ChemMedChem最新文献_第5页

New Binding Sites for JAK2 Inhibition in Myeloproliferative Neoplasms: Structural Insights, Therapeutic Potential, and Future Directions 骨髓增殖性肿瘤中JAK2抑制的新结合位点：结构见解，治疗潜力和未来方向

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-31 DOI: 10.1002/cmdc.202501079

Gang Zhao, Junyu Guo, Xinying Cheng, Renbing Wang, Ahmed R. Ali, Yucheng Tian, Zhiyu Li, Jinlei Bian, Huidan Huang

{"title":"New Binding Sites for JAK2 Inhibition in Myeloproliferative Neoplasms: Structural Insights, Therapeutic Potential, and Future Directions","authors":"Gang Zhao, Junyu Guo, Xinying Cheng, Renbing Wang, Ahmed R. Ali, Yucheng Tian, Zhiyu Li, Jinlei Bian, Huidan Huang","doi":"10.1002/cmdc.202501079","DOIUrl":"10.1002/cmdc.202501079","url":null,"abstract":"Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders driven in large part by aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway via the JAK2 V617F and related mutations. The success of first-generation ATP competitive JAK2 inhibitors has validated JAK2 as a therapeutic target, yet clinical benefits remain constrained by issues of off target toxicity, limited mutation allele burden reduction, and the emergence of persistence or resistance. In this review, we focus on a rapidly emerging design paradigm: targeting novel binding sites on JAK2 beyond the canonical ATP pocket—including allosteric sites, covalent anchor residues, and pseudokinase regulatory domains. We summarize structural and computational insights into these new sites, compare mechanistic and therapeutic advantages (such as enhanced selectivity, reduced cross JAK inhibition and potential to overcome resistance) and evaluate preclinical and early clinical evidence. We further identify remaining challenges in the development of next generation JAK2 inhibitors—such as site validation, ligand residence time, covalent binding safety, and rational combination therapies—and propose future directions for translation into the MPN clinic. By refocusing the JAK2 inhibitor field around novel binding site exploitation, we suggest a path toward more potent, selective and enduring therapies for MPN patients.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147579966","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 New CDDO-Imidazole Derivatives as Potential Antitumor Agents 新的cddo -咪唑衍生物作为潜在的抗肿瘤药物的发现。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-31 DOI: 10.1002/cmdc.202600008

Yanqing Li, Lingjie Zhang, Qunfeng Luo, Yanzi Li, Siqi Zhang, Jianghong Pei, Mingming Qi, Na Li, Li Chen

引用次数: 0

Bioactive Transition Metal(II) Hydrazone Complexes: Spectral Elucidation, Antimalarial, Antioxidant, and Antimicrobial Activities Correlated With Molecular Docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity 生物活性过渡金属（II）腙配合物：光谱解析、抗疟、抗氧化和抗菌活性与分子对接、吸收、分布、代谢、排泄和毒性相关。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-31 DOI: 10.1002/cmdc.202501071

Manisha Rathi, Jai Devi, Nishu Dhillayan, Sonika Asija

{"title":"Bioactive Transition Metal(II) Hydrazone Complexes: Spectral Elucidation, Antimalarial, Antioxidant, and Antimicrobial Activities Correlated With Molecular Docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity","authors":"Manisha Rathi, Jai Devi, Nishu Dhillayan, Sonika Asija","doi":"10.1002/cmdc.202501071","DOIUrl":"10.1002/cmdc.202501071","url":null,"abstract":"Resistance to conventional antimalarial remains a major challenge, and hydrazone-based metal chelates offer a promising strategy due to their flexibility, redox behavior, and improved pharmacological efficacy. Hydrazone ligands (1-20) were synthesized from ethylcarbazate and salicylaldehyde derivatives and subsequently coordinated with Co(II), Ni(II), Cu(II), and Zn(II) metals. The compounds were structurally characterized through NMR (1H and 13C), mass spectrometry, fourier transform infrared (FT-IR), ultraviolet–visible (UV–Vis), scanning electron microscopy, electron spin resonance, powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), and conductivity studies, revealing an octahedral geometry. Biological activity of the synthesized compounds was analyzed for antimalarial, antioxidant, and antimicrobial properties employing microassay, DPPH radical scavenging and serial dilution method, respectively. In vitro screening of the synthesized compounds for antimalarial and antimicrobial activities revealed that compounds (15) and (16) were most active, demonstrating superior IC50 values 0.066–0.067 µg/mL against P. falciparum and (MIC values of 0.0332–0.0408 μmol/mL against bacterial strain and 0.0087 μmol/mL against fungal strain, respectively. The antioxidant assessments showed that complexes (17), (19), and (20) were the most effective in attenuating oxidative stress, as indicated by their minimal IC50 values (3.1 ± 0.026 μM–4.2 ± 0.0004 μM). Molecular docking supported the bioactivity, showing higher binding affinities for complexes (15) and (16). The compound's oral drug-like structure was confirmed by absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147579931","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

Snake Venom Protease Detection and Inhibition in Serum 血清中蛇毒蛋白酶的检测及抑制作用。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-31 DOI: 10.1002/cmdc.202501099

Mareike Riedel, Christian Kersten

{"title":"Snake Venom Protease Detection and Inhibition in Serum","authors":"Mareike Riedel, Christian Kersten","doi":"10.1002/cmdc.202501099","DOIUrl":"10.1002/cmdc.202501099","url":null,"abstract":"Snake bites remain major threats with only limited diagnostic and therapeutic options. Current antibody-based antivenoms show only limited effectiveness against local tissue damage and require complex manufacturing and cold chain logistics. To overcome these limitations, a fluorescence-based assay was established to enable the sensitive detection of snake venom metalloprotease (SVMP) and serine protease (SVSP) activities in crude viper venoms from Crotalus atrox, Bothrops jararaca, and Echis carinatus. The assays showed species-specific activity profiles with detection limits in the sub-microgram per 45 and 100 µL range for SVSP and SVMP, respectively. Notably, protease activity in bovine and human blood sera, with only a slight loss of sensitivity compared to isolated venom in buffer, can be measured. Inhibitory effects of small molecule protease inhibitors, batimastat, marimastat, ilomastat, nafamostat, and leupeptin, were determined, showing strong SVMP or SVSP inhibition, respectively. Based on this proof-of-concept, the combination of such activity-based assays with selective small-molecule inhibitors could open new opportunities for rapid venom detection in diagnosis and complementary therapy, particularly in resource-poor settings.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13037691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147579960","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

Discovery of a Prodrug of Bardoxolone Methyl for the Treatment of Acute Lung Injury 甲基巴多洛酮治疗急性肺损伤前药的发现。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-31 DOI: 10.1002/cmdc.202501062

Shuai Wen, Yingping Li, Xi Li, Fan Huo, Qiulan Chen, Hongkai Sha, Yan Wang, Yao Zhao, Zhengyu Jiang, Yi Mou

引用次数: 0

Front Cover: Comprehensive Magnetic Resonance Imaging Relaxometry of Gadolinium-Based Contrast Agents: A Systematic Study of Transmetallation and Transchelation Processes With Zinc Ions and Heparin (ChemMedChem 6/2026) 封面：钆基造影剂的综合磁共振成像弛豫测量：锌离子和肝素的金属转化和转运过程的系统研究（ChemMedChem 6/2026）

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-30 DOI: 10.1002/cmdc.70274

Patrick Werner, Leif Schröder

引用次数: 0

Functionalized Cyclic Beta-Amino Acid Derivatives With Antiviral Potential 具有抗病毒潜力的功能化环β -氨基酸衍生物。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-30 DOI: 10.1002/cmdc.202500862

Melinda Nonn, Marta Denel-Bobrowska, Balázs Volk, Agnieszka B. Olejniczak, Loránd Kiss

引用次数: 0

Design and Discovery of Substituted 1,3,4-Thiadiazole–1,3,5-Triazine Hybrids as Human Immunodeficiency Virus-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Anti-SARS-CoV-2 and Antibacterial Activities 具有抗sars - cov -2和抗菌活性的1,3,4-噻二唑-1,3,5-三嗪取代型人类免疫缺陷病毒-1非核苷类逆转录酶抑制剂的设计和发现

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-30 DOI: 10.1002/cmdc.202501109

Saumya Singh, Kumar Saurabh Srivastava, Mukesh Kumar Kumawat, Hans Raj Bhat, Angela Corona, Enzo Tramontano, Debashis Mitra, Udaya Pratap Singh

{"title":"Design and Discovery of Substituted 1,3,4-Thiadiazole–1,3,5-Triazine Hybrids as Human Immunodeficiency Virus-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Anti-SARS-CoV-2 and Antibacterial Activities","authors":"Saumya Singh, Kumar Saurabh Srivastava, Mukesh Kumar Kumawat, Hans Raj Bhat, Angela Corona, Enzo Tramontano, Debashis Mitra, Udaya Pratap Singh","doi":"10.1002/cmdc.202501109","DOIUrl":"10.1002/cmdc.202501109","url":null,"abstract":"A new series of substituted 1,3,4-thiadiazole–1,3,5-triazine hybrids was rationally designed, synthesized, and evaluated for their antiviral and antibacterial potential. The target di-substituted (9a–e) and tri-substituted (11a–e) derivatives were obtained via a stepwise nucleophilic substitution strategy from cyanuric chloride and characterized by spectroscopic techniques. Molecular docking studies against human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) revealed that para-substituted analogs displayed superior binding within the non-nucleoside reverse transcriptase inhibitor pocket through key hydrogen bonding, π–π stacking, and electrostatic interactions. In vitro evaluation identified compounds 11a as the most active candidate. Compound 11a exhibited 83.93% inhibition of RT activity at 1 μM, an EC50 of 72.7 nM, and effective suppression of HIV-1 replication in CEM–GFP T cells (85.19% p24 inhibition) with a favorable therapeutic index (TI = 471). Both compounds also demonstrated inhibition of SARS-CoV-2-induced cytopathic effects in Vero E6 cells at noncytotoxic concentrations. In addition, several derivatives showed moderate to good antibacterial activity against tested bacterial strains, with SAR analysis highlighting the importance of substituent electronics and positional effects on bioactivity. Overall, this study establishes substituted 1,3,4-thiadiazole–1,3,5-triazine hybrids as promising multifunctional scaffolds for antiviral and antibacterial drug development.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147579952","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

Cover Feature: Novel Vancomycin-β-Lactam Hybrids: Structure–Activity Relationships and Therapeutic Potential Against VISA and VRE (ChemMedChem 6/2026) 封面专题：新型万古霉素-β-内酰胺杂交体：结构-活性关系和抗VISA和VRE的治疗潜力（ChemMedChem 6/2026）

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-30 DOI: 10.1002/cmdc.70276

Taopeng Chang, Fang Li, Chengtao Feng, Xiaowen Wang, Dongliang Guan

引用次数: 0

Cover Feature: An Internal Sulfur–Lone Pair Interaction Enabled the Discovery of Potent and Sub-Family Selective PKMYT1 Inhibitors (ChemMedChem 6/2026) 封面特征：内部硫-孤独对相互作用使得发现有效的亚家族选择性PKMYT1抑制剂（ChemMedChem 6/2026）

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-03-30 DOI: 10.1002/cmdc.70275

Yazhou Wang, Chao Wang, Xiaomin Wang, Tingting Liu, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Xiao Ding, Alex Zhavoronkov

{"title":"Cover Feature: An Internal Sulfur–Lone Pair Interaction Enabled the Discovery of Potent and Sub-Family Selective PKMYT1 Inhibitors (ChemMedChem 6/2026)","authors":"Yazhou Wang, Chao Wang, Xiaomin Wang, Tingting Liu, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Xiao Ding, Alex Zhavoronkov","doi":"10.1002/cmdc.70275","DOIUrl":"https://doi.org/10.1002/cmdc.70275","url":null,"abstract":"This study reports the discovery of a novel class of potent and selective PKMYT1 inhibitors enabled by the deliberate exploitation of an intramolecular sulfur–lone pair interaction. By assistance of AI-powered generative chemistry, comprehensive SAR analysis, and structure guided optimization, a thiazole based scaffold was identified that enforces a near coplanar conformation. The lead compound A4 with favorable structural novelty exhibits strong PKMYT1 potency, high selectivity over WEE1, and potential drug-like properties. This work highlights the utility of nonclassical intramolecular interactions as an effective strategy in kinase inhibitor design. More details can be found in the Research Article by Xiao Ding, Alex Zhavoronkov, and co-workers (DOI: 10.1002/cmdc.202501029).\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture>\u0000 </div>\u0000 </figure>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147668841","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