Medicinal Chemistry Research最新文献_第9页

Dynamic tail amine interactions drive isoform selectivity for potent human neuronal nitric oxide synthase inhibitors 动态尾胺相互作用驱动有效的人类神经元一氧化氮合酶抑制剂的异构体选择性

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-04-10 DOI: 10.1007/s00044-026-03552-3

Amardeep Awasthi, Koon Mook Kang, Richard B. Silverman

{"title":"Dynamic tail amine interactions drive isoform selectivity for potent human neuronal nitric oxide synthase inhibitors","authors":"Amardeep Awasthi, Koon Mook Kang, Richard B. Silverman","doi":"10.1007/s00044-026-03552-3","DOIUrl":"10.1007/s00044-026-03552-3","url":null,"abstract":"<div><p>Achieving isoform-selective inhibition of neuronal nitric oxide synthase (nNOS) remains a significant challenge due to the high structural similarity with other NOS isoforms. Here, we report the design, synthesis, and characterization of novel nNOS inhibitors <b>3</b> and <b>4</b>, incorporating dimethylamino-substituted tail groups to exploit hnNOS-specific peripheral pocket interactions. Both compounds retained sub-20 nM potency against human nNOS with enhanced selectivity over endothelial (hn/he > 1500-fold) and inducible (hn/hi > 229-fold) isoforms. Molecular dynamics simulations and MM-GBSA calculations suggested that hnNOS selectivity arises from a dynamically formed cation-π interaction between the terminal amino group and W311(B), which is precluded in heNOS due to the steric hindrance from F105. PAMPA-BBB assays inḍdicated moderate blood-brain barrier permeability, supporting CNS applications. These findings highlight peripheral pocket interactions as key drivers of isoform selectivity and guide future nNOS inhibitor optimization for neurodegenerative diseases and melanoma.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"757 - 764"},"PeriodicalIF":3.1,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03552-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Drug law versus common parlance of medicinal chemists on “new chemical entity” of novel drug designations 药品法与药物化学家关于新药名称“新化学实体”的常用说法

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-04-09 DOI: 10.1007/s00044-026-03546-1

Sarah K. Branch, Israel Agranat

引用次数: 0

Tropanes in natural products, syntheses, and drugs: some insights from the new millennium 天然产物、合成物和药物中的Tropanes：来自新千年的一些见解

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-04-08 DOI: 10.1007/s00044-026-03547-0

Maris A. Cinelli, Sabrina A. Mata, Tyler Watson

{"title":"Tropanes in natural products, syntheses, and drugs: some insights from the new millennium","authors":"Maris A. Cinelli, Sabrina A. Mata, Tyler Watson","doi":"10.1007/s00044-026-03547-0","DOIUrl":"10.1007/s00044-026-03547-0","url":null,"abstract":"<div><p>The term “tropane” refers to the 8-azabicyclo[3.2.1]octane core, first discovered in the tropane alkaloids produced by certain families of plants. These alkaloids, which are likely plant defense compounds, have well-precedented bioactivities such as muscarinic receptor antagonism and dopamine transporter (DAT) inhibition. The long-standing usefulness of alkaloids such as atropine, scopolamine, and cocaine has encouraged the incorporation of the tropane moiety into multiple other approved drugs, likely cementing its place as a privileged scaffold. Because of their diverse utility and efficacy, tropane-containing compounds are still an area of very active investigation. A quarter of the way through the new century, novel tropane alkaloids are still being discovered, imaginative and applicable ways to make these compounds are being revealed, and tropane-containing molecules have proven to be promising avenues for treatment of central nervous system (CNS) disorders, cancer, diabetes, viral infections, and many other conditions, as well as effective diagnostic agents and tool compounds. This review summarizes recent (2015–2025) developments concerning tropane-containing molecules. New natural products, synthetic strategies to construct and functionalize the tropane core, drug hits, leads, and clinical candidates, and other relevant molecules containing tropane moieties are described. An overview of where the “tropane field” is headed, with focus on finding, analyzing, and obtaining high-value alkaloids and analogs (and re-imagining drug synthesis and discovery in an increasingly technological and environmentally conscious age) is also provided.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"686 - 710"},"PeriodicalIF":3.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754438","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}

引用次数: 0

Proangiogenic effect and molecular mechanism of a new cytosporin derivative from the marine fungus Eutypella sp. D-1 海洋真菌真typella sp. D-1新细胞孢素衍生物的促血管生成作用及其分子机制

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-04-07 DOI: 10.1007/s00044-026-03548-z

Xiaoyue Sun, Ranran Zhu, Qijia Feng, Peihai Li, Yun Zhang, Qing Xia, Kechun Liu, Xuehui Jian, Yuanshuai YU, Xue Wang, Chen Sun, Haobing YU

{"title":"Proangiogenic effect and molecular mechanism of a new cytosporin derivative from the marine fungus Eutypella sp. D-1","authors":"Xiaoyue Sun, Ranran Zhu, Qijia Feng, Peihai Li, Yun Zhang, Qing Xia, Kechun Liu, Xuehui Jian, Yuanshuai YU, Xue Wang, Chen Sun, Haobing YU","doi":"10.1007/s00044-026-03548-z","DOIUrl":"10.1007/s00044-026-03548-z","url":null,"abstract":"<div><p>A new cytosporin derivative, cytoeutypellane D, was isolated from a culture extract of the Arctic-derived fungus <i>Eutypella</i> sp. D-1. Its structure was determined based on a detailed nuclear magnetic resonance spectroscopic interpretation, a mass spectrometry data analysis, and a literature review. Zebrafish were used in in vivo experiments to discover that the isolated compound significantly promoted angiogenesis in a dose-dependent manner. Further studies regarding the underlying mechanisms revealed that it may target the VEGF/VEGFR2 signaling pathway and rescue abnormal expressions of the <i>cdk1</i>, <i>aurkb</i>, <i>topbp1</i>, and <i>brca2</i> genes to improve vascular endothelial cell proliferation and migration in zebrafish. In summary, our findings suggested that this novel compound isolated from the fungus <i>Eutypella</i> sp. D-1 might be used as a promising molecule for vascular injury disease treatment.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 5","pages":"974 - 985"},"PeriodicalIF":3.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008847","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}

引用次数: 0

Discovery of phenylacetamide derivatives as novel STAT3 antagonists 苯乙酰胺衍生物作为新型STAT3拮抗剂的发现

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-04-04 DOI: 10.1007/s00044-026-03545-2

Po-Chang Shih

{"title":"Discovery of phenylacetamide derivatives as novel STAT3 antagonists","authors":"Po-Chang Shih","doi":"10.1007/s00044-026-03545-2","DOIUrl":"10.1007/s00044-026-03545-2","url":null,"abstract":"<div><p>Signal transducer and activator of transcription 3 (STAT3) is a central transcription factor in the JAK–STAT signaling axis and is commonly considered to be an anti-cancer drug target. However, no inhibitors that directly target STAT3 have been approved for use in patients. Targeting STAT3 SH2 domain and DNA-binding domain remain the two principle strategies when developing STAT3 inhibitors. In this study, a series of compounds with a phenylacetamide core were designed, synthesized, and biologically evaluated. Two fluorescence polarization (FP) assays were used, where STAT3:DNA FP assay was to understand inhibition of STAT3 DNA-binding potential, whereas STAT3:phosphopeptide FP assay was to understand abrogation of STAT3 dimerization potential. The FP findings showed that the phenylacetamide derivatives were prone to inhibit STAT3 dimerization than STAT3 DNA-binding, showing selectivity over the STAT3 SH2 domain. Compounds <b>P10</b>, <b>P15</b>, and <b>P21</b> showed potent STAT3 dimerization inhibition with FP-determined IC<sub>50</sub> values of ~15.6, ~29.4, ~6.49 μM respectively. Molecular docking results showed that compounds <b>P10</b>, <b>P15</b>, and <b>P21</b> may bind between the Linker and SH2 domains, and they displayed potential hydrogen bonding in the binding pocket. Prediction results of drug-likeness and physiochemical property values warrant <b>P10</b>, <b>P15</b>, and <b>P21</b> to be further investigated.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 5","pages":"961 - 973"},"PeriodicalIF":3.1,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008574","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}

引用次数: 0

Misconceptions among medicinal chemists regarding ADME and PK optimization 药物化学家对ADME和PK优化的误解

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-04-03 DOI: 10.1007/s00044-026-03543-4

Yue Pan

引用次数: 0

Discovery of 3-(N-phenylsulfamoyl)-l-phenylalanine derivatives as novel and orally available LAT1-selective inhibitors 发现3-（n -苯基磺胺酰）- l -苯丙氨酸衍生物作为新的口服lat1选择性抑制剂。

IF 3.5 4区医学

Medicinal Chemistry Research Pub Date : 2026-03-31 DOI: 10.1007/s00044-026-03541-6

Shuhei Uesugi, Tomoyuki Tsunemi, Hidenobu Murafuji, Kumiko Kadoshima-Yamaoka, Masao Murakawa, Naoyuki Makita, Urara Tomita, Yukiko Doke, Hiroshi Yukiura, Makoto Koyama, Yasuhiro Hayashi, Kyoko Yamashiro, Kazunori Yoshikiyo, Toshiki Tabata, Hiroshi Maruoka

{"title":"Discovery of 3-(N-phenylsulfamoyl)-l-phenylalanine derivatives as novel and orally available LAT1-selective inhibitors","authors":"Shuhei Uesugi, Tomoyuki Tsunemi, Hidenobu Murafuji, Kumiko Kadoshima-Yamaoka, Masao Murakawa, Naoyuki Makita, Urara Tomita, Yukiko Doke, Hiroshi Yukiura, Makoto Koyama, Yasuhiro Hayashi, Kyoko Yamashiro, Kazunori Yoshikiyo, Toshiki Tabata, Hiroshi Maruoka","doi":"10.1007/s00044-026-03541-6","DOIUrl":"10.1007/s00044-026-03541-6","url":null,"abstract":"<div><p>In this study, we discovered and optimized a novel series of <span>l</span>-type amino acid transporter 1 (LAT1)-selective inhibitors. Starting from compound <b>1</b>, efforts to explore the structure–activity relationship and optimize selectivity over <span>l</span>-type amino acid transporter 2 (LAT2) revealed the importance of the orientation of the terminal aromatic ring and led to the highly potent and LAT1-selective 2-phenoxy-substituted compound <b>19</b>. Pharmacokinetic studies of <b>19</b> demonstrated that it is orally bioavailable (10 mg/kg, p.o., mouse, AUC:2354 ng·h/mL). Further optimization of the aromatic ring improved its metabolic stability and resulted in highly LAT1-selective and orally bioavailable (10 mg/kg, p.o., mouse, AUC:3449 ng·h/mL) compound <b>26</b>. This series of compounds should be useful for research on LAT1 inhibitors.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 10","pages":"2028 - 2035"},"PeriodicalIF":3.5,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434626","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}

引用次数: 0

Discovery of aporphine derivatives with improved antidepressant activity by regulating SERT and 5-HT2AR. 阿啡衍生物通过调节SERT和5-HT2AR改善抗抑郁活性的发现。

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-03-26 DOI: 10.1007/s00044-026-03542-5

Chunyu Wu, Shasha Yue, Benqin Tang, Jianbo Sun

{"title":"Discovery of aporphine derivatives with improved antidepressant activity by regulating SERT and 5-HT2AR.","authors":"Chunyu Wu, Shasha Yue, Benqin Tang, Jianbo Sun","doi":"10.1007/s00044-026-03542-5","DOIUrl":"10.1007/s00044-026-03542-5","url":null,"abstract":"<div><p>Fifteen novel regulators targeting 5-HT<sub>2A</sub>R and serotonin transporter (SERT) were designed and synthesized, and their antidepressant activities were evaluated. Aporphine alkaloids and their derivatives have potential antidepressant activity. Fragments exhibiting 5-HT<sub>2A</sub>R antagonism and organic nitrate NO donors were introduced into the aporphine scaffold. Among all the target compounds, <b>I</b><sub><b>15</b></sub> was screened with the best protective effect against corticosterone-induced PC12 cell injury. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells. In addition, <b>I</b><sub><b>15</b></sub> significantly ameliorated the depression-like behavior of mice. Molecular docking indicated that <b>I</b><sub><b>15</b></sub> was able to occupy the active cavity of 5-HT<sub>2A</sub>R and SERT. Further study showed that the antidepressant mechanism of <b>I</b><sub><b>15</b></sub> was associated with the downregulation of both 5-HT<sub>2A</sub>R and SERT. In general, <b>I</b><sub><b>15</b></sub> could be a potential antidepressant candidate for further study.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 5","pages":"932 - 945"},"PeriodicalIF":3.1,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148010099","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}

引用次数: 0

Defining a lipophilicity window for the antimicrobial activity of 7-Alkoxy-3-Amino coumarin amphiphiles 确定7-烷氧基-3-氨基香豆素两亲体抗菌活性的亲脂性窗口

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-03-26 DOI: 10.1007/s00044-026-03540-7

Samuel O. Nitschke, Alysha G. Elliott, Shane M. Hickey, Sally E. Plush

{"title":"Defining a lipophilicity window for the antimicrobial activity of 7-Alkoxy-3-Amino coumarin amphiphiles","authors":"Samuel O. Nitschke, Alysha G. Elliott, Shane M. Hickey, Sally E. Plush","doi":"10.1007/s00044-026-03540-7","DOIUrl":"10.1007/s00044-026-03540-7","url":null,"abstract":"<div><p>The continued rise of antimicrobial resistance (AMR) demands the research and development of novel antimicrobial agents that act via mechanisms less prone to resistance. Cationic antimicrobial peptides (CAMPs) are naturally occurring molecules that exhibit potent antimicrobial activity but have not encountered significant AMR. Synthetic mimetics of CAMPs offer a cost-effective route to new antimicrobials. We have previously reported a series of amphiphilic coumarin derivatives that elicit potent activity against several pathogenic bacterial strains, including planktonic methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and MRSA biofilms. Although compound lipophilicity plays a significant role in antimicrobial activity, this relationship needs to be accurately defined for each class of compound to facilitate the design of improved therapeutic agents. In this study, six cationic coumarin amphiphiles were designed with varying lipophilic character. These compounds were synthesised, characterised, and evaluated against a panel of clinically relevant pathogenic bacteria (<i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and MRSA) and fungi (<i>Candida albicans</i> and <i>Cryptococcus neoformans</i>), to establish a lipophilic range that correlates to potent activity for this family of compounds. Our results suggest that when these compounds exist in their cationic state, a cLog<i>P</i> range of 0.75–1.82 correlates with best activity, with minimum inhibitory concentration (MIC) values as low as 0.02 µg/mL against <i>C. neoformans</i> and 1 µg/mL against MRSA obtained for derivatives that fall within this lipophilicity window.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 5","pages":"946 - 960"},"PeriodicalIF":3.1,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03540-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148010097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Site-Specific incorporation of lysine acetyl-methylation into proteins 赖氨酸乙酰甲基化与蛋白质的位点特异性结合

IF 3.1 4区医学

Medicinal Chemistry Research Pub Date : 2026-03-25 DOI: 10.1007/s00044-026-03544-3

Jingxiang Zhao, Xinlong Guo, Xuelian Ren, Jiyang Yu, Xiaohan Song, He Huang

{"title":"Site-Specific incorporation of lysine acetyl-methylation into proteins","authors":"Jingxiang Zhao, Xinlong Guo, Xuelian Ren, Jiyang Yu, Xiaohan Song, He Huang","doi":"10.1007/s00044-026-03544-3","DOIUrl":"10.1007/s00044-026-03544-3","url":null,"abstract":"<div><p>Lysine acetyl-methylation (Kam) is a novel protein post-translational modification (PTM) recently identified on histone H4, yet its biological functions on non-histone proteins remain largely unexplored. Here, we engineered an orthogonal <i>Methanosarcina barkeri</i> pyrrolysyl-tRNA synthetase (<i>Mb</i>PylRS) variant and tRNA<sub>CUA</sub><sup>Pyl</sup> pair for site-specific Kam incorporation into proteins in mammalian cells. Using this system, we identified endogenous Kam sites at K28 of adenylate kinase 2 (AK2) and K207 of pyruvate kinase M2 (PKM2) through proteomic analysis. Functional characterization revealed that Kam at these evolutionarily conserved residues significantly attenuated enzymatic activity. These findings demonstrate that Kam serves as a regulatory mechanism for non-histone proteins, and the ability to generate proteins harboring Kam at defined sites provides a valuable approach for investigating the biological roles of this newly identified PTM.</p><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"770 - 777"},"PeriodicalIF":3.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754386","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}

引用次数: 0