MedChemComm最新文献_第4页

Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches 基于金刚烷胺的流感A型M2质子通道抑制剂：基于结构的设计、生物学评价和合成方法

IF 3.597

MedChemComm Pub Date : 2026-02-23 DOI: 10.1039/D5MD01027F

Marianna Stampolaki, Maria-Eleni Kouridaki, Kyriakos Georgiou and Antonios Kolocouris

{"title":"Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches","authors":"Marianna Stampolaki, Maria-Eleni Kouridaki, Kyriakos Georgiou and Antonios Kolocouris","doi":"10.1039/D5MD01027F","DOIUrl":"10.1039/D5MD01027F","url":null,"abstract":"The influenza A matrix 2 (AM2) protein, a prototype of viroporins, conducts protons along a chain of water molecules and ionizable side chains, including histidine-37. Solid-state NMR (ssNMR) and high-resolution X-ray crystal structures have been obtained for AM2 wild-type (WT) constructs in complex with adamantanamines, as well as for mutant AM2 channels that confer resistance to amantadine and adamantanamines across different pH levels. For the structure of AM2 S31N channels in complex with second-generation adamantane derivatives, consisting of an amantadine analog linked to an aryl group via a methylene bridge, X-ray crystal structures are still unavailable. These complexes have been studied in some detail to date, primarily using solution NMR spectroscopy in micelles or ssNMR in lipid bilayers, providing insights into the inhibition mechanisms of these drugs. These findings, when combined with advances in computational methods, can inform the design and synthesis of adamantane-based blockers targeting WT and mutant AM2 channels. The most popular testing assays were presented. Selected synthetic chemistry routes leading to complex adamantanamines, other saturated polycyclic amines, and second-generation adamantane-based inhibitors were provided. Extensive and long-term research on the druggable M2 channel has provided the scientific society with fundamental tools of structure-based drug design, a synthetic chemistry toolbox, and a library of adamantane-based compounds that can be useful antivirals due to the frequent viral AM2 mutations.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1811-1846"},"PeriodicalIF":3.597,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ZRMQ-22, a novel DYRK1A inhibitor, attenuates neuroinflammation and cognitive impairments in LPS-induced mice: a potential strategy for Alzheimer's disease ZRMQ-22是一种新型DYRK1A抑制剂，可减轻lps诱导小鼠的神经炎症和认知障碍：治疗阿尔茨海默病的潜在策略。

IF 3.597

MedChemComm Pub Date : 2026-02-20 DOI: 10.1039/D6MD00007J

Mengyu Ren, Huanhua Chen, Zhenshu Li, Jiacheng Zhuang, Aizhu Yang, Xiangdong Li, Xinyu Li, Xinpeng Wang, Zonghe Xu, Xianghuan Liu, Jiawen Song, Tianhao Jiang, Zihua Xu, Xudong Gao and Qingchun Zhao

{"title":"ZRMQ-22, a novel DYRK1A inhibitor, attenuates neuroinflammation and cognitive impairments in LPS-induced mice: a potential strategy for Alzheimer's disease","authors":"Mengyu Ren, Huanhua Chen, Zhenshu Li, Jiacheng Zhuang, Aizhu Yang, Xiangdong Li, Xinyu Li, Xinpeng Wang, Zonghe Xu, Xianghuan Liu, Jiawen Song, Tianhao Jiang, Zihua Xu, Xudong Gao and Qingchun Zhao","doi":"10.1039/D6MD00007J","DOIUrl":"10.1039/D6MD00007J","url":null,"abstract":"Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and memory loss. Targeting the kinase DYRK1A has emerged as a promising therapeutic strategy, as it plays a critical role in multiple key AD pathologies, including tau phosphorylation, β-amyloid (Aβ) production, and the regulation of neuroinflammatory processes. In this study, a series of novel quinazoline derivatives were designed and synthesized as DYRK1A inhibitors. Through preliminary anti-neuroinflammatory screening in a lipopolysaccharide (LPS)-induced BV2 microglial cell model, ZRMQ-22 was identified as a promising candidate that targets neuroinflammatory pathways in AD. This compound exhibits potent nanomolar-range inhibitory activity against DYRK1A, with an IC50 value of 0.35 nM. In LPS-stimulated BV2 cells, ZRMQ-22 concentration-dependently inhibited nitric oxide (NO) production, showing an IC50 of approximately 1 μM. Furthermore, at a concentration of 1 μM, it significantly suppressed the secretion of pro-inflammatory cytokines TNF-α and IL-6, with inhibition rates of 64.99% and 114.35%, respectively. In vivo experiments demonstrated that ZRMQ-22 effectively reduced levels of inflammatory markers and improved cognitive function in an LPS-induced neuroinflammation mouse model using C57BL/6 mice. These findings highlight ZRMQ-22 as a potent and safe DYRK1A inhibitor with significant efficacy in alleviating neuroinflammation and cognitive impairment, supporting its further development as a therapeutic candidate for AD.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 2036-2052"},"PeriodicalIF":3.597,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147378405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PROTAC approaches against drug-resistant EGFRC797S/L858R/T790M mutants: biological evaluation and SAR studies (2020–2025) 抗耐药EGFRC797S/L858R/T790M突变体的PROTAC方法：生物学评价和SAR研究（2020-2025）

IF 3.597

MedChemComm Pub Date : 2026-02-18 DOI: 10.1039/D5MD01113B

Ankush Kumar, Vishakha Sharma, Pallvi Kumari, Rajwinder Kaur and Rohit Bhatia

{"title":"PROTAC approaches against drug-resistant EGFRC797S/L858R/T790M mutants: biological evaluation and SAR studies (2020–2025)","authors":"Ankush Kumar, Vishakha Sharma, Pallvi Kumari, Rajwinder Kaur and Rohit Bhatia","doi":"10.1039/D5MD01113B","DOIUrl":"10.1039/D5MD01113B","url":null,"abstract":"The development of epidermal growth factor receptor (EGFR) C797S/L858R/T790M mutation has become a major barrier to tyrosine kinase inhibitors (TKIs). These mutations reduce the drug binding and increase the adenosine triphosphate (ATP) competition, which continues the EGFR signaling. As C797S/L858R/T790M resistance rates continue to rise, there is an urgent need for therapeutic strategies that are capable of eliminating the wild type and mutated forms of EGFR. Proteolysis-targeting chimera (PROTAC)-based degraders have recently gained significant attention as next-generation targeted degradation rather than simply enzymatic inhibition. PROTACs work through protein degradation and can bypass the many limitations of classical inhibitors. Recent studies from 2020–2025 have reported many EGFR-directed PROTACs for such mutations. Several of these degraders showed excellent activity against C797S as well as L858R and T790M. In this review, the authors have compiled the PROTACs designed in this duration. The authors have also discussed their medicinal chemistry, structure–activity relationship (SAR), and key features that could improve the binding and degradation efficiency. Overall, this review provides an updated overview of next-generation EGFR degraders and their potential to overcome the C797S/L858R/T790M-mediated drug resistance.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1888-1906"},"PeriodicalIF":3.597,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147378389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Medicinal attributes of nitrogen heterocycles directing aldose reductase selectivity and potency 氮杂环化合物对醛糖还原酶选择性和效力的影响。

IF 3.597

MedChemComm Pub Date : 2026-02-04 DOI: 10.1039/D5MD01038A

Anita Kumari, Shyamal Kumar Manna, Kajal Rani, Rupali Kohal, Ghanshyam Das Gupta and Sant Kumar Verma

{"title":"Medicinal attributes of nitrogen heterocycles directing aldose reductase selectivity and potency","authors":"Anita Kumari, Shyamal Kumar Manna, Kajal Rani, Rupali Kohal, Ghanshyam Das Gupta and Sant Kumar Verma","doi":"10.1039/D5MD01038A","DOIUrl":"10.1039/D5MD01038A","url":null,"abstract":"Diabetic complications arise primarily from hyperglycemia-induced metabolic disturbances, among which the polyol pathways play a significant role through the overactivation of aldose reductase. ARIs have therefore emerged as a potent therapeutic approach to prevent or delay diabetes-associated microvascular oxidative damage. In recent years, nitrogen-based heterocyclic compounds have gained prominence as potent ARIs due to their structural variability and pharmacodynamic profiles. This review comprehensively analyzes the structural features and target interactions of various nitrogen-containing scaffolds, including quinoxalines, pyrazolines, imidazoles, oxadiazoles, pyrazoles, triazoles, pyrimidines, thiazoles, and purines, as ARIs. SAR analysis reveals that acidic or bioisosteric head groups and electrostatic interactions with key ALR2 residues, such as Tyr48, His110, and Trp111, thereby increase potency and selectivity over related aldo–keto reductases. Similarly, physicochemical parameters, including lipophilicity, pKa, and H-bond donor and acceptor properties, influence tissue penetration and pharmacokinetic behavior. Additionally, molecular docking and binding analyses reveal common interaction patterns in the anion-binding and specificity pockets of ALR2, providing mechanistic insight into heterocycle-mediated inhibition. Overall, this review identifies design trends and limitations in nitrogen heterocycle-based ARIs, offering valuable guidance for structure-guided drug design of selective, potent, and clinically therapeutic agents for managing diabetic complications.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1445-1473"},"PeriodicalIF":3.597,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147309531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Leveraging fragment-based drug discovery to advance 3D scaffolds into potent ligands: application to the histamine H1 receptor 利用基于片段的药物发现将3D支架推进到有效的配体：应用于组胺H1受体。

IF 3.597

MedChemComm Pub Date : 2026-01-29 DOI: 10.1039/D5MD01081K

Tom Dekker, Oscar P. J. van Linden, Herman D. Lim, Mabel E. Dekker, Henry F. Vischer, Rob Leurs, Tiffany van der Meer, Maurice C. M. L. Buzink, David J. Hamilton, Barbara Zarzycka, Elwin Janssen, Maikel Wijtmans and Iwan J. P. de Esch

{"title":"Leveraging fragment-based drug discovery to advance 3D scaffolds into potent ligands: application to the histamine H1 receptor","authors":"Tom Dekker, Oscar P. J. van Linden, Herman D. Lim, Mabel E. Dekker, Henry F. Vischer, Rob Leurs, Tiffany van der Meer, Maurice C. M. L. Buzink, David J. Hamilton, Barbara Zarzycka, Elwin Janssen, Maikel Wijtmans and Iwan J. P. de Esch","doi":"10.1039/D5MD01081K","DOIUrl":"10.1039/D5MD01081K","url":null,"abstract":"Fragment-based drug discovery (FBDD) often relies on screening simple, 2D aromatic fragments, with the introduction of 3D character typically being reserved for later stages of hit optimization. The use of 3D screening fragments has been limited because of concerns about reduced hit rates and limited availability arising from synthetic accessibility constraints. Consequently, the chemical diversity of screening libraries has been restricted, and the potential of 3D scaffolds remains underexplored. To address these limitations, we developed novel synthetic methodologies for constructing 3D scaffolds and integrated them into FBDD workflows, which we consider an optimal strategy to advance these chemistries into hit optimization programs. Here, we report the screening of a focused 3D fragment library and the identification of a cyclobutane-containing hit for the histamine H1 receptor. A subsequent hit exploration yielded high-affinity antagonist 17a (VUF26691, pKi = 8.8). Overall, we demonstrate that FBDD is an efficient method to achieve the incorporation of novel (3D) chemistries into biologically active compounds.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1483-1492"},"PeriodicalIF":3.597,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12895670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Harnessing carlina oxide scaffold for the management of vector-borne diseases: synthesis and structure–activity relationship 利用氧化carlina支架管理媒介传播疾病：合成和构效关系。

IF 3.597

MedChemComm Pub Date : 2026-01-21 DOI: 10.1039/D5MD01032B

Eleonora Spinozzi, Alessia Piergentili, Marta Ferrati, Cecilia Baldassarri, Giada Trebaiocchi, Paolo Rossi, Fabrizio Araniti, Alice Zambelli, Loredana Cappellacci, Laura Zeppa, Martina Giangrossi, Alessandro Palmieri, Roman Pavela, Filippo Maggi and Riccardo Petrelli

{"title":"Harnessing carlina oxide scaffold for the management of vector-borne diseases: synthesis and structure–activity relationship","authors":"Eleonora Spinozzi, Alessia Piergentili, Marta Ferrati, Cecilia Baldassarri, Giada Trebaiocchi, Paolo Rossi, Fabrizio Araniti, Alice Zambelli, Loredana Cappellacci, Laura Zeppa, Martina Giangrossi, Alessandro Palmieri, Roman Pavela, Filippo Maggi and Riccardo Petrelli","doi":"10.1039/D5MD01032B","DOIUrl":"10.1039/D5MD01032B","url":null,"abstract":"Vector-borne diseases are causes of global health concern and mosquitoes are the primary transmitters of health-threatening pathogens. Botanicals are sources of compounds structurally modifiable into versatile hits for novel plant-based insecticides. Carlina oxide (1) is a natural compound isolated from Carlina acaulis L. (Asteraceae) with promising insecticidal potential, whose industrial production is limited by the absence of a plant supply chain. Herein, a one-step synthesis producing 1 in 81% yield was developed and a structure–activity relationship (SAR) study for the larvicidal activity on Aedes albopictus (Skuse, 1894) and Anopheles stephensi (Liston, 1901) was performed. The most promising analogue (5) displayed an encouraging larvicidal action (LC50 < 6.0 μg mL−1), safety profile on human keratinocytes (IC50 > 100 μg mL−1) and non-target organisms if compared to 1. Untargeted metabolomic analysis on mosquito larvae revealed that 1 and 5 target the carbohydrates and amino acid metabolism.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 912-931"},"PeriodicalIF":3.597,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Parallels between the chloro and methoxy groups for potency optimization 氯基和甲氧基之间的相似之处用于效价优化。

IF 3.597

MedChemComm Pub Date : 2026-01-19 DOI: 10.1039/D5MD00848D

Debora Chiodi and Yoshihiro Ishihara

{"title":"Parallels between the chloro and methoxy groups for potency optimization","authors":"Debora Chiodi and Yoshihiro Ishihara","doi":"10.1039/D5MD00848D","DOIUrl":"10.1039/D5MD00848D","url":null,"abstract":"Small substituents such as chloro (Cl), fluoro, methyl, and methoxy (OCH3) are often used in drug discovery to optimize ligand–protein interactions. Even though Cl is an electron-withdrawing group and OCH3 is an electron-donating group exerting opposite effects on an aromatic ring, Cl and OCH3 also display similarities in that they both exhibit dual electrostatic behavior. In a C–Cl bond, Cl is electronegative and adopts negative electrostatic potential, but at the same time, it has a σ-hole that is depleted of electron density and has an area of positive electrostatic potential. Similarly, the oxygen atom of OCH3 displays negative electrostatic potential, but inductive electron-withdrawing effects bestow positive electrostatic potential at the terminal methyl group. This dual nature allows a versatile interaction with partially positive (δ+) and partially negative (δ−) regions of a protein pocket. In this study, four main types of intermolecular interactions are discussed from the vantage point of Cl and OCH3 substituents: 1) hydrogen bonding, 2) orthogonal multipolar interactions, 3) halogen bonding and CH–O hydrogen bonding, and 4) Cl–π bonding and CH–π bonding. A comprehensive search of the PDB and analysis of X-ray co-crystal structures for each type of interaction unveiled parallels between Cl and OCH3 in the manner in which these substituents engage with amino acid residues. The opposing electronic effects of Cl and OCH3 substituents on an aromatic ring, along with the dual electrostatic versatility of these two groups, render them useful scouts to probe protein pockets for potency optimization.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 2","pages":" 1207-1230"},"PeriodicalIF":3.597,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endoperoxide delivered singlet oxygen: the future of PDT, without light or oxygen 内过氧化物输送单线态氧：PDT的未来，无需光或氧。

IF 3.597

MedChemComm Pub Date : 2026-01-17 DOI: 10.1039/D5MD00887E

Wanwan Wang, Lei Wang, Rensong Sun, Xiao Qian, Ziang Liu and Engin U. Akkaya

引用次数: 0

Discovery of RP-37 analogues as potent, selective irreversible inhibitors targeting DNA polymerase theta (POLθ) 发现RP-37类似物作为靶向DNA聚合酶theta （POLθ）的有效，选择性不可逆抑制剂。

IF 3.597

MedChemComm Pub Date : 2026-01-16 DOI: 10.1039/D5MD00830A

Zhenwei Wang, Mengyuan Qiu, Deming Liu, Yanzhen Yu, Dongyan Gu, FengMin Zhang and Rong Sheng

引用次数: 0

Exploring pyrazoline-thiophene hybrids as CDK2 inhibitors: synthesis, mechanism, biological studies, and computational insights 探索吡唑啉-噻吩复合物作为CDK2抑制剂：合成、机制、生物学研究和计算见解。

IF 3.597

MedChemComm Pub Date : 2026-01-15 DOI: 10.1039/D5MD00910C

Heba M. Abosalim, Tarek F. El-Moselhy, Nabaweya Sharafeldin, Mohamed S. Nafie, Mohamed K. Diab, Mervat H. El-Hamamsy and Haytham O. Tawfik

{"title":"Exploring pyrazoline-thiophene hybrids as CDK2 inhibitors: synthesis, mechanism, biological studies, and computational insights","authors":"Heba M. Abosalim, Tarek F. El-Moselhy, Nabaweya Sharafeldin, Mohamed S. Nafie, Mohamed K. Diab, Mervat H. El-Hamamsy and Haytham O. Tawfik","doi":"10.1039/D5MD00910C","DOIUrl":"10.1039/D5MD00910C","url":null,"abstract":"Pyrazoline-linked thiophenes (4a–p), a novel family of compounds, were designed and synthesized, and their anticancer potential was assessed. The most effective analogues of bis-thiophene (4n and 4o) and tris-thiophene (4p) were discovered to have sub-micromolar cytotoxicity against MCF-7 breast cancer (IC50 = 0.17 μM) and A549 lung cancer (IC50 = 0.78 μM) cells. Using flow cytometry, compound 4p triggered apoptosis in the MCF-7 cells, and caused G1/S-phase arrest (36.74% total apoptotic cells, compared to 0.99% in the control). The intrinsic apoptotic pathway was activated, as evidenced by downregulation of Bcl-2 and upregulation of P53, Bax, PUMA, and caspases-3 and -9, as validated by RT-PCR analysis. The potency of compound 4p (IC50 = 148 nM) against CDK2 was much higher than that of roscovitine (IC50 = 700 nM). Molecular docking supported these results by demonstrating stable hydrogen-bond interactions with Leu83 and Lys89, as well as significant hydrophobic interactions in the ATP-binding region. In vivo, 4p significantly reduced tumor burden in the Ehrlich carcinoma model (TIR% = 32.2%), recovered hematological parameters, and demonstrated negligible systemic toxicity. ADMET projections further highlighted positive drug-like qualities. Taking together, compound 4p is a promising anticancer candidate that targets CDK2 and exhibits strong in vivo efficacy, with supporting molecular evidence.","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 3","pages":" 1651-1671"},"PeriodicalIF":3.597,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0