Pub Date : 2026-03-18DOI: 10.1016/j.ejmech.2026.118785
Peixian Chen, Rui Wang, Ting Zhou, Yi Sun, Frank Kirchhoff, Zhenyuan Miao, Chunlin Zhuang
Alzheimer's disease (AD) is the leading cause of dementia worldwide, with no disease-modifying treatments to halt or reverse progressive neurodegeneration. Chronic neuroinflammation is a core unresolved pathological driver of AD, and signal transducer and activator of transcription 3 (STAT3) has emerged as a critical yet controversial master mediator of the associated neuroinflammatory and neurodegenerative processes. This review systematically explores the multifaceted, cell-type-specific relationship between STAT3 signaling and AD pathology, focusing on its roles in neuroinflammation, amyloid precursor protein processing, tau phosphorylation, neuronal survival, and synaptic function. We further critically evaluate therapeutic strategies targeting STAT3 pathways in AD, underscoring the immediate relevance of STAT3 as both a promising biomarker and a tractable target for translational drug development.
{"title":"Targeting STAT3 in Alzheimer's Disease: Potential Mechanisms and Therapeutic Implications","authors":"Peixian Chen, Rui Wang, Ting Zhou, Yi Sun, Frank Kirchhoff, Zhenyuan Miao, Chunlin Zhuang","doi":"10.1016/j.ejmech.2026.118785","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118785","url":null,"abstract":"Alzheimer's disease (AD) is the leading cause of dementia worldwide, with no disease-modifying treatments to halt or reverse progressive neurodegeneration. Chronic neuroinflammation is a core unresolved pathological driver of AD, and signal transducer and activator of transcription 3 (STAT3) has emerged as a critical yet controversial master mediator of the associated neuroinflammatory and neurodegenerative processes. This review systematically explores the multifaceted, cell-type-specific relationship between STAT3 signaling and AD pathology, focusing on its roles in neuroinflammation, amyloid precursor protein processing, tau phosphorylation, neuronal survival, and synaptic function. We further critically evaluate therapeutic strategies targeting STAT3 pathways in AD, underscoring the immediate relevance of STAT3 as both a promising biomarker and a tractable target for translational drug development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"69 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478585","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}
Pub Date : 2026-03-18DOI: 10.1016/j.ejmech.2026.118788
Shihui Mao, Tao Lei, Fangrong Shi, Jieyu Xu, Weihao Zhuang, Jialiang Lu, Xiaowu Dong, Haiyan Yang
Pyroptosis, a lytic and pro-inflammatory form of programmed cell death executed by gasdermin (GSDM) family proteins through plasma membrane pore formation, represents a double-edged sword in cancer therapy. Initially distinguished from apoptosis and necrosis by its dependence on inflammatory caspases and inflammasome activation, pyroptosis is now understood to be fundamentally driven by the N-terminal fragments of cleaved GSDMs, which oligomerize to form cytotoxic pores. In cancer, pyroptosis induction exerts potent anti-tumor effects by directly eliminating malignant cells and stimulating immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that recruit and activate immune cells, thereby synergizing with immune checkpoint blockade. Key strategies to induce tumor pyroptosis include chemotherapy, targeted agents, engineered bispecific antibodies, innovative nanoplatforms delivering bioactive N-terminal domains of GSDMs or pyroptosis inducers, and specific natural compounds. However, this therapeutic potential is counterbalanced by significant challenges: constitutive GSDM expression in normal tissues underlies severe chemotherapy toxicity; chronic pyroptosis in hypoxic tumor cores promotes immunosuppressive necrosis and metastasis; and non-lytic functions of GSDM can suppress anti-tumor immunity. Furthermore, cancer cells evade pyroptosis through epigenetic silencing, alternative splicing generating dominant-negative isoforms, and ubiquitin-mediated degradation of GSDMs. Harnessing the anti-tumor potential of pyroptosis while circumventing its detrimental roles requires precise targeting strategies, leveraging biomarkers for patient stratification, and understanding context-dependent outcomes.
{"title":"The double-edged sword of pyroptosis targeting in cancer therapy","authors":"Shihui Mao, Tao Lei, Fangrong Shi, Jieyu Xu, Weihao Zhuang, Jialiang Lu, Xiaowu Dong, Haiyan Yang","doi":"10.1016/j.ejmech.2026.118788","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118788","url":null,"abstract":"Pyroptosis, a lytic and pro-inflammatory form of programmed cell death executed by gasdermin (GSDM) family proteins through plasma membrane pore formation, represents a double-edged sword in cancer therapy. Initially distinguished from apoptosis and necrosis by its dependence on inflammatory caspases and inflammasome activation, pyroptosis is now understood to be fundamentally driven by the N-terminal fragments of cleaved GSDMs, which oligomerize to form cytotoxic pores. In cancer, pyroptosis induction exerts potent anti-tumor effects by directly eliminating malignant cells and stimulating immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that recruit and activate immune cells, thereby synergizing with immune checkpoint blockade. Key strategies to induce tumor pyroptosis include chemotherapy, targeted agents, engineered bispecific antibodies, innovative nanoplatforms delivering bioactive N-terminal domains of GSDMs or pyroptosis inducers, and specific natural compounds. However, this therapeutic potential is counterbalanced by significant challenges: constitutive GSDM expression in normal tissues underlies severe chemotherapy toxicity; chronic pyroptosis in hypoxic tumor cores promotes immunosuppressive necrosis and metastasis; and non-lytic functions of GSDM can suppress anti-tumor immunity. Furthermore, cancer cells evade pyroptosis through epigenetic silencing, alternative splicing generating dominant-negative isoforms, and ubiquitin-mediated degradation of GSDMs. Harnessing the anti-tumor potential of pyroptosis while circumventing its detrimental roles requires precise targeting strategies, leveraging biomarkers for patient stratification, and understanding context-dependent outcomes.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":"118788"},"PeriodicalIF":6.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496338","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}
Pub Date : 2026-03-18DOI: 10.1016/j.ejmech.2026.118780
Yong Huang, Li Mu, Yuanqing Qu, Yuan Liu
Tumor necrosis factor (TNF) is a multifunctional cytokine that plays a central role in inflammation and autoimmune diseases. While TNF-neutralizing biologics have transformed treatment paradigms, their limitations, including parenteral administration, high cost, and immunogenicity have driven intensive efforts to develop oral small-molecule inhibitors. This review provides a comprehensive overview of small-molecule TNF/TNFR inhibitors, focusing on three major design strategies: disruption of TNF trimer formation, allosteric stabilization of an asymmetric receptor-incompetent TNF conformation, and direct TNFR binding. We also present a quantitative comparative assessment of affinity versus toxicity across synthetic small molecules, cyclic peptides, and natural products. Critical translational considerations are evaluated, including pharmacokinetic optimization strategies for improving oral bioavailability and metabolic stability; the synergistic potential of combining small-molecule inhibitors with biologics; and systematic off-target analysis using proteomic platforms and cellular assays to predict safety liabilities. By integrating mechanistic insights with emerging translational data, this review provides a roadmap for developing next-generation TNF inhibitors with improved efficacy and safety profiles.
{"title":"Unlocking the potential of TNF: From biologic agents to small-molecule inhibitors","authors":"Yong Huang, Li Mu, Yuanqing Qu, Yuan Liu","doi":"10.1016/j.ejmech.2026.118780","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118780","url":null,"abstract":"Tumor necrosis factor (TNF) is a multifunctional cytokine that plays a central role in inflammation and autoimmune diseases. While TNF-neutralizing biologics have transformed treatment paradigms, their limitations, including parenteral administration, high cost, and immunogenicity have driven intensive efforts to develop oral small-molecule inhibitors. This review provides a comprehensive overview of small-molecule TNF/TNFR inhibitors, focusing on three major design strategies: disruption of TNF trimer formation, allosteric stabilization of an asymmetric receptor-incompetent TNF conformation, and direct TNFR binding. We also present a quantitative comparative assessment of affinity versus toxicity across synthetic small molecules, cyclic peptides, and natural products. Critical translational considerations are evaluated, including pharmacokinetic optimization strategies for improving oral bioavailability and metabolic stability; the synergistic potential of combining small-molecule inhibitors with biologics; and systematic off-target analysis using proteomic platforms and cellular assays to predict safety liabilities. By integrating mechanistic insights with emerging translational data, this review provides a roadmap for developing next-generation TNF inhibitors with improved efficacy and safety profiles.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"51 1","pages":"118780"},"PeriodicalIF":6.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496339","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}
Pub Date : 2026-03-18DOI: 10.1016/j.ejmech.2026.118742
Olivier Provot, Abdallah Hamze, Mouad Alami
Since the discovery in 1989 of combretastatin A-4 and its exceptional antitumor activities, many groups of medicinal chemists have studied the structure-activity relationships around this natural molecule. This critical review summarizes the most significant advances made by 12 leading groups of medicinal chemists in this field. We have organized this review by grouping the most relevant and cytotoxic molecules discovered by these teams, whose antitumor activities will be discussed. At the end of this article, we have selected the best modifications of CA-4 and some perspectives are proposed to potentially develop effective and well-tolerated drugs.
{"title":"Who's Who in the Field of Combretastatin A4 Analogues: ?Π","authors":"Olivier Provot, Abdallah Hamze, Mouad Alami","doi":"10.1016/j.ejmech.2026.118742","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118742","url":null,"abstract":"Since the discovery in 1989 of combretastatin A-4 and its exceptional antitumor activities, many groups of medicinal chemists have studied the structure-activity relationships around this natural molecule. This critical review summarizes the most significant advances made by 12 leading groups of medicinal chemists in this field. We have organized this review by grouping the most relevant and cytotoxic molecules discovered by these teams, whose antitumor activities will be discussed. At the end of this article, we have selected the best modifications of <strong>CA-4</strong> and some perspectives are proposed to potentially develop effective and well-tolerated drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478583","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}
Pub Date : 2026-03-17DOI: 10.1016/j.ejmech.2026.118784
Antonia D’Aniello, Veronica Folliero, Roberto Bello-Madruga, Vincenzo Mazzarella, Alessandra Del Bene, Federica Dell’Annunziata, Ilaria Cosimato, Flora Salzano, Ida De Chiara, Milena Della Gala, Roberto Cutolo, Martina Torino, Salvatore Mottola, Anna Messere, Lidia Muscariello, Sandro Cosconati, David Andreu, Marc Torrent Burgas, Gianluigi Franci, Salvatore Di Maro
Antimicrobial peptides (AMPs) show great therapeutic potential due to their unique mechanism of action that guarantees broad-spectrum efficacy and limits bacterial antibiotic resistance. However, challenges such as limited stability and cytotoxicity toward host cells still limit their clinical translation, highlighting the need for new approaches, such as size reduction and lipid conjugation, to enhance their efficacy, cell penetration, stability, and safety. Herein, we report the de novo design of a library of ultra-short lipopeptides based on a rigid l-Arg–l-Pro–l-Arg core, conceived to control conformational restriction and amphiphilic organization rather than mimicking longer natural AMPs. The compounds were synthesized and preliminarily evaluated in vitro against three gram-negative and three gram-positive strains. Systematic modulation of lipid positioning and linker orientation in this minimal scaffold led to the identification of promising candidates displaying MIC values in the low-μM range against both gram-negative and gram-positive bacteria. Of the newly developed compounds, 15 exhibited optimal lipophilicity, excellent human-serum stability and a favourable safety profile, showing only low to moderate toxicity toward renal, hepatic, and red blood cells. Additionally, 15 proved effective in reducing S. aureus biofilm formation and showed strong activity against five clinical isolates. It acts as a bacteriostatic agent by perturbing bacterial membrane integrity, positioning it as a promising starting point for the development of a new class of chemotypes that could offer an alternative strategy for treating infections caused by this gram-positive pathogen.
{"title":"Targeting Staphylococcus aureus with Potent De Novo-Designed Proline-Core Short Antimicrobial Lipopeptides","authors":"Antonia D’Aniello, Veronica Folliero, Roberto Bello-Madruga, Vincenzo Mazzarella, Alessandra Del Bene, Federica Dell’Annunziata, Ilaria Cosimato, Flora Salzano, Ida De Chiara, Milena Della Gala, Roberto Cutolo, Martina Torino, Salvatore Mottola, Anna Messere, Lidia Muscariello, Sandro Cosconati, David Andreu, Marc Torrent Burgas, Gianluigi Franci, Salvatore Di Maro","doi":"10.1016/j.ejmech.2026.118784","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118784","url":null,"abstract":"Antimicrobial peptides (AMPs) show great therapeutic potential due to their unique mechanism of action that guarantees broad-spectrum efficacy and limits bacterial antibiotic resistance. However, challenges such as limited stability and cytotoxicity toward host cells still limit their clinical translation, highlighting the need for new approaches, such as size reduction and lipid conjugation, to enhance their efficacy, cell penetration, stability, and safety. Herein, we report the <ce:italic>de novo</ce:italic> design of a library of ultra-short lipopeptides based on a rigid <ce:small-caps>l</ce:small-caps>-Arg–<ce:small-caps>l</ce:small-caps>-Pro–<ce:small-caps>l</ce:small-caps>-Arg core, conceived to control conformational restriction and amphiphilic organization rather than mimicking longer natural AMPs. The compounds were synthesized and preliminarily evaluated in vitro against three gram-negative and three gram-positive strains. Systematic modulation of lipid positioning and linker orientation in this minimal scaffold led to the identification of promising candidates displaying MIC values in the low-μM range against both gram-negative and gram-positive bacteria. Of the newly developed compounds, <ce:bold>15</ce:bold> exhibited optimal lipophilicity, excellent human-serum stability and a favourable safety profile, showing only low to moderate toxicity toward renal, hepatic, and red blood cells. Additionally, <ce:bold>15</ce:bold> proved effective in reducing <ce:italic>S. aureus</ce:italic> biofilm formation and showed strong activity against five clinical isolates. It acts as a bacteriostatic agent by perturbing bacterial membrane integrity, positioning it as a promising starting point for the development of a new class of chemotypes that could offer an alternative strategy for treating infections caused by this gram-positive pathogen.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465773","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}
Bortezomib, as a first-generation proteasome inhibitor, is one of the cornerstone drugs in the treatment of multiple myeloma. However, its long-term clinical efficacy is severely limited by both primary and acquired resistance. Studies have shown that the Janus kinase 3/Signal transducer and activator of transcription (JAK/STAT) signaling pathway may be persistently activated in certain bortezomib-resistant myeloma cells. Herein, we designed, synthesized, and evaluated a series of acrylamide group-bearing 2-arylaminopyrimidine derivatives as potent Janus kinase 3 (JAK3) inhibitors. Among them, 7n, a promising compound, exhibited a strong combining capability with JAK3 (half-maximal inhibitory concentration [IC50] = 0.7473 nM) and effective antiproliferative activities against Bortezomib-resistant KM3 cells (IC50 = 0.2452 μM). The results of the pharmacokinetics analysis showed that 7n presented good oral bioavailability with an F value of 39.11%. Furthermore, 7n showed notable inhibition of tumor growth in a murine Bortezomib-resistant KM3 cell xenograft model. Additionally, the analysis of the mechanism of action validated that compound 7n inhibited cell migration, promoted cell apoptosis and arrested the JAK–signal transducers and activators of the transcription pathway. Notably, 7n displayed the strongest inhibitory activities against JAK3 in 76 kinase profiles with the inhibitory rate of 96.87% at the concentration of 5 nM. Altogether, these findings suggest that JAK3 is a potential target to develop the inhibitor for treating Bortezomib-resistant multiple myeloma and 7n can be considered a promising candidate for further research.
硼替佐米作为第一代蛋白酶体抑制剂，是多发性骨髓瘤治疗的基础药物之一。然而，其长期临床疗效受到原发性和获得性耐药的严重限制。研究表明，在某些硼替佐米耐药骨髓瘤细胞中，Janus kinase 3/Signal transducer and activator of transcription （JAK/STAT）信号通路可能持续被激活。在此，我们设计、合成并评价了一系列含丙烯酰胺基团的2-芳基氨基嘧啶衍生物作为JAK3抑制剂。其中，7n与JAK3具有较强的结合能力（半最大抑制浓度[IC50] = 0.7473 nM），对bortezomib耐药的KM3细胞具有较强的抗增殖活性（IC50 = 0.2452 μM）。药代动力学分析结果表明，7n具有良好的口服生物利用度，F值为39.11%。此外，7n在抗硼替佐米小鼠KM3细胞异种移植模型中显示出明显的肿瘤生长抑制作用。此外，通过作用机制分析，证实化合物7n抑制细胞迁移，促进细胞凋亡，阻断转录途径的jak信号转导和激活因子。值得注意的是，7n在76个激酶谱中对JAK3的抑制活性最强，在5 nM浓度下的抑制率为96.87%。总之，这些发现表明JAK3是开发治疗硼替佐米耐药多发性骨髓瘤抑制剂的潜在靶点，7n可以被认为是进一步研究的有希望的候选者。
{"title":"Covalent JAK3 inhibitors based on 2-arylamino and 7H-pyrrolo[2,3-d]pyrimidine scaffold: design, synthesis, and biological evaluation for the potential treatment of Bortezomib-resistant multiple myeloma","authors":"Liangliang Tian, Jiaxun Li, Jiawen Yu, Qingxuan Han, Nafiseh Bolghanabadi, Ke Wang, Zhiping Chen, Xu Zheng, Peng Chu, Lixue Chen","doi":"10.1016/j.ejmech.2026.118764","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118764","url":null,"abstract":"Bortezomib, as a first-generation proteasome inhibitor, is one of the cornerstone drugs in the treatment of multiple myeloma. However, its long-term clinical efficacy is severely limited by both primary and acquired resistance. Studies have shown that the Janus kinase 3/Signal transducer and activator of transcription (JAK/STAT) signaling pathway may be persistently activated in certain bortezomib-resistant myeloma cells. Herein, we designed, synthesized, and evaluated a series of acrylamide group-bearing 2-arylaminopyrimidine derivatives as potent Janus kinase 3 (JAK3) inhibitors. Among them, <strong>7n</strong>, a promising compound, exhibited a strong combining capability with JAK3 (half-maximal inhibitory concentration [IC<sub>50</sub>] = 0.7473 nM) and effective antiproliferative activities against Bortezomib-resistant KM3 cells (IC<sub>50</sub> = 0.2452 μM). The results of the pharmacokinetics analysis showed that <strong>7n</strong> presented good oral bioavailability with an <em>F</em> value of 39.11%. Furthermore, <strong>7n</strong> showed notable inhibition of tumor growth in a murine Bortezomib-resistant KM3 cell xenograft model. Additionally, the analysis of the mechanism of action validated that compound <strong>7n</strong> inhibited cell migration, promoted cell apoptosis and arrested the JAK–signal transducers and activators of the transcription pathway. Notably, <strong>7n</strong> displayed the strongest inhibitory activities against JAK3 in 76 kinase profiles with the inhibitory rate of 96.87% at the concentration of 5 nM. Altogether, these findings suggest that JAK3 is a potential target to develop the inhibitor for treating Bortezomib-resistant multiple myeloma and <strong>7n</strong> can be considered a promising candidate for further research.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478631","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}
Pub Date : 2026-03-16DOI: 10.1016/j.ejmech.2026.118781
, Shankar Gupta, Gaurav Joshi, Muhammad Wahajuddin, Bhupinder Kumar
Chronic inflammation is being recognised as a pivotal contributor to the onset and progression of cancer and other severe conditions. The cyclooxygenase (COX) is an essential enzyme in inflammation. Although this enzyme is typically overexpressed by inflammation, in many diseases like liver cirrhosis, thyroiditis, multiple sclerosis, neurological disorders, rheumatoid arthritis, Crohn's disease, ulcerative colitis, and cancer, its level increases persistently. This consistent expression contributes to its crucial role in tumour initiation and development. Additionally, COX-2 plays a dual role, generating both pro- and anti-inflammatory mediators, highlighting its multifaceted, dichotomous nature. Because of its dual role and significant implication in several diseases, it is now seen as a vital target in medicinal chemistry, leading to the development of drugs that specifically block its activity. In this work, we focus on the strong correlation between long-term inflammation and cancer. Furthermore, it explains the key molecular processes involved in this link. It also provides an overview of recent progress in clinical trials, along with FDA-approved drugs, showing their role and importance in treating such conditions. Recent developments over the last seven years (2020-2026) have been analysed, with a particular focus on scaffolds bearing five-membered azole-based heterocyclic compounds. It also provides an insightful resource for medicinal chemists working on the rational design and development of new molecules for the management of inflammation and cancer. Furthermore, oncologists and pharmacologists need to understand the evolving therapeutic model for COX-2-targeted drugs.
{"title":"COX-2 Inhibitors in Inflammation and Cancer: Recent Developments in Medicinal Chemistry","authors":", Shankar Gupta, Gaurav Joshi, Muhammad Wahajuddin, Bhupinder Kumar","doi":"10.1016/j.ejmech.2026.118781","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118781","url":null,"abstract":"Chronic inflammation is being recognised as a pivotal contributor to the onset and progression of cancer and other severe conditions. The cyclooxygenase (COX) is an essential enzyme in inflammation. Although this enzyme is typically overexpressed by inflammation, in many diseases like liver cirrhosis, thyroiditis, multiple sclerosis, neurological disorders, rheumatoid arthritis, Crohn's disease, ulcerative colitis, and cancer, its level increases persistently. This consistent expression contributes to its crucial role in tumour initiation and development. Additionally, COX-2 plays a dual role, generating both pro- and anti-inflammatory mediators, highlighting its multifaceted, dichotomous nature. Because of its dual role and significant implication in several diseases, it is now seen as a vital target in medicinal chemistry, leading to the development of drugs that specifically block its activity. In this work, we focus on the strong correlation between long-term inflammation and cancer. Furthermore, it explains the key molecular processes involved in this link. It also provides an overview of recent progress in clinical trials, along with FDA-approved drugs, showing their role and importance in treating such conditions. Recent developments over the last seven years (2020-2026) have been analysed, with a particular focus on scaffolds bearing five-membered azole-based heterocyclic compounds. It also provides an insightful resource for medicinal chemists working on the rational design and development of new molecules for the management of inflammation and cancer. Furthermore, oncologists and pharmacologists need to understand the evolving therapeutic model for COX-2-targeted drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"12 1","pages":"118781"},"PeriodicalIF":6.7,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147464913","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}
Pub Date : 2026-03-15Epub Date: 2026-01-23DOI: 10.1016/j.ejmech.2026.118616
Xiong Chen , Zong-Zheng Li , Xing-Yu Yao, Xiao-Min Han, Kai-Le Zeng, Hao-Yun Chen, Wen-Jing Gao, Tian-Yue Zhu, Lei Niu, Tao Zhuang
Dual-acting ligands targeting the sigma-1 receptor (σ1R) and histamine H3 receptor (H3R) are emerging as promising candidates for novel and safe analgesics. In this work, we designed, synthesized, and evaluated twenty-nine 3-indolealkylamines as dual σ1R/H3R ligands. In vitro radioligand receptor binding assay or surface plasmon resonance assay were performed to determine their affinities toward σ1R or H3R. Among them, compound 67 demonstrated high binding affinity for both σ1R (Kᵢ = 8.8 nM) and H3R (KD = 31.2 nM). Further in vivo pharmacological evaluations confirmed its antagonistic activity at both receptors. Compound 67 exhibited significant antinociceptive effects in the acetic acid-induced constriction test (ED50 = 0.18 mg/kg) and paclitaxel-induced neuropathic pain model (ED50 = 0.06 mg/kg), which demonstrated potency superior to that of marketed drug gabapentin. Moreover, compound 67 showed no side effects in the open-field test and rotarod test, and acute toxicity studies revealed a high safety profile with an excellent therapeutic window (LD50 > 250 mg/kg, TI > 1388.9). These findings demonstrated that compound 67 is a promising dual σ1R/H3R ligand to develop safe and effective analgesics.
{"title":"Discovery of 3-indolealkylamines as novel dual-target σ1R/H3R ligands with potent analgesia","authors":"Xiong Chen , Zong-Zheng Li , Xing-Yu Yao, Xiao-Min Han, Kai-Le Zeng, Hao-Yun Chen, Wen-Jing Gao, Tian-Yue Zhu, Lei Niu, Tao Zhuang","doi":"10.1016/j.ejmech.2026.118616","DOIUrl":"10.1016/j.ejmech.2026.118616","url":null,"abstract":"<div><div>Dual-acting ligands targeting the sigma-1 receptor (σ<sub>1</sub>R) and histamine H<sub>3</sub> receptor (H<sub>3</sub>R) are emerging as promising candidates for novel and safe analgesics. In this work, we designed, synthesized, and evaluated twenty-nine 3-indolealkylamines as dual σ<sub>1</sub>R/H<sub>3</sub>R ligands. <em>In vitro</em> radioligand receptor binding assay or surface plasmon resonance assay were performed to determine their affinities toward σ<sub>1</sub>R or H<sub>3</sub>R. Among them, compound <strong>67</strong> demonstrated high binding affinity for both σ<sub>1</sub>R (Kᵢ = 8.8 nM) and H<sub>3</sub>R (K<sub>D</sub> = 31.2 nM). Further <em>in vivo</em> pharmacological evaluations confirmed its antagonistic activity at both receptors. Compound <strong>67</strong> exhibited significant antinociceptive effects in the acetic acid-induced constriction test (ED<sub>50</sub> = 0.18 mg/kg) and paclitaxel-induced neuropathic pain model (ED<sub>50</sub> = 0.06 mg/kg), which demonstrated potency superior to that of marketed drug gabapentin. Moreover, compound <strong>67</strong> showed no side effects in the open-field test and rotarod test, and acute toxicity studies revealed a high safety profile with an excellent therapeutic window (LD<sub>50</sub> > 250 mg/kg, TI > 1388.9). These findings demonstrated that compound <strong>67</strong> is a promising dual σ<sub>1</sub>R/H<sub>3</sub>R ligand to develop safe and effective analgesics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118616"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033859","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}
Pub Date : 2026-03-15Epub Date: 2026-01-27DOI: 10.1016/j.ejmech.2026.118623
De-Chang Li , Nan-Nan Chen , Qi-Dong You , Xiao-Li Xu
Necroptosis, a regulated form of programmed necrosis mediated by the RIPK1/RIPK3/MLKL signaling pathway, plays a pivotal role in the pathogenesis of diverse diseases, including neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, infections, and cancer. This review comprehensively summarizes the significant progress in developing small-molecule modulators targeting core components of the pathway. It systematically details the classification, mechanisms of action, and SAR of RIPK1, RIPK3, and MLKL inhibitors and inducers. Notably, Several RIPK1 inhibitors (e.g., DNL-788, DNL-758, R-552) have advanced to Phase II clinical trials for indications like multiple sclerosis, ulcerative colitis, and rheumatoid arthritis. Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research.
{"title":"Small-molecule modulators of the necroptotic pathway: A medicinal chemistry perspective","authors":"De-Chang Li , Nan-Nan Chen , Qi-Dong You , Xiao-Li Xu","doi":"10.1016/j.ejmech.2026.118623","DOIUrl":"10.1016/j.ejmech.2026.118623","url":null,"abstract":"<div><div>Necroptosis, a regulated form of programmed necrosis mediated by the RIPK1/RIPK3/MLKL signaling pathway, plays a pivotal role in the pathogenesis of diverse diseases, including neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, infections, and cancer. This review comprehensively summarizes the significant progress in developing small-molecule modulators targeting core components of the pathway. It systematically details the classification, mechanisms of action, and SAR of RIPK1, RIPK3, and MLKL inhibitors and inducers. Notably, Several RIPK1 inhibitors (e.g., DNL-788, DNL-758, R-552) have advanced to Phase II clinical trials for indications like multiple sclerosis, ulcerative colitis, and rheumatoid arthritis. Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118623"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071905","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}
Pub Date : 2026-03-15Epub Date: 2026-01-23DOI: 10.1016/j.ejmech.2026.118615
Shuang Luo , Zhiyun Peng , Guangcheng Wang
To achieve new multi-target inhibitors simultaneously acting on α-glucosidase, α-amylase, and protein tyrosine phosphatase 1B (PTP1B), twenty-one novel carbazole-5-phenyl-1,3,4-oxadiazole derivatives (5a-5u) were synthesized and screened for in vitro enzyme inhibitory activity. All synthesized derivatives 5a-5u showed noticeable anti-α-glucosidase and anti-α-amylase activities (IC50: 9.79 ± 0.21–132.65 ± 1.52 μM, 6.15 ± 0.11–25.16 ± 0.75 μM, respectively) in comparison with the standard acarbose (IC50: 210.57 ± 0.91 μM, 26.17 ± 1.12 μM, respectively). The compound 5l that possessed the best inhibition activity on both α-glucosidase and α-amylase (IC50 = 9.79 ± 0.21, 6.36 ± 0.16 μM, respectively) also exhibited a fine inhibitory effect on PTP1B with an IC50 value of 19.08 ± 4.52 μM, as the reference drug ursolic acid of 4.43 ± 0.40 μM. Kinetic measurement, multispectral techniques, and molecular docking study were used to reveal the interaction mechanism of preferred compound 5l with α-glucosidase, α-amylase, and PTP1B. The derivative 5l could inhibit the activity of these enzyme proteins via binding to the enzyme or its substrate complex, quenching their intrinsic fluorescence, or affecting the conformation of enzyme proteins, and forming hydrophobic interactions and hydrogen bonds with them. In conjunction with the potential properties of compound 5l in inhibiting the postprandial blood glucose rise and low cytotoxicity, the title derivatives are expected to become lead molecules in developing new multi-target antidiabetes drugs.
{"title":"Construction and biological evaluation of novel carbazole-5-phenyl-1,3,4-oxadiazole derivatives as multi-target hypoglycemic agents","authors":"Shuang Luo , Zhiyun Peng , Guangcheng Wang","doi":"10.1016/j.ejmech.2026.118615","DOIUrl":"10.1016/j.ejmech.2026.118615","url":null,"abstract":"<div><div>To achieve new multi-target inhibitors simultaneously acting on α-glucosidase, α-amylase, and protein tyrosine phosphatase 1B (PTP1B), twenty-one novel carbazole-5-phenyl-1,3,4-oxadiazole derivatives (<strong>5a-5u</strong>) were synthesized and screened for <em>in vitro</em> enzyme inhibitory activity. All synthesized derivatives <strong>5a-5u</strong> showed noticeable anti-α-glucosidase and anti-α-amylase activities (IC<sub>50</sub>: 9.79 ± 0.21–132.65 ± 1.52 μM, 6.15 ± 0.11–25.16 ± 0.75 μM, respectively) in comparison with the standard acarbose (IC<sub>50</sub>: 210.57 ± 0.91 μM, 26.17 ± 1.12 μM, respectively). The compound <strong>5l</strong> that possessed the best inhibition activity on both α-glucosidase and α-amylase (IC<sub>50</sub> = 9.79 ± 0.21, 6.36 ± 0.16 μM, respectively) also exhibited a fine inhibitory effect on PTP1B with an IC<sub>50</sub> value of 19.08 ± 4.52 μM, as the reference drug ursolic acid of 4.43 ± 0.40 μM. Kinetic measurement, multispectral techniques, and molecular docking study were used to reveal the interaction mechanism of preferred compound <strong>5l</strong> with α-glucosidase, α-amylase, and PTP1B. The derivative <strong>5l</strong> could inhibit the activity of these enzyme proteins <em>via</em> binding to the enzyme or its substrate complex, quenching their intrinsic fluorescence, or affecting the conformation of enzyme proteins, and forming hydrophobic interactions and hydrogen bonds with them. In conjunction with the potential properties of compound <strong>5l</strong> in inhibiting the postprandial blood glucose rise and low cytotoxicity, the title derivatives are expected to become lead molecules in developing new multi-target antidiabetes drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118615"},"PeriodicalIF":5.9,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043115","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}
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