Current medicinal chemistry最新文献

{"title":"New Indazole Derivatives as Potential Scaffolds for the Development of Anticancer, Antiviral, and Anti-tuberculosis Chemotherapeutic Compounds.","authors":"Khandazhinskaya Anastasia, Kondrashova Evgenya, Sokhraneva Vera, Novikova Olga, Velikorodnaya Yulia, Gorshenin Andrey, Andreevskaya Sofia, Smirnova Tatyana, Moroz Maxim, Kirillov Ilya, Fedyakina Irina, Chizhov Alexandr, Kochetkov Sergey, Matyugina Elena","doi":"10.2174/0109298673389070250822065247","DOIUrl":"https://doi.org/10.2174/0109298673389070250822065247","url":null,"abstract":"<p><strong>Introduction: </strong>Chemotherapy remains essential despite advances in immunotherapy, radiotherapy, and biological therapy. However, the wide range of chemical drugs is limited by a narrow therapeutic index, low selectivity, and the development of resistance. In this regard, new high-efficiency drugs are in extremely high demand. The indazole moiety, a scaffold found in many biologically active compounds, was selected for use in new drug design.</p><p><strong>Methods: </strong>Six new indazole derivatives were synthesized via Suzuki-Miyaura coupling starting from bromoindazole. Their antiviral (against influenza A and SARS-CoV-2), antibacterial (against M. tuberculosis), and antiproliferative activities (against neuroblastoma, glioma, leukemia cell lines) were evaluated in vitro. Acute toxicity was assessed in mice of both sexes via single intragastric administration, with toxicometric parameters and pathomorphological changes studied.</p><p><strong>Results: </strong>6-(1H-pyrazol-4-yl)-1H-indazole (8) suppressed the reproduction of the influenza virus at non-toxic doses to the MDCK cells and showed cytotoxicity against cancer cell lines, with an IC50 between 4 and 14 μM. However, it exhibited significant acute toxicity in mice (LD50 40 mg/kg), causing systemic organ damage.</p><p><strong>Discussion: </strong>Derivative 8 demonstrated promising antiviral and antiproliferative activities but exhibited considerable acute toxicity in vivo. The antiviral efficacy, although lower than oseltamivir, is meaningful and justifies further optimization and investigation. Its antibacterial activity against M. tuberculosis adds to its potential as a multifunctional agent.</p><p><strong>Conclusion: </strong>While derivative 8 has shown potential as an antiviral and anticancer agent, its high toxicity highlights the need for further studies to define a safe and effective therapeutic window. Overall, the indazole scaffold remains a valuable platform for the development of new therapeutic compounds.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014080","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":"Interdisciplinary Frontiers in Medicinal Chemistry: Nanomedicine, Photodynamic Therapy, and Computational Drug Design.","authors":"Jianmin Chen","doi":"10.2174/0109298673441397250902101911","DOIUrl":"https://doi.org/10.2174/0109298673441397250902101911","url":null,"abstract":"","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014044","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":"Azole Antifungals Under Pressure: Therapeutic Challenges and Multifaceted Resistance Mechanisms.","authors":"Andre L S Santos, Lívia S Ramos, Thais P Mello, Livia Viganor, Noely M B M Nonato, Raizza E E Pinheiro, Marta H Branquinha","doi":"10.2174/0109298673413219250826055238","DOIUrl":"https://doi.org/10.2174/0109298673413219250826055238","url":null,"abstract":"<p><p>Fungal infections have increased markedly in both incidence and severity over recent decades, driven in part by the emergence of novel pathogenic species harboring sophisticated resistance mechanisms against commonly used antifungal agents. This alarming trend is especially pronounced with azoles, which remain widely used in clinical settings due to their broad-spectrum activity and favorable oral bioavailability. Azoles exert their antifungal effect by inhibiting lanosterol 14α-demethylase, a key enzyme in the ergosterol biosynthesis pathway, thereby compromising the integrity, fluidity, and functionality of the fungal cell membrane. However, the escalating prevalence of multidrug-resistant fungal strains, particularly those resistant to azoles, has significantly complicated therapeutic strategies and represents a growing threat to global public health. This perspective explores the diverse and increasingly complex mechanisms of azole resistance in clinically relevant fungi, particularly species of Candida and Aspergillus, highlighting the urgent need for enhanced surveillance, novel therapeutic approaches, and responsible antifungal stewardship.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999828","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":"Circulating proteins and bone mineral density: A Proteome-Wide Mendelian Randomization Study.","authors":"Tianyi Wang, Liu Liu, Ruiying Han, Yikai He, Yubin Cao, Ding Bai, Yongwen Guo","doi":"10.2174/0109298673385463250811030618","DOIUrl":"https://doi.org/10.2174/0109298673385463250811030618","url":null,"abstract":"<p><strong>Introduction: </strong>Current osteoporosis medications often prove ineffective for various reasons. Alongside optimizing available agents, new genetic targets should be proposed for drug development. Mendelian randomization (MR) may resolve throughput and confounding issues in traditional observational studies for druggable targets.</p><p><strong>Methods: </strong>We employed two-sample MR with protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) data as exposures and six bone mineral density (BMD) sites as outcomes. By meta-analyzing pQTL evidence, validating eQTL evidence, conducting MR sensitivity tests, and assessing druggability, key druggable targets for BMD were identified. Additionally, we performed functional analysis, drug repurposing annotation, transcriptome analysis, in-house PCR, ELISA, and micro-CT validation to further investigate the functionality and expression levels of these targets across different tissues and conditions.</p><p><strong>Results: </strong>Out of 5,928 pQTLs from deCODE and UKB-PPP datasets, 16 were identified as prioritized targets with significant meta pQTL evidence. Tyrosine-protein kinase Lyn (LYN, meta beta -0.09, 95% CI -0.13 to -0.05), Chondroadherin (CHAD, meta beta -0.39, 95% CI -0.18 to -0.20), Tumor necrosis factor receptor superfamily member 19 (TNFRSF19, meta beta -0.03, 95% CI -0.05 to -0.02), and Transforming growth factor beta induced (TGFBI, meta beta -0.04, 95% CI -0.06 to -0.03) were identified as key druggable targets for BMD. R-spondin-3 (RSPO3) and SPARC-related modular calcium- binding protein 2 (SMOC2) were also suggested with consistent MR associations with previous studies.</p><p><strong>Discussion: </strong>We identified four novel BMD-related targets (CHAD, LYN, TGFBI, TNFRSF19) through pQTL meta-analysis, and validated RSPO3/SMOC2's positive effects. By integrating multi-tissue transcriptomics and OVX experiments, we further revealed elevated expression of TNFRSF19/TGFBI negatively correlated with BMD, providing new therapeutic insights.</p><p><strong>Conclusion: </strong>This large-scale Proteome-Wide MR study introduced novel targets for BMD and osteoporosis at transcriptional and translational levels, presenting new prospects for drug repurposing and development.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999857","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":"Mechanisms of Inflammation Chronification: Genetic and Epigenetic Regulation of Intolerant Response (Trained Immunity).","authors":"Alexander Nikolaevich Orekhov, Andrey Vladimirovich Omelchenko, Alexander Dmitrievich Zhuravlev, Andrey Yurievich Vinokurov, Natalia Vladimirovna Elizova, Vasily Vladimirovich Sinyov, Igor Alexandrovich Sobenin, Vasily Nikolaevich Sukhorukov","doi":"10.2174/0109298673431092250819054506","DOIUrl":"https://doi.org/10.2174/0109298673431092250819054506","url":null,"abstract":"","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999889","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":"PROTACs Targeting Molecular Targets in Triple-Negative Breast Cancer.","authors":"Gyas Khan, Sarfaraz Ahmad, Md Sadique Hussain","doi":"10.2174/0109298673384371250806104406","DOIUrl":"https://doi.org/10.2174/0109298673384371250806104406","url":null,"abstract":"<p><p>Triple-Negative Breast Cancer (TNBC) is defined as a type of breast cancer having the absence of estrogen, progesterone, and human epidermal growth factor receptors. So far, chemotherapeutic drugs and immunotherapy have several issues, such as being resistant to treatment, being harmful to the body, and not being fully effective. Lately, PROTACs have been discovered to assist in the breakdown of difficult-to-target oncoproteins employing the ubiquitin-proteasome system. This review focuses on PROTACs used in TNBC, identifying BET proteins, SRC-1, PARP1, FAK, c-Myc, and CDKs as the primary molecular targets of PROTACs in this type of cancer. PROTACs can help overcome drug resistance, degrade harmful proteins over a prolonged period, and enhance the performance of these new therapies in clinical research. BETd-246, ND1-YL2, and pal-pom PROTACs have shown promise in reducing cancer progression and spread in TNBC. Additionally, the use of PROTACs to target EZH2, AR, and TRIM24 demonstrates that this approach offers great flexibility. While these findings are promising, it remains challenging to achieve better pharmacokinetics, maintain product stability, increase bioavailability, enhance selectivity, and prevent potential toxicity. New developments in PROTAC design and clinical results suggest that the strategy could lead to improved treatments for TNBC patients, helping them live longer and better.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999910","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":"Diagnosis and Potential Therapy of Brain Diseases Using 64Cu: A Scoping Review.","authors":"Yumei An, Xinqi Huang, Mingyuan Xu, Xianzhe Li, Haiyan Shan, Mingyang Zhang","doi":"10.2174/0109298673354343250728095946","DOIUrl":"https://doi.org/10.2174/0109298673354343250728095946","url":null,"abstract":"<p><strong>Introduction: </strong>This paper provides a comprehensive review examining the application of copper radionuclides, particularly 64Cu, in the diagnosis and potential therapy of various brain diseases.</p><p><strong>Methods: </strong>Two researchers conducted an independent search of the PubMed and Web of Science databases for original research articles published in English. Following a screening process based on titles and abstracts, 42 publications reporting the use of copper radionuclides for diagnosing or treating brain diseases were selected for this review.</p><p><strong>Results: </strong>The analysis revealed that several copper isotopes, namely 60 Cu, 61 Cu, 62 Cu, 64Cu, and 67Cu, have been explored for diagnostic or therapeutic purposes in conditions including Alzheimer's disease, Wilson's disease, brain tumors, and traumatic brain injury. The isotopes 60 Cu, 61 Cu, and 62 Cu were primarily associated with diagnostic uses. In contrast, 64Cu and 67Cu were identified as having potential for both diagnosis and therapy (theranostic). Furthermore, the availability of 64Cu was noted to be better compared to 67Cu.</p><p><strong>Discussion: </strong>64Cu radionuclides are frequently employed in imaging techniques for brain pathologies. While their role in radiographic applications is prominent, the therapeutic potential of 64Cu is currently underdeveloped, and current evidence is primarily derived from preclinical studies, highlighting the critical need for clinical trials to validate 64Cu's efficacy and safety as a theranostic agent in neurological conditions.</p><p><strong>Conclusion: </strong>64Cu holds significant potential for both diagnosis and therapy of various brain diseases. Continued research and development in this area are crucial to unlock its full therapeutic potential and improve patient outcomes.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999894","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":"Cutting-Edge Innovations: Recent Patents in Medicinal Chemistry.","authors":"Arshleen Kaur, Rajesh K Singh, Rohit Bhatia","doi":"10.2174/0109298673397069250807094444","DOIUrl":"https://doi.org/10.2174/0109298673397069250807094444","url":null,"abstract":"","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999845","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":"Beneficial Role of Zinc in Metabolic Syndrome: Understanding the Underlying Pathophysiological Mechanisms.","authors":"Abdullah Al Lawati, Emir Ličina, Patrycja Głoćko, Shaymaa Salah Abdelnaeim Hefny, Donia Elnemr, Ahmed Al Maskari, Srijit Das","doi":"10.2174/0109298673370733250807110441","DOIUrl":"https://doi.org/10.2174/0109298673370733250807110441","url":null,"abstract":"<p><p>Metabolic syndrome (MetS) is a complex disorder that comprises metabolic abnormalities such as central obesity, insulin resistance, dyslipidemia, and hypertension. Eventually, MetS leads to type 2 diabetes (T2DM) and increases the risk of other cardiovascular diseases. Patients with MetS are approximately five times more prone to develop T2DM. The increase in global prevalence of MetS is a major cause of concern. The microelement zinc is an essential trace element that plays a pivotal role in numerous biological processes occurring in the body. We carried out a thorough search of published studies in Scopus, PubMed, and Google Scholar databases. Zinc plays an important role in the functioning of the immune system, wound healing, protein synthesis, metabolism, inflammation, and different oxidative stress pathways. It is also vital for insulin homeostasis and signaling. The potential role of zinc in managing insulin resistance may be a key component in the treatment of MetS. Zinc acts via various signaling pathways, such as AMPK and mTOR, and influences lipid and glucose metabolism. The regulation of zinc metabolism at the cellular level is important for various biological processes, and disruption in zinc homeostasis results in the development of many diseases. The present review aims to discuss the role of zinc in MetS. It is concluded that zinc level modulation may be a key point in the prevention and treatment of MetS.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946020","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":"PREFACE.","authors":"Atta-Ur Rahman","doi":"10.2174/0109298673439579250825104543","DOIUrl":"https://doi.org/10.2174/0109298673439579250825104543","url":null,"abstract":"","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945984","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}