Current topics in medicinal chemistry最新文献

{"title":"Systematic Review of Hybrid Nanosystems as Emerging Tools in Targeted Cancer Therapy and Future Aspects.","authors":"Swati Paliwal, Arzoo Pannu, Vivek Yadav, Saroj Verma, Uma Agarwal, Rajiv Kumar Tonk","doi":"10.2174/0115680266437574260421051017","DOIUrl":"https://doi.org/10.2174/0115680266437574260421051017","url":null,"abstract":"<p><strong>Introduction: </strong>Hybrid Nanosystems (HNSs) are a type of advanced drug carrier that can be made from various materials, including organic compounds, inorganic particles, lipids, polymers, and biomimetic components. This combined framework facilitates functionalities such as medication distribution, imaging support, and modification of therapeutic responses. This renders them highly promising for oncological therapy. The main goal of this study was to identify studies on HNSs that investigated their development, underlying characteristics, and therapeutic efficacy.</p><p><strong>Methods: </strong>A comprehensive review of the literature was performed, utilizing platforms such as Google Scholar, Scopus, Web of Science, and PubMed. It systematically collected data on various aspects, including cancer types studied, nanomaterial compositions, targeting techniques, combination therapies, safety profiles, and therapeutic significance. The analysis encompassed findings from 197 preclinical and clinical studies published between 2010 and 2025. This study highlights recent advancements in cancer treatment methods, their mechanisms of action, and the critical challenges that must be addressed prior to clinical application.</p><p><strong>Results: </strong>The findings indicate that HNSs are under investigation for several cancer types, including breast, lung, liver, colon, and brain tumors. These technologies facilitate targeted drug delivery, initiate programmed cell death (apoptosis), inhibit cancer proliferation, and assist in real-time imaging for diagnostic applications. An analysis of 197 research papers published from 2010 to 2025 revealed that HNSs markedly improve anticancer efficacy by optimizing drug transport, tumor targeting, and multimodal therapy strategies. HNS-based systems attained tumor suppression rates of 70-90%, enhanced apoptosis, diminished systemic toxicity, and successfully addressed multidrug resistance and immune evasion. Multifunctional platforms that integrate chemotherapy, phototherapy, gene therapy, and immunotherapy have shown significant synergistic effects, with combination indices between 0.4 and 0.8. Despite the highly encouraging preclinical results, additional studies are necessary to evaluate long-term safety, scalability, and regulatory obstacles for effective clinical translation.</p><p><strong>Discussion: </strong>The results highlight the growing promise of hybrid nanostructures as sophisticated cancer therapies that can combine targeted delivery, multimodal treatment, and diagnostic capabilities on a single platform. Their capacity to overcome significant drawbacks of traditional medicines, such as multidrug resistance, inadequate bioavailability, and off-target toxicity, highlights their translational significance. Nonetheless, additional endeavours are necessary to ensure long-term safety, manufacturing uniformity, and regulatory structures to enable effective clinical implementation.</p><p><st","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioisosteric Replacement of Carboxylic Acids in PPAR Agonists: A Mini Review.","authors":"Adriana Coricello, Alessio De Simone, Giovanni Bottegoni","doi":"10.2174/0115680266466273260722130035","DOIUrl":"https://doi.org/10.2174/0115680266466273260722130035","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate metabolic homeostasis and represent important therapeutic targets for conditions such as type 2 diabetes, dyslipidemia, and cardiovascular disease. While classical modulators often rely on carboxylic acid moieties to anchor receptor binding through hydrogen bonding, such groups are associated with suboptimal pharmacokinetic profiles, including poor bioavailability, rapid metabolism, and limited tissue penetration. This review explores the strategic use of bioisosteres, such as thiazolidinediones, tetrazoles, oxadiazolones, sulfonamides, and acetamides, as alternative polar headgroups in the design of PPAR ligands. We provide an overview of several aspects, highlighting how structural modifications to polar headgroups influence binding modes, receptor selectivity, and agonist profiles in the development of safer and more effective PPAR modulators. Emphasis is placed on synthetic approaches that prioritize convergent, high-yield, and late-stage diversification to facilitate parallel structure-activity relationship (SAR) exploration. Together, these bioisosteric strategies highlight the synergy between medicinal chemistry and synthetic innovation in the pursuit of next-generation PPAR modulators. Future efforts aimed at partial, biased, or tissue-selective agonists will benefit from continued exploration of novel headgroups, enabling safer and more effective therapies for metabolic and inflammatory diseases. Overall, a comparison of the different bioisosteric classes underscores the pivotal role of polar headgroup design in tuning potency, selectivity, and safety, guiding the rational development of future PPAR-targeted therapeutics.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EBF1: A Multidimensional Role Integrating Metabolism and Metabolic Diseases.","authors":"Yining Pan, Haoran Liu, Jiayi Ma, Cheng Chen, Tongtong Li, Yaqi Hu, Min Liang, Chengfu Yuan","doi":"10.2174/0115680266450035260716195550","DOIUrl":"https://doi.org/10.2174/0115680266450035260716195550","url":null,"abstract":"<p><strong>Introduction: </strong>Early B-cell factor 1 (EBF1) is a multifunctional transcription factor. It plays a pivotal role in regulating biological processes such as B-lymphocyte development and neuronal differentiation. EBF1 has been implicated in metabolic disorders such as diabetes and central obesity through epigenetic modifications and underlying signaling pathways. However, the molecular mechanisms and functions of EBF1's direct regulation of metabolic targets have yet to be systematically analyzed. This review aims to integrate the multidimensional functions and regulatory networks of EBF1 in metabolic control, while summarizing its mechanistic contributions to metabolic diseases.</p><p><strong>Methods: </strong>This review systematically summarizes and speculates on the biological functions and related mechanisms of EBF1 in normal metabolic activities and metabolic diseases by comprehensively searching the current studies through the PubMed database.</p><p><strong>Results: </strong>(1) EBF1 promotes lipogenesis during early adipocyte differentiation. (e.g., PPARγ and C/EBPα) (2) EBF1 regulates insulin signaling (e.g., PI3K/AKT, MAPK) and inflammatory pathways (e.g., Toll-like receptors, JAK-STAT) in mature adipocytes. (3) EBF1 SNPs and methylation play crucial roles in various metabolic disorders.</p><p><strong>Discussion: </strong>EBF1 plays a crucial role in both early adipocyte differentiation and the maintenance of homeostasis in mature adipocytes; however, these findings may vary across models. The epigenetic regulation of EBF1 is a key mechanism underlying metabolic dysregulation and warrants further investigation.</p><p><strong>Conclusion: </strong>Given its multifaceted roles in lipogenesis, inflammation, and insulin resistance, EBF1 holds potential as a diagnostic biomarker and therapeutic target for various metabolic diseases.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiproliferative Activity, DNA/HSA Interactions and Human Topoisomerase Inhibition Evaluations of Indole-Thiazolidinone Derivatives: Are Two Indole Rings Better than One?","authors":"Maksuelly Libanio de Lima, Rafael David Souto de Azevedo, Fernanda Carvalho Manito Ferreira, Josival Emanuel Ferreira Alves, Elizabeth Almeida Lafayette, Jessica Celerino Dos Santos, Gleyton Leonel Silva Sousa, Maria do Carmo Alves de Lima, Sinara Mônica Vitalino de Almeida","doi":"10.2174/0115680266457267260721075824","DOIUrl":"https://doi.org/10.2174/0115680266457267260721075824","url":null,"abstract":"<p><strong>Introduction: </strong>Indole derivatives are promising candidates for anticancer drug discovery due to their occurrence in biologically active molecules and their ability to modulate cellular targets. This study aimed to evaluate the antiproliferative effects, biomolecular interactions, and topoisomerase inhibition potential of four indole-thiazolidinone derivatives.</p><p><strong>Methods: </strong>DNA and HSA binding were investigated by UV-Vis absorption, fluorescence spectroscopy, and molecular docking. Topoisomerase inhibition was evaluated in vitro. Antiproliferative activity and effects on cell migration were assessed in human cancer cell lines using the sulforhodamine B (SRB) and wound healing assays, respectively.</p><p><strong>Results: </strong>The bis-indole derivative (4a) showed the strongest affinity for DNA (Kb = 1.34 × 10⁶ M⁻¹) and HSA (Kb = 1.30 × 10⁶ M⁻¹), altering the IIA hydrophobic microenvironment. In vitro, 4a displayed potent antiproliferative activity against MCF-7 breast cancer cells (GI₅₀ = 4.53 μM) and inhibited cell migration by 11.65% at 1 μM. No significant inhibition of topoisomerase I and II was observed at 10 and 50 μM.</p><p><strong>Discussion: </strong>The findings suggest that the cytotoxic activity of compound 4a is more closely associated with its interaction with DNA than with topoisomerase inhibition. Spectroscopic and computational analyses indicated the occurrence of multiple binding modes with DNA and HSA, supporting its favourable interaction profile. Furthermore, the high affinity for HSA may contribute to compound transport and distribution in biological systems, while the observed reduction in cell migration indicates a potential effect on tumour progression.</p><p><strong>Conclusion: </strong>Compound 4a is the most active in the series, representing a significant starting point for the development of new derivatives with potential anti-tumour activity.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycogen Synthase Kinase-3β in Alzheimer's Disease: Targets for Therapy and Imaging.","authors":"Jianhua Jia","doi":"10.2174/0115680266497019260720045602","DOIUrl":"https://doi.org/10.2174/0115680266497019260720045602","url":null,"abstract":"<p><p>Glycogen synthase kinase-3β (GSK-3β) is a key regulator of the pathogenesis of Alzheimer's disease (AD), capable of simultaneously modulating core pathological processes such as amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, synaptic damage, and neuroinflammation. Therefore, it has become one of the core druggable molecular nodes for AD intervention. This review is mainly divided into two parts. The first part focuses on the GSK-3β inhibitors that have been validated in AD-related cell and animal models. These inhibitors are specifically classified into four categories: metal ion-based compounds, adenosine triphosphate (ATP)-competitive inhibitors, non-ATP-competitive inhibitors, and multi-target inhibitors. The second part focuses on GSK-3β-specific positron emission tomography (PET) radioligands, which can non-invasively monitor GSK-3β enzyme activity in vivo, providing quantitative in vivo molecular imaging tracers for the study of AD pathogenesis and quantitative assessment of treatment effects. This review systematically summarizes GSK-3β-related inhibitors and PET radioligands in AD, thereby providing key references for the rational design of next-generation AD therapeutic drugs and diagnostic agents.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Heterocyclic Derivatives for Aromatase Inhibition in Hormone-Dependent Breast Cancer.","authors":"Harsimran Kaur, Kawalpreet Kaur, Gurdeep Singh","doi":"10.2174/0115680266452626260702092804","DOIUrl":"https://doi.org/10.2174/0115680266452626260702092804","url":null,"abstract":"<p><p>Breast cancer is one of the most common causes of cancer death among women in the world, and the number of tumors that depend on hormones occupies a significant percentage of cases that are diagnosed. The estrogen factor is central to the development of these cancers; hence, aromatase, the central enzyme involved in estrogen production, is a critical therapeutic target. Aromatase Inhibitors (AIs), in particular, have emerged to play an important role in endocrine therapy in postmenopausal breast cancer patients. Heterocyclic compounds, in particular, have also been receiving significant focus in the design of AI scaffolds, because they are structurally diverse and capable of binding the heme iron in the aromatase active site. This review provides extensive coverage of recent developments in heterocyclic aromatase inhibitors, including large classes such as azoles, indoles, quinolines, coumarins, benzofurans, and other fused heterocyclic systems. The focus is on trends in Structure-Activity Relationships (SAR), with emphasis on the patterns of substitution and pharmacophoric features that can modulate potency and selectivity. Mechanistic information from molecular docking and other computational studies is also presented to elucidate binding interactions and inform rational drug design. In addition, new approaches such as the development of hybrid molecules and multi-target-directed ligands are listed to illustrate emerging trends aimed at enhancing efficacy and pharmacokinetic properties. Together with heterocyclic structures, these frameworks are still offering viable and bright platforms on which next-generation aromatase inhibitors can be developed to treat breast cancer better.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biotransformation-Driven Structural Remodeling of Natural Products by Ganoderma lucidum Fermentation: Mechanisms and Enhanced Bioactivities.","authors":"Yuchen Liu, Bing Liu, Ting Zhu, Ning Chen, Junyao Chu, Hongyue Wei, Wenlan Li","doi":"10.2174/0115680266461232260515094327","DOIUrl":"https://doi.org/10.2174/0115680266461232260515094327","url":null,"abstract":"<p><p>Ganoderma lucidum fermentation (GLF) serves as a sustainable biotransformation platform that precisely modulates the chemical profiles and bioactivities of natural products through enzymatic hydrolysis, microbial metabolic remodeling, and substrate-microbe crosstalk. This review systematically elucidates the GLF-driven structural modifications of key compounds- including polysaccharides, saponins, triterpenoids, flavonoids, and proteins. These structural optimizations synergistically enhance multiple bioactivities: the increased content of deglycosylated ginsenosides enhances antitumor activity, while the antioxidant and prebiotic effects of polysaccharides are potentiated through the regulation of gut microbiota and short-chain fatty acid (SCFA) production. The core mechanisms involve a sophisticated interplay of specific enzyme catalysis, fungal endogenous biosynthesis, and a dynamic \"substrate degradation-product synthesis\" metabolic cycle. Finally, we emphasize that integrating multi-omics and synthetic biology is crucial for achieving precision control of GLF and advancing its translation in functional foods and drug discovery.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupting Bacterial Quorum Sensing: A Review of Protein Families and Natural Inhibitors for Combating Resistance.","authors":"Asghar Ali, Andaleeb Zahra, Mohan Kamthan, Md Salik Noorani, Mohammad Abid","doi":"10.2174/0115680266385347250529040422","DOIUrl":"https://doi.org/10.2174/0115680266385347250529040422","url":null,"abstract":"<p><p>The Quorum Sensing (QS) system plays a central role in regulating several processes that influence bacterial physiology, communication, and pathogenesis. It governs the production of virulence factors, facilitates biofilm formation, and contributes to the development of antibiotic resistance, all of which are critical to bacterial survival and pathogenicity. QS enables both intraspecies and inter-species bacterial communication, operating through distinct pathways in Gram-positive and Gram-negative bacteria. This review provides a comprehensive overview of the major families of quorum-sensing proteins involved in the working of the signalling molecules. It examines the structural features, functional roles, and mechanisms of action of these proteins, highlighting their significance in bacterial behaviour. Furthermore, the study explores the potential of plant-derived secondary metabolites as natural inhibitors targeting QS systems to disrupt bacterial pathogenicity. Finally, it discusses the implications of exploiting these inhibitors as promising strategies to address the growing challenge of antibiotic resistance in bacterial infections.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidiabetic Potential of Garcinia atroviridis Griff: In Vitro and In Vivo Evaluation of Glucose Metabolism and Enzyme Inhibition.","authors":"Ibrahim Mahmood, Song Zhu, Douglas Law, Lunasmrita Saikia, Partha Pratim Dutta, Saikat Sen, Shazrul Fazry, Ahmed Najm","doi":"10.2174/0115680266449106260626205346","DOIUrl":"https://doi.org/10.2174/0115680266449106260626205346","url":null,"abstract":"<p><p>Diabetes mellitus (DM) is characterized by hyperglycemia, insulin resistance, and pancreatic β-cell failure, necessitating novel treatments. Garcinia atroviridis, rich in hydroxy citric acid (HCA), flavonoids, and polyphenols, shows potential against diabetes. In vitro and in vivo studies assessed its effects on glucose absorption, enzyme inhibition, and glycemic control in diabetic rats. The extract exhibited significant total phenolic (10.09 ± 0.24 mg GAE/g) and flavonoid (9.44 ± 0.11 mg QE/g) content. It demonstrated moderate direct antioxidant activity (DPPH IC₅₀ 15.14 ± 0.55 mg/mL) and inhibited α-glucosidase, α-amylase, and DPP-4 (IC₅₀ 35.04 ± 0.22 mg/mL, 22.21 ± 0.13 mg/mL). Crucially, in L6 myoblast cells, it enhanced glucose absorption (165.25% at 62.5 µg/mL) without cytotoxicity (IC₅₀ 3.12 ± 0.027 mg/mL). In diabetic rats, G. atroviridis (400 mg/kg) significantly reduced fasting blood glucose (69.33 mg/dL by day 21) and improved glucose tolerance. The findings suggest that the antidiabetic potential of G. atroviridis is likely driven by a multi-mechanistic synergy between its moderate direct antioxidant capacity, enzyme inhibition, and, most notably, its potent ability to enhance cellular glucose uptake at low concentrations. This positions G. atroviridis as a promising natural adjunct for diabetes treatment, warranting further research into its active compounds and clinical applications.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research Progress on the Role of AMPK Signaling Pathway in the Regulation of Neural Injury.","authors":"JiaTai An, XiuHua Li, TangNa Zhao, Aiping Zheng, XinJian Yang, Liang Xu","doi":"10.2174/0115680266464264260627162948","DOIUrl":"https://doi.org/10.2174/0115680266464264260627162948","url":null,"abstract":"<p><strong>Introduction: </strong>Nerve Injury (NI) imposes a severe clinical burden involving energy failure, neuroinflammation, oxidative stress, and apoptosis. This review aims to systematically synthesize structural insights into AMP-activated protein kinase (AMPK), elucidate its multifaceted molecular mechanisms in NI, and evaluate AMPK-targeted pharmacological interventions.</p><p><strong>Methods: </strong>A comprehensive literature search across major databases (PubMed, Web of Science, Scopus, and Google Scholar) identified peer-reviewed in vitro and in vivo studies focusing on AMPK mechanisms, structural pharmacology, signaling networks (e.g., AMPK/mTOR, AMPK/SIRT1), and drug targeting in various neural injury models.</p><p><strong>Results: </strong>Upon cellular energy deficit, AMPK induces neuroprotective autophagy via the AMPK/mTOR/ULK1 axis and combats oxidative stress and neuroinflammation by promoting PGC-1α-mediated mitochondrial biogenesis and suppressing NF-κB. Conversely, AMPK dysregulation exacerbates neuronal death. Pharmacological agents demonstrate robust preclinical neuroprotection, though clinical application is hindered by off-target systemic toxicity and poor Blood-Brain Barrier (BBB) permeability.</p><p><strong>Discussion: </strong>The findings highlight AMPK as a pivotal modulator of interconnected metabolic stress response cascades. While pharmacological agents demonstrate robust preclinical neuroprotection, their clinical application is currently hindered by off-target systemic toxicity, lack of isoform specificity, and poor blood-brain barrier (BBB) permeability.</p><p><strong>Conclusion: </strong>AMPK represents a highly promising therapeutic target for mitigating NI. Translating preclinical successes into clinical practice demands rigorous Structure-Activity Relationship (SAR) optimization to develop CNS-penetrant, isoform-selective modulators, thereby maximizing targeted neuroprotection while minimizing adverse systemic effects.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}