Medicinal Chemistry Research最新文献

{"title":"Misconceptions among medicinal chemists regarding ADME and PK optimization","authors":"Yue Pan","doi":"10.1007/s00044-026-03543-4","DOIUrl":"10.1007/s00044-026-03543-4","url":null,"abstract":"","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 4","pages":"668 - 685"},"PeriodicalIF":3.1,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754383","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":"Site-Specific incorporation of lysine acetyl-methylation into proteins","authors":"Jingxiang Zhao,&nbsp;Xinlong Guo,&nbsp;Xuelian Ren,&nbsp;Jiyang Yu,&nbsp;Xiaohan Song,&nbsp;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_CUA^Pyl 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}

{"title":"Inactivation of ornithine aminotransferase by (1R,4S)-4-Amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid via a stable quinonoid intermediate","authors":"Koon Mook Kang,&nbsp;Abigail L. Vargas,&nbsp;Wei Zhu,&nbsp;Inna Sokolenko,&nbsp;Dali Liu,&nbsp;Richard B. Silverman","doi":"10.1007/s00044-026-03538-1","DOIUrl":"10.1007/s00044-026-03538-1","url":null,"abstract":"<div><p>Ornithine aminotransferase (OAT), a pyridoxal 5’-phosphate (PLP)-dependent enzyme, is a key contributor to glutamine supply in cancer cells, suggesting its therapeutic potential for hepatocellular carcinoma (HCC), the most common form of liver cancer. To identify an initial set of OAT inactivators, we have tested inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), a homologous PLP-dependent enzyme, with human OAT (<i>h</i>OAT) and identified several co-inactivators. Among the active molecules, (1<i>R</i>,4<i>S</i>)-4-amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid (<b>2</b>) has not been thoroughly investigated for its time-dependent kinetics and mechanistic pathways with OAT. In this study, we evaluated the time-dependent inactivation of <i>h</i>OAT by <b>2</b> and investigated the underlying mechanism, primarily based on X-ray crystallography. The results demonstrated that <b>2</b> acts as a time-dependent OAT inactivator with an inactivation efficiency (<i>k</i>_inact/<i>K</i>_I = 5.1 min⁻¹mM⁻¹) approximately 30-fold higher than that for GABA-AT (<i>k</i>_inact/<i>K</i>_I = 0.17 min⁻¹mM⁻¹) and, notably, revealed an inactivation pathway that proceeds via a stable quinonoid intermediate, as evidenced by the UV-Vis spectroscopy.</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":"792 - 803"},"PeriodicalIF":3.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03538-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754487","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}

{"title":"Siderophore–Porphyrin conjugates for bacteria-selective antimicrobial photodynamic therapy","authors":"Jinyoung Oh,&nbsp;Seunghyun Choi,&nbsp;Woojin Yang,&nbsp;Jieun Choi,&nbsp;Jiwon Seo","doi":"10.1007/s00044-026-03537-2","DOIUrl":"10.1007/s00044-026-03537-2","url":null,"abstract":"<div><p>Targeted delivery of photosensitizers represents a key strategy for improving the selectivity and efficacy of antimicrobial photodynamic therapy (aPDT). Herein, we describe the synthesis and biological evaluation of siderophore-conjugated photosensitizers designed to exploit bacterial iron acquisition pathways. Four distinct photosensitizers—neutral porphyrin (TPP), cationic porphyrin (TMPyP), metalloporphyrin (PdTMPyP), and chlorin (Ce6)—were covalently linked to deferoxamine B (DFO), a clinically approved hydroxamate siderophore. The resulting conjugates retained their intrinsic photophysical properties while exhibiting iron-dependent antimicrobial activity against siderophore-utilizing pathogens. TMPyP-DFO (<b>3</b>) was determined as the best compound, demonstrating potent antimicrobial photodynamic activity against <i>Staphylococcus aureus</i> and <i>Acinetobacter baumannii</i> under iron-deficient conditions (MIC₅₀ = 6.3–12.5 µM) with low mammalian cytotoxicity (LC₅₀ = 146.6 µM). Neutral porphyrin- and chlorin-siderophore conjugates (<b>1</b> and <b>2</b>, respectively) demonstrated either poor activity or lack of selectivity. These findings validate the ‘Trojan horse’ delivery strategy—achieved through the conjugation of cationic porphyrins with siderophores—as a promising strategy for enhancing bacterial selectivity in aPDT.</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":"804 - 813"},"PeriodicalIF":3.1,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754472","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":"Synthesis and structure-activity relationship evaluation of hypoglycemic activity of novel borneol and isoborneol containing (hydroxyphenyl)propanoic acids as FFAR1 agonists","authors":"Sergey O. Kuranov,&nbsp;Mikhail V. Larin,&nbsp;Irina D. Levchenko,&nbsp;Yulia V. Meshkova,&nbsp;Mariya K. Marenina,&nbsp;Olga A. Luzina,&nbsp;Mikhail V. Khvostov,&nbsp;Tatiana G. Tolstikova,&nbsp;Nariman F. Salakhutdibov","doi":"10.1007/s00044-026-03532-7","DOIUrl":"10.1007/s00044-026-03532-7","url":null,"abstract":"<div><p>Free Fatty Acid Receptor-1 (FFAR1) agonists are promising candidates for the treatment of type 2 diabetes mellitus due to their glucose-lowering ability. Previously, we have shown that a benzyloxyphenylpropanoic acid derivative <b>QS-619</b> (<b>5d</b>) containing a (−)-borneol residue acts as an effective FFAR1 agonist and exerts a hypoglycemic effect in mice. To establish the initial structure-activity relationships (SAR) for this chemotype, with a particular focus on the critical role of the terpene fragment’s stereochemistry, we synthesized a series of its structural analogues with variations in the configuration of stereocenters and the position of substituents in the aromatic rings. The effect of borneol stereochemistry on hypoglycemic activity was studied. The cytotoxicity of the synthesized compounds was evaluated on HepG2 and HEK293T cell lines. The hypoglycemic activity of these compounds was assessed in an oral glucose tolerance test (OGTT) in mice at doses of 15 mg/kg and 30 mg/kg. The most potent hypoglycemic agent identified was compound <b>5e</b> which bears a (+)-bornyl moiety. It demonstrated a strong effect at both doses, showed no cytotoxicity (CC₅₀ &gt;100 µM), but exhibited acute toxicity at a dose of 1000 mg/kg. Compounds <b>5f</b> and <b>5g</b>, containing (−)- and (+)-isobornyl moieties, respectively, showed a less pronounced hypoglycemic effect compared to the bornyl derivatives <b>5d</b> and <b>5e</b>. The cyclohexyl derivative <b>5h</b> was active only at the 30 mg/kg dose. Furthermore, co-administration of an FFAR1 antagonist was found to suppress the hypoglycemic activity of the studied compounds in the OGTT, supporting an FFAR1-mediated mechanism of action.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 3","pages":"649 - 663"},"PeriodicalIF":3.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429374","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":"Discovery of quinazoline-based derivatives as novel autophagy inhibitors in pancreatic cancer","authors":"Dongxuan Ni,&nbsp;Man Jin,&nbsp;Hongyuan Zhou,&nbsp;Ruoxi Xue,&nbsp;Fudong Wu,&nbsp;Tongyi Pu,&nbsp;Bin Liang,&nbsp;Ruihan Zhang,&nbsp;Jia Su,&nbsp;Weilie Xiao","doi":"10.1007/s00044-026-03533-6","DOIUrl":"10.1007/s00044-026-03533-6","url":null,"abstract":"<div><p>Pancreatic cancer remains a highly lethal malignancy with limited treatment options. Given the versatile bioactivity of quinazoline derivatives, which are regarded as a promising scaffold for anticancer drug discovery, we designed and synthesized a series of novel quinazoline analogues. Their cytotoxicity was evaluated in three pancreatic cancer cell lines (HPAC, AsPC-1, and MIA PaCa-2), leading to the identification of compound <b>5a</b>, which exhibited potent effects across all tested cell lines. Further investigation of anticancer activity indicated that <b>5a</b> significantly inhibited DNA synthesis, clonogenesis, and migration in MIA PaCa-2 cells. Mechanism study revealed that <b>5a</b> disrupted autophagy, as evidenced by downregulation of Beclin-1 expression and accumulation of LC3B-II and p62, through a mechanism independent of the canonical AMPK-mTOR-ULK1 signaling pathway. This study provides a promising active scaffold for the development of anti-pancreatic cancer agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 3","pages":"634 - 648"},"PeriodicalIF":3.1,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429375","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":"Volkameria (L.): A comprehensive review of its traditional medicine uses, phytochemistry and pharmacology","authors":"Shreyanshi Kulshreshtha,&nbsp;Bhawana Jangra,&nbsp;Yogita B. Tandalekar,&nbsp;Alok Goyal,&nbsp;Sanjay M. Jachak","doi":"10.1007/s00044-026-03531-8","DOIUrl":"10.1007/s00044-026-03531-8","url":null,"abstract":"<div><p>The genus <i>Volkameria</i>, belonging to the family Lamiaceae, comprises flowering plants with a pantropical distribution and a rich diversity of traditional applications and phytochemical compositions. Currently, 13 species are classified under this genus, which were previously categorized under different genera. This review aims to summarize the most up-to-date botanical descriptions, geographical distributions, ethnobotanical uses, phytochemistry, and pharmacological activities of <i>Volkameria</i> plants. Various databases and search engines, such as PubMed, Science Direct, Google Scholar, Sci-finder, Research Gate, online floras, and other published/unpublished resources, were consulted to compile this article. <i>Volkameria</i> species have been extensively used in traditional medicinal practices across different cultures to treat conditions such as fever, malaria, edema, cough, skin diseases, ulcers, inflammation, and rheumatism. Among the 13 accepted species, only four have been phytochemically investigated, with significant research focused on <i>Volkameria inermis</i>. Nearly 145 phytochemicals belonging to various classes, including flavonoids, diterpenoids, triterpenoids, steroids, and phenolic/lignan/iridoid/megastigmane glycosides, have been isolated and reported. Notably, flavonoids, diterpenoids, and triterpenoids have shown significant biological activities. <i>V. glabra</i>, and <i>V. inermis</i> have been studied for their pharmacological properties, such as antioxidant, anti-inflammatory, antimicrobial (including antibacterial, antiviral, antifungal, antimalarial, neuroprotective, anti-motor tics, insecticidal, and antifeedant effects. However, the remaining species require further investigation. Comprehensive studies, including preclinical and clinical trials, are essential to validate the efficacy and safety of these plants for medicinal use.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 3","pages":"506 - 547"},"PeriodicalIF":3.1,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429367","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":"Design, synthesis and insecticidal activities of novel meta-diamide compounds containing ethyl group","authors":"Dong Li,&nbsp;Zhu Xia,&nbsp;Jiyong Liu,&nbsp;Juncheng Xiang,&nbsp;Qiqi Huang,&nbsp;Liang Lv,&nbsp;Hang Gong,&nbsp;Kangming Li","doi":"10.1007/s00044-026-03529-2","DOIUrl":"10.1007/s00044-026-03529-2","url":null,"abstract":"<div><p>To develop structurally novel and efficient insecticides, a series of ethylpyridine-containing meta-diamide derivatives were designed and synthesized using cyproflanilide as the lead compound. The core bioactive scaffold was retained while integrating active substructure combination and pharmacophore fusion strategies. All compounds were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. Preliminary bioassay data showed that some target compounds exhibited good insecticidal activity against <i>Plutella xylostella</i>, <i>Mythimna separata</i>, and <i>Tetranychus cinnabarinus</i>. Particularly, compound 7 g exhibited 100% lethality at a concentration of 1 mg/L against both <i>Plutella xylostella</i> and <i>Mythimna separata</i>; meanwhile, compound 7q achieved complete lethality against <i>Tetranychus cinnabarinus</i> at a concentration of 100 mg/L. Further structure–activity relationship (SAR) analysis based on in vitro efficacy data provided a theoretical foundation for developing next-generation acaricides/insecticides. These findings offer valuable insights for designing novel meta-diamide agrochemicals with enhanced efficacy.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 3","pages":"625 - 633"},"PeriodicalIF":3.1,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429356","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":"FabH (β-Ketoacyl-ACP Synthase III) -- Promising Novel Antibacterial Target and Its Inhibitors","authors":"Gui-Wen Li,&nbsp;Qing-Yun Rong,&nbsp;Wen Zhang,&nbsp;Guo-Wu Rao,&nbsp;Quan Zheng","doi":"10.1007/s00044-025-03522-1","DOIUrl":"10.1007/s00044-025-03522-1","url":null,"abstract":"<div><p>The worldwide spread of antimicrobial resistance (AMR) is a considerable challenge to global health, resulting in a substantial depletion of human and material resources. Conventional antimicrobial agents are often ineffective against contemporary resistant strains, making the identification of novel drug targets a priority in antimicrobial development. Inhibition of the bacterial type II fatty acid synthesis (FAS-II) pathway is recognized as an effective antimicrobial strategy. β-Ketoacyl-ACP synthase III (FabH), a crucial enzyme in the FAS-II, presents potential as a target for next-generation antimicrobial agents. In recent years (2006–2025), research on synthetic small-molecule inhibitors targeting FabH has attracted widespread attention among scientists. However, reviews on FabH inhibitors remain scarce, with reports scattered across the literature. This paper outlines the attributes of FabH in various bacterial species and compiles the currently documented synthetic inhibitors. It examines the inhibitory effects of various core structures on FabH and analyzes the structure-activity relationships of specific compounds, including triazoles, carbazoles, indoles, and pyrazoles, etc. The goal is to offer innovative perspectives for the future development and formulation of antibacterial agents targeting FabH.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 3","pages":"472 - 505"},"PeriodicalIF":3.1,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429376","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":"A fast high-throughput logP estimation method for peptide molecules based on liquid chromatography-mass spectrometry method","authors":"Jing Deng,&nbsp;Hengmao Zhang,&nbsp;Yixuan Zhai,&nbsp;Wenbo Sun,&nbsp;Jin Li,&nbsp;Guansai Liu,&nbsp;Wei Tang","doi":"10.1007/s00044-026-03530-9","DOIUrl":"10.1007/s00044-026-03530-9","url":null,"abstract":"<div><p>We have developed a complete end-to-end high-throughput protocol for rapid estimation of logP values of peptide molecules. This scheme combines two core technologies: firstly, the “pool and split” high-throughput synthesis technology is used to efficiently prepare peptide samples; secondly, a logP detection method based on ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was developed, which relies on high-resolution mass spectrometry to accurately identify hundreds of components in mixed samples. In addition, we innovatively established a linear correlation model between chromatographic capacity factor logK’ and logP, which has an excellent correlation (R² = 0.92) and can accelerate fully automated data analysis. Finally, we successfully synthesized and detected mixed samples containing 16, 81, and 256 peptide molecules, with a logP detection rate exceeding 85%. The sample processing capacity of this detection system can exceed 20000 per day, which can significantly accelerate the early screening process of lead molecules in drug development.</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":"765 - 769"},"PeriodicalIF":3.1,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754486","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}