugs suffered from poor cellular uptake. Herein, we reported the design, synthesis, and biological evaluation of a series of novel lipophilic integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs, in which cytoplasmic reductants catalyze the release of Pt(Ⅱ) and NO to produce synergistic antitumor effects in cancer cells. <em>In vitro</em> biological studies revealed that <strong>10k</strong> exhibited 1.3- to 4.4-fold lower IC₅₀ values than CDDP against esophageal cancer cell lines, correlating with significantly enhanced lipophilicity. The lipophilic modification at the axial position of complex <strong>10k</strong> significantly enhanced cellular Pt accumulation and DNA platination in KYSE-520 cells by 10.4- and 4.7-fold, respectively, compared to CDDP. The preferred complex <strong>10k</strong> demonstrated favorable stability and pharmacokinetic properties. Compared with CDDP, <strong>10k</strong> exhibited potent <em>in vivo</em> anti-esophageal cancer effects (71.1% tumor growth inhibition (TGI) against the KYSE-520 xenograft model) as well as inhibited lung metastasis, without significant systemic toxicity. Overall, the integrated prodrug <strong>10k</strong> represents a promising candidate for EC treatment and deserves further in-depth studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118221"},"PeriodicalIF":5.9,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182985","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":"Rational design of next-generation FLT3 inhibitors in acute myeloid leukemia: From laboratory to clinics","authors":"Shan Gao ,&nbsp;Xueting Wang ,&nbsp;Xiang Zhao ,&nbsp;Zhennan Xiao","doi":"10.1016/j.ejmech.2025.118214","DOIUrl":"10.1016/j.ejmech.2025.118214","url":null,"abstract":"<div><div>Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are among the most common genetic alterations in acute myeloid leukemia (AML), affecting approximately 30 % of patients and leading to a poor prognosis. The development of FLT3-targeted inhibitors has achieved significant progress. First-generation multi-kinase inhibitors like midostaurin and second-generation agents such as gilteritinib and quizartinib have shown success. However, drug resistance, often due to D835Y and F691L gatekeeper mutations, remains a major challenge. In response, a new generation of FLT3 inhibitors (FLT3i) have been designed to simultaneously target both FLT3 internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations. This review examines the mechanisms of FLT3 in the regulation of AML and examines preclinical research on novel FLT3i over the past five years. It discusses how these agents, including small-molecule like STI-8591, compounds <strong>36</strong> and <strong>80</strong> and novel therapeutic strategies such as CLN-049, and SENTI-202, are designed to combat resistance. The goal is to provide a medicinal chemistry perspective to provide insights for the design of novel small-molecule FLT3i.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118214"},"PeriodicalIF":5.9,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183370","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 potent indazole-based FXR agonists via scaffold hopping for MASH treatment","authors":"Da-Yu Shi ,&nbsp;Xin-Wei Shi ,&nbsp;Hang Shi ,&nbsp;Jing Yu ,&nbsp;Qing-Hua Li ,&nbsp;Ping Tian ,&nbsp;Cheng Huang ,&nbsp;Dingding Gao","doi":"10.1016/j.ejmech.2025.118203","DOIUrl":"10.1016/j.ejmech.2025.118203","url":null,"abstract":"<div><div>The farnesoid X receptor (FXR) plays a crucial role in regulating bile acid homeostasis, inflammation, fibrosis, as well as glucose and lipid metabolism, positioning it as a promising target for the treatment of Metabolic Associated Steatohepatitis (MASH). <strong>LMB763</strong> (<strong>Nidufexor)</strong>, a clinical-stage FXR agonist developed by Novartis, has demonstrated efficacy in alleviating hepatic steatosis, inflammation, and fibrosis in preclinical MASH models. Using <strong>LMB763</strong> as a lead compound, a series of novel compounds were designed and synthesized via a scaffold hopping strategy. The lead compound <strong>E2</strong> exhibited potent FXR agonist activity with an EC₅₀ value of 0.097 ± 0.009 μM and favorable hepatic microsomal metabolic stability. Additionally, compound <strong>E2</strong> displayed good selectivity against related nuclear receptors, including LXRα/β, PPARα/γ/<em>δ</em>, PXR, and TGR5. <em>In vivo</em> evaluation confirmed that compound <strong>E2</strong> improved hepatic steatosis in high-fat diet (HFD)-induced MASH mouse model. These findings highlight <strong>E2</strong> as a promising candidate for further development and provide valuable insights into the design of selective FXR agonists for MASH treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118203"},"PeriodicalIF":5.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153925","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":"In silico discovery and mechanistic profiling of STING agonists engaging the transmembrane domain","authors":"Ahmad Junaid ,&nbsp;Uddav Pandey ,&nbsp;Janine Ward ,&nbsp;Nilesh Meghani ,&nbsp;Shannon Miller ,&nbsp;Austin Negron ,&nbsp;Kendal Ryter ,&nbsp;David Burkhart ,&nbsp;Nobuyu Mizuno ,&nbsp;Victor R. DeFilippis ,&nbsp;Omer Rasheed","doi":"10.1016/j.ejmech.2025.118201","DOIUrl":"10.1016/j.ejmech.2025.118201","url":null,"abstract":"<div><div>Stimulator of interferon genes (STING) is an ER resident cytosolic pattern recognition receptor involved in innate immune signaling and is a promising therapeutic target in immuno-oncology and vaccine adjuvant design. While canonical STING agonists typically activate the receptor via direct engagement with the cytosolic cyclic dinucleotide (CDN)-binding domain (CBD), recent high-resolution structural studies have uncovered a distinct allosteric binding site within the transmembrane domain (TMD). Here, we report the identification and characterization of a novel STING agonist, compound <strong>7k</strong>, which uniquely engages the TMD rather than the cytosolic domain. Through comparative molecular docking and binding site validation, the TMD of STING was computationally identified as the preferential site of engagement, diverging from the classical CBD. This mode of activation is functionally significant, as it leads to a demonstrably distinct set of downstream molecular phenotypes. Furthermore, our study led to the discovery of structurally related series of potent, small-molecule human STING activators with potential utility as immunomodulatory therapeutics. A lead compound, <strong>7k</strong>, emerged with potent STING-dependent activity <em>in vitro</em> and displayed adjuvant efficacy <em>in vivo</em>, as shown by enhanced antigen-specific IgG production and Th1/Th2 cytokine responses in a genetically humanized STING mouse model. These findings support the TMD as a druggable allosteric site and highlight <strong>7k</strong> as a promising candidate for next-generation STING-targeted immunotherapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118201"},"PeriodicalIF":5.9,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153761","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":"Design, synthesis, and biological profiling of novel aryl-spirocyclic diamine derivatives with potential antidepressant-like properties","authors":"Jiefang Zheng ,&nbsp;Yaxin Tian ,&nbsp;Jiaxin Cheng ,&nbsp;Zhengtao Hu ,&nbsp;Junchi Zhang ,&nbsp;Feipu Yang ,&nbsp;Pengcheng Li ,&nbsp;Zhijuan Jiang ,&nbsp;Xudong Gong ,&nbsp;Qiongqiong Hou ,&nbsp;Guan Wang ,&nbsp;Vivien Shen ,&nbsp;Tianwen Hu ,&nbsp;Zhijian Xu ,&nbsp;Guanghui Tian ,&nbsp;Weiliang Zhu ,&nbsp;Yang He ,&nbsp;Jingshan Shen","doi":"10.1016/j.ejmech.2025.118198","DOIUrl":"10.1016/j.ejmech.2025.118198","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118198"},"PeriodicalIF":5.9,"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}