ChemMedChem最新文献_第3页

Benzoxazole Derivatives as Dual p38α Mitogen-Activated Protein Kinase and Acetylcholinesterase Inhibitors: Design, Synthesis, and Evaluation for Alzheimer's Disease and Cancer Therapy. 苯并恶唑衍生物作为双p38α丝裂原活化蛋白激酶和乙酰胆碱酯酶抑制剂：阿尔茨海默病和癌症治疗的设计、合成和评价。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-10-05 DOI: 10.1002/cmdc.202500669

Bayan Zoatier, Gizem Yildiztekin, Mehmet Abdullah Alagoz, Ceylan Hepokur, Esra Dilek, Oztekin Algul

{"title":"Benzoxazole Derivatives as Dual p38α Mitogen-Activated Protein Kinase and Acetylcholinesterase Inhibitors: Design, Synthesis, and Evaluation for Alzheimer's Disease and Cancer Therapy.","authors":"Bayan Zoatier, Gizem Yildiztekin, Mehmet Abdullah Alagoz, Ceylan Hepokur, Esra Dilek, Oztekin Algul","doi":"10.1002/cmdc.202500669","DOIUrl":"https://doi.org/10.1002/cmdc.202500669","url":null,"abstract":"Alzheimer's disease (AD), the most prevalent form of dementia, leads to progressive cognitive decline due to pathological hallmarks including amyloid plaques, neurofibrillary tangles, synaptic loss, neuroinflammation, and neuronal cell death, highlighting the urgent need for multitarget therapeutic strategies. The p38α mitogen-activated protein kinase (p38α MAPK) pathway is a key regulator of neuroinflammation and has been implicated in AD pathogenesis. Additionally, dysregulation of p38α MAPK is associated with tumorigenesis, making it a promising target for both neurodegenerative and proliferative diseases. In this article, a series of benzoxazole derivatives is designed and synthesized to evaluate their dual inhibitory potential against p38α MAPK and acetylcholinesterase (AChE), aiming for a multifaceted therapeutic approach to AD. A total of 31 compounds are synthesized and assessed for their antiproliferative activity, p38α MAPK inhibition, and AChE inhibitory effects. In vitro assays demonstrate that several compounds exhibit potent dual inhibition of p38α MAPK and AChE, while molecular docking studies provide insights into their binding interactions within the active sites. These findings suggest that benzoxazole-based scaffolds offer a promising framework for the development of dual-acting inhibitors targeting both neuroinflammation and tumorigenesis. Further in vivo and mechanistic studies are warranted to explore their therapeutic potential.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500669"},"PeriodicalIF":3.4,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145230992","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

Synthesis of Tacrine/Amiridine Conjugates with Aminomethylidene Derivatives of Trifluoroacetoacetic Ester and their Biological Potential for the Therapy of Alzheimer's Disease. 三氟乙酰乙酸酯氨基甲基衍生物与他克林/胺吡啶偶联物的合成及其治疗阿尔茨海默病的生物学潜力。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-10-05 DOI: 10.1002/cmdc.202500723

Maria V Grishchenko, Galina F Makhaeva, Yanina V Burgart, Nadezhda V Kovaleva, Natalia P Boltneva, Tatiana S Skornyakova, Elena V Rudakova, Tatiana Y Astakhova, Elena N Timokhina, Pavel G Pronkin, Evgeny V Shchegolkov, Victor Saloutin, Valery N Charushin

{"title":"Synthesis of Tacrine/Amiridine Conjugates with Aminomethylidene Derivatives of Trifluoroacetoacetic Ester and their Biological Potential for the Therapy of Alzheimer's Disease.","authors":"Maria V Grishchenko, Galina F Makhaeva, Yanina V Burgart, Nadezhda V Kovaleva, Natalia P Boltneva, Tatiana S Skornyakova, Elena V Rudakova, Tatiana Y Astakhova, Elena N Timokhina, Pavel G Pronkin, Evgeny V Shchegolkov, Victor Saloutin, Valery N Charushin","doi":"10.1002/cmdc.202500723","DOIUrl":"https://doi.org/10.1002/cmdc.202500723","url":null,"abstract":"To assess the influence of the nature of the anticholinesterase pharmacophore on the properties of potential multitarget Alzheimer's disease (AD) agents, new conjugates of tacrine (3a, b) and amiridine (5a, b) with ethyl-2-aminomethylidene-4,4,4-trifluoro-3-oxobutanoate linked by an alkylene spacer with n = 4,6 were synthesized. All conjugates are effective cholinesterase inhibitors with predominant inhibition of butyrylcholinesterase (BChE). The inhibitory activity of tacrine conjugates 3a, b toward acetylcholinesterase (AChE) and BChE increases with spacer elongation: IC50 AChE up to 0.185 µM, IC50 BChE up to 0.0806 µM. Amiridine conjugates 5a, b are less active as AChE inhibitors and their anti-AChE activity (IC50 up to 3.09 µM) remains virtually unchanged with spacer elongation, while anti-BChE activity increases significantly (n = 6, IC50 = 0.063 µM), which leads to increased selectivity toward BChE (up to 56). The effects are consistent with the results of kinetic studies and molecular docking of 3b and 5b. Both types of conjugates displace propidium from the AChE peripheral anionic site at the level of and above that of donepezil, and are capable of blocking self-aggregation of β-amyloid (up to 49.5%). The compounds demonstrate very weak antioxidant activity (tacrine conjugates) or its absence (amiridine). Thus, new conjugates are potential multitarget anti-AD agents with high selectivity toward BChE for amiridine derivative 5b.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500723"},"PeriodicalIF":3.4,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231007","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

Front Cover: Structure-Based Drug Design of Novel Heterocyclic Scaffolds as TgCDPK1 Inhibitors (ChemMedChem 18/2025) 封面：基于结构的新型杂环支架TgCDPK1抑制剂药物设计（ChemMedChem 18/2025）

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-29 DOI: 10.1002/cmdc.70056

Anoopjit Singh Kooner, Mariah Norman, Igi Vilza, Michael P. Mannino, Mary Savari Dhason, Jon Helander, Shrushti Patil, L. David Sibley, James W. Janetka

引用次数: 0

pH-Responsive Nanoscale Mixed Ligand Metal Organic Framework as a Carrier for Photosensitizer in Targeted Antibacterial Photodynamic Therapy. ph响应纳米级混合配体金属有机骨架作为光敏剂载体在靶向抗菌光动力治疗中的应用。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-28 DOI: 10.1002/cmdc.202500510

Fathima Fasna P H, Sreesha Sasi, Hareesh N Ramanathan, Jasna Vijayan, Mohamed Hatha Abdulla Ammanamveetil

{"title":"pH-Responsive Nanoscale Mixed Ligand Metal Organic Framework as a Carrier for Photosensitizer in Targeted Antibacterial Photodynamic Therapy.","authors":"Fathima Fasna P H, Sreesha Sasi, Hareesh N Ramanathan, Jasna Vijayan, Mohamed Hatha Abdulla Ammanamveetil","doi":"10.1002/cmdc.202500510","DOIUrl":"https://doi.org/10.1002/cmdc.202500510","url":null,"abstract":"The escalating multidrug-resistant bacterial infections underscore the urgent need for alternatives to conventional antibiotics. Antimicrobial photodynamic therapy emerges as a promising strategy, leveraging light-activated photosensitizers like methylene blue (MB) to generate bactericidal reactive oxygen species (ROS) that disrupt microbial membranes and DNA. This approach minimizes resistance development due to the nonspecific action of ROS and demonstrates efficacy against both Gram-positive and Gram-negative pathogens. A pH-responsive mixed-ligand metal-organic framework (ML-MOF) is synthesized as a nanocarrier for MB. Encapsulation of MB into ML-MOF (MB@ML-MOF50) resulted in a loading capacity of 29.67%, with a controlled and sustained release profile of 85% at pH 5.1 (infection-mimicking conditions). MB@ML-MOF50 exhibited twice the singlet oxygen generation efficiency (S = 0.2098) compared to free MB (S = 0.1058), confirming enhanced photodynamic activity. MB@ML-MOF50 under 650 nm laser irradiation achieved complete bacterial inhibition (0% survival) at 25 µM, surpassing free MB. Biofilm eradication studies using the crystal violet (CV) assay revealed 37.26% inhibition of Escherichia coli (E. coli) biofilm and 25.42% inhibition of Staphylococcus aureus (S. aureus) biofilm after 15 min of laser exposure compared to a nonirradiated control, indicating the potential for disrupting persistent infections. MB@ML-MOF50 is a promising multifunctional nanoplatform for targeted, pH-responsive, and enhanced photodynamic antibacterial therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500510"},"PeriodicalIF":3.4,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184355","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

A Warm Welcome to MedChem: The Frontiers in Medicinal Chemistry 2025. 热烈欢迎参加MedChem：药物化学前沿2025。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-25 Epub Date: 2025-08-25 DOI: 10.1002/cmdc.202500609

Matthias Schiedel, Marta Pinto, Andrea Unzue Lopez, Philipp Barbie, Felix Pape, Anika Tarasewicz, Gerhard Hessler, Peter Gmeiner, Christina Lamers, Matthias Gehringer

引用次数: 0

New Structure Activity Relationship Insight into the Role of the C-3 Extension on Rifamycin Antimycobacterial Activity. 新结构-活性关系对利福霉素抗细菌活性的影响

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-22 DOI: 10.1002/cmdc.202500673

Clinton G L Veale, Ewelina Smolarz, Aleksandra Leśniewska, Krystian Pyta, Piotr Przybylski

引用次数: 0

Benzoxazole-Acrylonitriles: Dual Bioactivity and DNA Binding from a Sustainable Synthetic Approach 苯并恶唑-丙烯腈：可持续合成方法的双重生物活性和DNA结合。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-22 DOI: 10.1002/cmdc.202500429

Marina Galić, Tamara Rohtek, Leentje Persoons, Dirk Daelemans, Mihailo Banjanac, Tea Bruketa, Marijana Radić Stojković, Marijana Hranjec

{"title":"Benzoxazole-Acrylonitriles: Dual Bioactivity and DNA Binding from a Sustainable Synthetic Approach","authors":"Marina Galić, Tamara Rohtek, Leentje Persoons, Dirk Daelemans, Mihailo Banjanac, Tea Bruketa, Marijana Radić Stojković, Marijana Hranjec","doi":"10.1002/cmdc.202500429","DOIUrl":"10.1002/cmdc.202500429","url":null,"abstract":"Efficient synthesis in aqueous media is employed to prepare targeted compounds to evaluate antiproliferative, antibacterial, and antiviral activity in vitro. The biological activity is influenced by the type and number of substituents placed at phenyl or benzoxazole ring. Acrylonitriles substituted with 3,4-dihydroxy 50, 51, 3,4,5-tryhidroxy 52, 53, and 4-N,N-diethyl-amino 55 groups demonstrate potent antiproliferative effects against cancer cell lines, with IC50 values from 0.7 to 5.8 μM. Their impact on normal cell viability is assessed. The most active benzoxazoles induce DNA damage and are analyzed for their interaction with ct-DNA. UV/Vis titrations, thermal melting assays, and circular dichroism suggest an intercalative mode for the 4-N,N-diethylamino 55 and partial intercalation for the 3,4-dihydroxy 50 and 3,4,5-tryhidroxy derivative 52. Derivative 55 induces apoptosis and cell cycle arrest in cancer cells. Among tested benzoxazoles, significant antiviral activity against HCoV OC43 is observed for the 2-naphthyl 32, 3-indolyl 41 and 42 and p-hydroxy derivative 48 (EC50 from 2.1 to 8.5 μM). Furthermore, antibacterial activity is most effective for the 3,4-dihydroxy and bromine substituted acrylonitrile 51 against S. aureus (MIC 8 μM) and the efflux pump-deleted mutant of E. coli (MIC 4 μM), which is also observed for the hydroxy and bromine substituted 49.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 19","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124107","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

Synthesis of Caerulomycins E and A Analogs for Studying Cytotoxic Activity. 绿霉素E和A类似物的合成及其细胞毒活性研究。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-22 DOI: 10.1002/cmdc.202500594

Pansachon Intamalee, Jesada Maneewong, Natthiya Saehlim, Patamawadee Silalai, Arthit Chairoungdua, Rungnapha Saeeng

{"title":"Synthesis of Caerulomycins E and A Analogs for Studying Cytotoxic Activity.","authors":"Pansachon Intamalee, Jesada Maneewong, Natthiya Saehlim, Patamawadee Silalai, Arthit Chairoungdua, Rungnapha Saeeng","doi":"10.1002/cmdc.202500594","DOIUrl":"https://doi.org/10.1002/cmdc.202500594","url":null,"abstract":"Caerulomycin A, a marine-derived natural product featuring a bipyridinic core and a substituted oxime functional group, was originally isolated from Streptomyces caeruleus and is known for its antibiotic, antifungal, and cytotoxic properties. In this study, we report the efficient synthesis of caerulomycin A and a series of novel analogs via a five-step synthetic route using readily available reagents. The structural diversification focused on the replacing the methoxy group with various benzyl ether substituents at C-4 and subsequent oxidation and condensation steps at C-6 to generate caerulomycin E and caerulomycin A analogs. These compounds were evaluated for their cytotoxic activity against six human cancer cell lines. Notably, several benzyl ether derivatives exhibited significantly enhanced cytotoxicity compared to the parent compound, with some analogs demonstrating greater potency than the reference drug ellipticine. The structure-activity relationship (SAR) analysis revealed that halogenated substituted benzyl ether groups at C-4 positions played a critical role in modulating cytotoxic activity and selectivity. These findings underscore the potential of synthetic caerulomycin derivatives as promising lead compounds for further development in cancer therapeutics.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500594"},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123846","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

5-Amino-7-Oxo-4,7-Dihydroazolo[1,5-a]pyrimidine-6-Carbonitriles: Synthesis and Study of Antitumor Effect In Vitro and In Silico. 5-氨基-7-氧-4,7-二氢偶氮[1,5-a]嘧啶-6-碳腈的合成及体外和硅内抗肿瘤作用研究

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-21 DOI: 10.1002/cmdc.202500535

Veronika V Dolgova, Konstantin V Savateev, Grigoriy V Urakov, Evgeniya T Shabunina, Tatiana E Sbrodova, Ekaterina A Lvova, Ilya I Butorin, Elena A Fesenko, Vsevolod V Melekhin, Maria D Tokhtueva, Anastasiya V Paramonova, Andrey A Zonov, Svetlana K Kotovskaya, Vladimir L Rusinov

{"title":"5-Amino-7-Oxo-4,7-Dihydroazolo[1,5-a]pyrimidine-6-Carbonitriles: Synthesis and Study of Antitumor Effect In Vitro and In Silico.","authors":"Veronika V Dolgova, Konstantin V Savateev, Grigoriy V Urakov, Evgeniya T Shabunina, Tatiana E Sbrodova, Ekaterina A Lvova, Ilya I Butorin, Elena A Fesenko, Vsevolod V Melekhin, Maria D Tokhtueva, Anastasiya V Paramonova, Andrey A Zonov, Svetlana K Kotovskaya, Vladimir L Rusinov","doi":"10.1002/cmdc.202500535","DOIUrl":"https://doi.org/10.1002/cmdc.202500535","url":null,"abstract":"A novel chemotype of nitrile-containing azolopyrimidines with potential antitumor activity has been proposed, and a method for the synthesis of the corresponding 5-amino-7-oxoazolo[1,5-a]pyrimidine-6-carbonitriles by cyclocondensation of various aminoazoles and ethyl 2-cyano-3-R-amino-3-(methylsulfanyl)acrylates has been developed. Cytotoxic effects of the obtained azolopyrimidines against glioblastoma (A-172), bladder carcinoma (T-24), lung carcinoma (A-549), and human embryonic kidney (HEK-293) cells have been investigated, and structure-activity relationships have been identified. 2-Phenyl-5-(morpholin-4-yl)-7-oxo-1,2,4-triazolo[1,5-a]pyrimidine-6-carbonitrile 5j has been found to exhibit selective cytotoxic activity against the T-24 cells (IC50 = 14.68 µM), whereas 3-bromo-5-(morpholin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine-6-carbonitrile 5v has shown selective toxicity against the A-172 cells (IC50 = 18.38 µM). Further studies on heterocycle 5j in the annexin V apoptosis assay indicate that the primary mechanism involves inhibition of proliferative activity rather than induction of cell death. The cyclin-dependent kinase 2 protein is suggested as a possible target for the cytotoxic action of the studied compounds 5 on the T-24 cell line according to the notable correlation between docking studies and MTT assay results.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500535"},"PeriodicalIF":3.4,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111565","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

AgamOBP1-Directed Discovery of Repellents to Control the Spread of Mosquito-Borne Diseases. 以agamobp1为导向的驱蚊剂的发现以控制蚊媒疾病的传播。

IF 3.4 4区医学

ChemMedChem Pub Date : 2025-09-21 DOI: 10.1002/cmdc.202500555

Evanthia Chazapi, Eftichia Kritsi, Constantinos Potamitis, Panagiota G V Liggri, Katerina E Tsitsanou, Christina E Drakou, Antonios Michaelakis, Dimitrios P Papachristos, Spyros E Zographos, Maria Zervou, Theodora Calogeropoulou

{"title":"AgamOBP1-Directed Discovery of Repellents to Control the Spread of Mosquito-Borne Diseases.","authors":"Evanthia Chazapi, Eftichia Kritsi, Constantinos Potamitis, Panagiota G V Liggri, Katerina E Tsitsanou, Christina E Drakou, Antonios Michaelakis, Dimitrios P Papachristos, Spyros E Zographos, Maria Zervou, Theodora Calogeropoulou","doi":"10.1002/cmdc.202500555","DOIUrl":"https://doi.org/10.1002/cmdc.202500555","url":null,"abstract":"Toward the discovery of novel efficient repellents, protein-directed dynamic combinatorial chemistry (pdDCC) coupled to saturation-transfer difference (STD) NMR spectroscopy was initially employed to identify modulators of the malaria vector Anopheles gambiae Odorant Binding Protein 1 (AgamOBP1). A library of potential binders of AgamOBP1 (secondary amines) generated from two amines and seven aldehydes was designed aiming to enable interactions with critical amino acids at the DEET-site and to bridge the DEET- and Icaridin sIC-binding pockets, both implicated in repellents recognition. Solubility issues hindered the clear identification of binders among the DCL members, except for one sublibrary, leading us to shift our strategy towards the synthesis of the designed amines, followed by direct evaluation of their binding to AgamOBP1 using 1H STD NMR spectroscopy. The identified binders were further validated in vitro by fluorescence competition assays, and the most potent compounds which also possessed suitable vapor pressure were evaluated as repellents in arm-in-cage behavioral assays against Aedes albopictus. Amines 2A, 3A, 4A, and 6A showed significant repellent activity. The most potent was compound 4A (4-methyl-N-(pyridin-4-ylmethyl)aniline) which acted as a a DEET-like repellent at 0.4 μL cm- 2 dose. Thus, our strategy showcased a promising scaffold for further optimization toward efficient mosquito repellents.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500555"},"PeriodicalIF":3.4,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111625","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