European Journal of Medicinal Chemistry最新文献

{"title":"Novel steroidal β-carboline derivatives as promising antibacterial candidates against methicillin-resistant Staphylococcus aureus","authors":"Haibo Huo ,&nbsp;Wenjia Dan ,&nbsp;Libo Qin ,&nbsp;Jiaxue Bo ,&nbsp;Xiaonan Zhang ,&nbsp;Chaofu Yang ,&nbsp;Bianxia Bai ,&nbsp;Jiahong Ren ,&nbsp;Baojun Shi ,&nbsp;Jian Li","doi":"10.1016/j.ejmech.2024.117187","DOIUrl":"10.1016/j.ejmech.2024.117187","url":null,"abstract":"<div><div>A novel series of steroidal <em>β</em>-carboline quaternary ammonium derivatives (SCQADs) derived from natural cholic acid and its derivatives was designed, synthesized and biologically evaluated against four Gram-positive bacteria for the first time. Most of these derivatives exhibited promising antibacterial activity against the tested strains, particularly, compound <strong>21g</strong> displayed strong antibacterial activity against MRSA (MIC = 0.5–1 μg/mL) with low cytotoxicity. Meanwhile, derivative <strong>21g</strong> was able to quickly kill Gram-positive bacteria within 0.5 h without inducing bacterial resistance. Preliminary mechanistic explorations indicated that compound <strong>21g</strong> destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, <strong>21g</strong> exhibited high in <em>vivo</em> efficacy and high survival protection in a mouse skin abscess model. These findings suggested that compound <strong>21g</strong> has great potential to develop as an antibacterial agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117187"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849020","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":"Synthetic approaches and clinical applications of representative HDAC inhibitors for cancer therapy: A review","authors":"Zhengming Lv ,&nbsp;Tianyi Ji ,&nbsp;Jie Liu,&nbsp;Xu Sun,&nbsp;Huimin Liang","doi":"10.1016/j.ejmech.2024.117185","DOIUrl":"10.1016/j.ejmech.2024.117185","url":null,"abstract":"<div><div>Histone deacetylase (HDAC) inhibitors are a promising class of epigenetic modulators in cancer therapy. This review provides a comprehensive analysis of recent synthetic strategies and clinical applications of key HDAC inhibitors for oncology. HDACs play a critical role in modulating chromatin structure and gene expression by removing acetyl groups from histone proteins, leading to transcriptional repression of tumor suppressor genes. By inhibiting HDAC activity, HDAC inhibitors restore normal acetylation patterns, reactivating silenced tumor suppressor genes and inducing cell cycle arrest, apoptosis, and autophagy in cancer cells. The review explores synthetic approaches to developing representative HDAC inhibitors that have been approved or in various clinical trials. Through an integrated perspective on the synthesis, mechanism of action, and clinical advancements of HDAC inhibitors, this review aims to guide future research toward next-generation HDAC inhibitors that could enhance cancer treatment efficacy while minimizing toxicity, offering insights for chemists and clinicians in the field of oncology.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117185"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Antibacterial and antifungal pyrazoles based on different construction strategies” [Euro. J. Med. Chem. 282 (2025) 117081]","authors":"Muneeb Ur Rehman ,&nbsp;Fang He ,&nbsp;Xi Shu,&nbsp;Ju Guo,&nbsp;Ziwei Liu,&nbsp;Shuang Cao,&nbsp;Sihui Long","doi":"10.1016/j.ejmech.2024.117147","DOIUrl":"10.1016/j.ejmech.2024.117147","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117147"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797410","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":"Impact of natural compounds on peroxisome proliferator-activated receptor: Molecular effects and its importance as a novel therapeutic target for neurological disorders","authors":"Zhe Zhu ,&nbsp;Yadi Guan ,&nbsp;Songlan Gao ,&nbsp;Feng Guo ,&nbsp;Dong Liu ,&nbsp;Honglei Zhang","doi":"10.1016/j.ejmech.2024.117170","DOIUrl":"10.1016/j.ejmech.2024.117170","url":null,"abstract":"<div><div>Neurological disorders refer to the pathological changes of the nervous system involving multiple pathological mechanisms characterized by complex pathogenesis and poor prognosis. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor that is a member of the nuclear receptor superfamily. PPAR has attracted considerable attention in the past decades as one of the potential targets for the treatment of neurological disorders. Several <em>in vivo</em> and <em>in vitro</em> studies have confirmed that PPARs play a neuroprotective role by regulating multiple pathological mechanisms. Several selective PPAR ligands, such as thiazolidinediones and fibrates, have been approved as pharmacological agonists. Nevertheless, PPAR agonists cause a variety of adverse effects. Some natural PPAR agonists, including wogonin, bergenin, jujuboside A, asperosaponin VI, monascin, and magnolol, have been introduced as safe agonists, as evidenced by clinical or preclinical experiments. This review summarizes the effects of phytochemicals on PPAR receptors in treating various neurological disorders. Further, it summarizes recent advances in phytochemicals as potential, safe, and promising PPAR agonists to provide insights into understanding the PPAR-dependent and independent cascades mediated by phytochemicals. The phytochemicals exhibited potential for treating neurological disorders by inhibiting neuroinflammation, exerting anti-oxidative stress and anti-apoptotic activities, promoting autophagy, preventing demyelination, and reducing brain edema and neurotoxicity. This review presents data that will help clarify the potential mechanisms by which phytochemicals act as pharmacological agonists of PPARs in the treatment of neurological disorders. It also provides insights into developing new drugs, highlighting phytochemicals as potential, safe, and promising PPAR agonists. Additionally, this review aims to enhance understanding of both PPAR-dependent and independent pathways mediated by phytochemicals.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117170"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816077","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 dual V1a/V2 antagonists containing triazolobenzazepine scaffold","authors":"Gábor Varró,&nbsp;Éva Bozó,&nbsp;Krisztina Vukics,&nbsp;Ferenc Baska,&nbsp;Gábor Szántó,&nbsp;Balázs Krámos,&nbsp;Katalin Domány-Kovács,&nbsp;Krisztina Szondiné Kordás,&nbsp;Mónika Vastag,&nbsp;Ildikó Magdó,&nbsp;Imre Bata","doi":"10.1016/j.ejmech.2024.117069","DOIUrl":"10.1016/j.ejmech.2024.117069","url":null,"abstract":"<div><div>The development of a dual V1a/V2 antagonist compound is a complex and challenging task. Conivaptan is up to now the only known V1a/V2 antagonist which was approved for the treatment of euvolemic hyponatremia. Previously, we reported <strong>RGH-122</strong>, a novel selective V1a antagonist compound. Herein, we describe several promising dual antagonist compounds, which are derived from <strong>RGH-122</strong> by using modifications in its tail region. These modifications can result in excellent binding affinity on both V1a and V2 receptors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117069"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735841","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":"Tyrosine kinase 2 inhibitors: Synthesis and applications in the treatment of autoimmune diseases","authors":"Lin Pan ,&nbsp;Juan Xu ,&nbsp;Hongming Xie ,&nbsp;Yingjun Zhang ,&nbsp;Huanfeng Jiang ,&nbsp;Yongqi Yao ,&nbsp;Wanqing Wu","doi":"10.1016/j.ejmech.2024.117114","DOIUrl":"10.1016/j.ejmech.2024.117114","url":null,"abstract":"<div><div>Janus kinase (JAK), a class of non-receptor tyrosine kinases, are essential in modulating the cytokine signaling cascade of cytokines associated with immune responses. Despite their potential in the treatment of autoimmune diseases, JAK inhibitors are associated with safety concerns, regarding cytokine suppression and significant side effects. Tyrosine kinase 2 (TYK2), a prominent member of the JAK family, is central to the signaling of interleukins (ILs) and interferons (IFNs), such as IL-12, IL-23 and IFNs. Targeted TYK2 inhibitors that specifically target the Janus Homology 1 (JH1) and pseudokinase (JH2) domains show enhanced specificity. JH1 acts as an ATP-competitive inhibitor, while JH2 acts as an allosteric regulator, contributing to reduced systemic side effects and improved therapeutic outcomes in clinical settings. This review summarizes the recent advances on the synthetic strategies of TYK2 inhibitors and their applications in the treatment of autoimmune diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117114"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756373","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 evaluations of 5-aryl-pyrazole-3-carboxamide derivatives as selective CB2 receptor agonists for the treatment of colitis","authors":"Bei-Er Jiang ,&nbsp;Ying He ,&nbsp;Jie Chen ,&nbsp;Xing-Wu Jiang ,&nbsp;Zi-Liang Qiu ,&nbsp;Qiu-Wen Liang ,&nbsp;Xin-Long Gao ,&nbsp;Han-Kun Zhang ,&nbsp;Hai-Gang Tian ,&nbsp;Ming-Yao Liu ,&nbsp;Wei-Qiang Lu ,&nbsp;Li-Fang Yu","doi":"10.1016/j.ejmech.2024.117117","DOIUrl":"10.1016/j.ejmech.2024.117117","url":null,"abstract":"<div><div>Synthetic CB2 receptor agonists exhibit great potential in the treatment of neurodegenerative diseases, chronic and neuropathic pain, cancer, and inflammation-associated pathologies while avoiding adverse psychoactive effects caused by interactions with CB1 receptors. Herein, a class of 5-aryl-pyrazole-3-carboxamide derivatives was thus designed, synthesized, and biologically evaluated. Among the compounds tested, compound <strong>33</strong>, one of the most potent leads, showed a remarkably high potency and selectivity at the CB2 receptor (EC_{50, CB2} = 16.2 nM, EC_{50, CB1} &gt; 10⁵ nM). Furthermore, <strong>33</strong> treatment significantly attenuate colon inflammation in a dextran sodium sulfate (DSS)-induced mouse model of colitis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating colitis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117117"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760026","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":"High potency 3-carboxy-2-methylbenzofuran pendrin inhibitors as novel diuretics","authors":"Riya J. Master ,&nbsp;Joy Karmakar ,&nbsp;Peter M. Haggie ,&nbsp;Joseph Anthony-Tan ,&nbsp;Tifany Chu ,&nbsp;Alan S. Verkman ,&nbsp;Marc O. Anderson ,&nbsp;Onur Cil","doi":"10.1016/j.ejmech.2024.117133","DOIUrl":"10.1016/j.ejmech.2024.117133","url":null,"abstract":"<div><div>Pendrin (SLC26A4) is an anion exchanger expressed in epithelial cells of kidney and lung. Pendrin inhibition is a potential treatment approach for edema, hypertension and inflammatory lung diseases. We have previously identified first-in-class pendrin inhibitors by high-throughput screening, albeit with low potency for pendrin inhibition (IC₅₀ ∼10 μM). Here, we performed a de novo small molecule screen with follow-on structure-activity studies to identify more potent pendrin inhibitors. Screening of 50,000 synthetic small molecules identified four novel classes of pendrin inhibitors with diverse scaffolds, including 5-benzyloxy-2-methylbenzofurans, N-aryl urea substituted 5-methyltryptamines, N-aryl urea substituted anthranilic acids, and substituted N-benzyl 3-carboxyindoles. The most potent inhibitor from the initial screen, a 3-carboxy-2-methylbenzofuran (<strong>1a</strong>), had IC₅₀ of 4.1 μM. Structure-activity studies using 732 benzofuran analogs identified <strong>1d</strong> with IC₅₀ ∼ 0.5 μM for pendrin inhibition. Selectivity studies showed that <strong>1d</strong> has minimal or no activity against related ion channels/transporters including SLC26A3, SLC26A6 and CFTR at high concentrations. <strong>1d</strong> administration to mice at 10 mg/kg had no effect on urine volume when used alone, but potentiated the diuretic effect of furosemide by 45 %. In conclusion, we have identified novel pendrin inhibitors with greatly improved potency and good in vivo efficacy. These compounds can be used as pharmacological tools to study the roles of pendrin, and potentially developed as drug candidates for edema, hypertension and lung diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117133"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760787","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":"Expanding the therapeutic window of gramicidin S towards a safe and effective systemic treatment of methicillin-resistant S. aureus infections","authors":"Yifei Wang ,&nbsp;John T. Kalyvas ,&nbsp;Jack D. Evans ,&nbsp;Luis Toronjo-Urquiza ,&nbsp;John R. Horsley ,&nbsp;Andrew D. Abell","doi":"10.1016/j.ejmech.2024.117128","DOIUrl":"10.1016/j.ejmech.2024.117128","url":null,"abstract":"<div><div>The rise of multidrug-resistant bacteria, such as Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), necessitates the development of new antibacterial therapies. Antimicrobial peptides offer a promising alternative to conventional antibiotics due to their unique mechanisms of action. Gramicidin S exhibits potent bactericidal activity against <em>S. aureus</em>, however, high haemolytic toxicity currently limits its application to topical use. A new series of gramicidin S analogues is presented with rational modifications to the β-turn and β-strand regions, to reduce haemolytic and nephrotoxic effects, while preserving antibacterial potency. The minimum inhibitory concentration (MIC) for each analogue was determined against benchmark methicillin-sensitive <em>S. aureus</em> (MSSA) and MRSA clinical isolates, with toxicity characterised <em>in vitro</em> using human red blood cells and human embryonic kidney cells (HEK-293). Peptide <strong>12</strong> demonstrated a significant two-fold increase in antibacterial activity against both MSSA and MRSA (MIC: 2 μg/mL) compared to gramicidin S (MIC: 4 μg/mL), albeit with increased cytotoxicity. Similarly, peptide <strong>15</strong> showed exceptional efficacy (MIC: 3 μg/mL), but with reduced cytotoxicity, culminating in a two-fold improvement to the therapeutic index (TI) of gramicidin S. Peptides <strong>14</strong> (HC₅₀: 50.48 ± 1.15 μg/mL, IC₅₀: 38.09 μg/mL) and <strong>16</strong> (HC₅₀: 84.09 ± 1.02 μg/mL, IC₅₀: 12.60 μg/mL) also significantly reduced haemolytic toxicity and nephrotoxicity, compared to gramicidin S (HC₅₀: 12.34 ± 0.27 μg/mL, IC₅₀: 6.45 μg/mL). Detailed NMR, CD and computational modelling were used to provide critical insights into how molecular conformation influences both antibacterial potency and cytotoxicity. Collectively, these results expand the therapeutic window of gramicidin S by up to 12-fold, with negligible cytotoxicity observed at concentrations well beyond the acceptable safety threshold, which indicates the potential for safe systemic administration in the treatment of infection caused by resistant pathogens.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117128"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gold(I) complexes bearing EGFR-inhibiting ligands as anti-HCC agents through dual targeting of EGFR and TrxR","authors":"Yawen Wang ,&nbsp;Xiaoyan Ma ,&nbsp;Xuejie Chen ,&nbsp;Zhenfan Wen ,&nbsp;Chunyang Bi ,&nbsp;Zhongren Xu ,&nbsp;Wukun Liu","doi":"10.1016/j.ejmech.2024.117137","DOIUrl":"10.1016/j.ejmech.2024.117137","url":null,"abstract":"<div><div>Overexpression of epidermal growth factor receptor (EGFR) and thioredoxin reductase (TrxR) are commonly associated with an adverse prognosis in hepatocellular carcinoma (HCC). This makes them key targets for the treatment of HCC. Studies have shown that the clinical efficacy of the EGFR tyrosine kinase inhibitor gefitinib alone in treating HCC is limited. Herein, we developed a series of novel gold(I) complexes using a “dual-targeting strategy” by combining gold(I) complexes with different gefitinib derivatives. Among them, the best complex <strong>6g</strong> exhibits significant antiproliferative activity against Huh7 cells and Huh7R (lenvatinib-resistant) cells. Remarkably, complex <strong>6g</strong> inhibits the expression of phosphorylated EGFR while also effectively inhibiting intracellular TrxR activity. In addition, complex <strong>6g</strong> causes a significant increase in the accumulation of reactive oxygen species (ROS), disrupts mitochondrial membrane potential (MMP), arrests the cell cycle in the G0/G1 phase, and induces apoptosis. Collectively, our findings demonstrate that complex <strong>6g</strong> exhibits potential anti-HCC effects via dual-targeting of EGFR and TrxR.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"283 ","pages":"Article 117137"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763532","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}