Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第8页

Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities. 作为具有强效抗癌活性的秋水仙碱结合部位抑制剂的 1h 吡咯并[3,2-c]吡啶衍生物的设计、合成和生物评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-14 DOI: 10.1080/14756366.2024.2302320

Chao Wang, Yujing Zhang, Shanbo Yang, Lingyu Shi, Rong Rong, Tingting Zhang, Yudong Wu, Dongming Xing

{"title":"Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities.","authors":"Chao Wang, Yujing Zhang, Shanbo Yang, Lingyu Shi, Rong Rong, Tingting Zhang, Yudong Wu, Dongming Xing","doi":"10.1080/14756366.2024.2302320","DOIUrl":"10.1080/14756366.2024.2302320","url":null,"abstract":"A new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 μM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 μM and 5 μM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 μM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 μM, 0.24 μM, and 0.36 μM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnβ349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski's rule of five.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2302320"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10791102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification and evaluation of antiviral activity of novel compounds targeting SARS-CoV-2 virus by enzymatic and antiviral assays, and computational analysis. 通过酶学和抗病毒试验以及计算分析，鉴定和评估针对 SARS-CoV-2 病毒的新型化合物的抗病毒活性。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-14 DOI: 10.1080/14756366.2024.2301772

Ivana Nemčovičová, Katarína Lopušná, Iveta Štibrániová, Fabio Benedetti, Federico Berti, Fulvia Felluga, Sara Drioli, Mattia Vidali, Jaroslav Katrlík, Lucia Pažitná, Alena Holazová, Jana Blahutová, Simona Lenhartová, Monika Sláviková, Boris Klempa, Miroslav Ondrejovič, Daniela Chmelová, Barbora Legerská, Stanislav Miertuš, Mária Klacsová, Daniela Uhríková, Lukáš Kerti, Vladimír Frecer

{"title":"Identification and evaluation of antiviral activity of novel compounds targeting SARS-CoV-2 virus by enzymatic and antiviral assays, and computational analysis.","authors":"Ivana Nemčovičová, Katarína Lopušná, Iveta Štibrániová, Fabio Benedetti, Federico Berti, Fulvia Felluga, Sara Drioli, Mattia Vidali, Jaroslav Katrlík, Lucia Pažitná, Alena Holazová, Jana Blahutová, Simona Lenhartová, Monika Sláviková, Boris Klempa, Miroslav Ondrejovič, Daniela Chmelová, Barbora Legerská, Stanislav Miertuš, Mária Klacsová, Daniela Uhríková, Lukáš Kerti, Vladimír Frecer","doi":"10.1080/14756366.2024.2301772","DOIUrl":"10.1080/14756366.2024.2301772","url":null,"abstract":"The viral genome of the SARS-CoV-2 coronavirus, the aetiologic agent of COVID-19, encodes structural, non-structural, and accessory proteins. Most of these components undergo rapid genetic variations, though to a lesser extent the essential viral proteases. Consequently, the protease and/or deubiquitinase activities of the cysteine proteases Mpro and PLpro became attractive targets for the design of antiviral agents. Here, we develop and evaluate new bis(benzylidene)cyclohexanones (BBC) and identify potential antiviral compounds. Three compounds were found to be effective in reducing the SARS-CoV-2 load, with EC50 values in the low micromolar concentration range. However, these compounds also exhibited inhibitory activity IC50 against PLpro at approximately 10-fold higher micromolar concentrations. Although originally developed as PLpro inhibitors, the comparison between IC50 and EC50 of BBC indicates that the mechanism of their in vitro antiviral activity is probably not directly related to inhibition of viral cysteine proteases. In conclusion, our study has identified new potential noncytotoxic antiviral compounds suitable for in vivo testing and further improvement.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2301772"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10791089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents. 青霉素结合蛋白 1b 的硼酸抑制剂：丝氨酸和赖氨酸标记剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-02-27 DOI: 10.1080/14756366.2024.2305833

Levente Kollár, Katarina Grabrijan, Martina Hrast Rambaher, Krištof Bozovičar, Tímea Imre, György G Ferenczy, Stanislav Gobec, György M Keserű

{"title":"Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents.","authors":"Levente Kollár, Katarina Grabrijan, Martina Hrast Rambaher, Krištof Bozovičar, Tímea Imre, György G Ferenczy, Stanislav Gobec, György M Keserű","doi":"10.1080/14756366.2024.2305833","DOIUrl":"10.1080/14756366.2024.2305833","url":null,"abstract":"Penicillin-binding proteins (PBPs) contribute to bacterial cell wall biosynthesis and are targets of antibacterial agents. Here, we investigated PBP1b inhibition by boronic acid derivatives. Chemical starting points were identified by structure-based virtual screening and aliphatic boronic acids were selected for further investigations. Structure-activity relationship studies focusing on the branching of the boron-connecting carbon and quantum mechanical/molecular mechanical simulations showed that reaction barrier free energies are compatible with fast reversible covalent binding and small or missing reaction free energies limit the inhibitory activity of the investigated boronic acid derivatives. Therefore, covalent labelling of the lysine residue of the catalytic dyad was also investigated. Compounds with a carbonyl warhead and an appropriately positioned boronic acid moiety were shown to inhibit and covalently label PBP1b. Reversible covalent labelling of the catalytic lysine by imine formation and the stabilisation of the imine by dative N-B bond is a new strategy for PBP1b inhibition.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2305833"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10901194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Elucidation of critical chemical moieties of metallo-β-lactamase inhibitors and prioritisation of target metallo-β-lactamases. 阐明金属-β-内酰胺酶抑制剂的关键化学分子并确定目标金属-β-内酰胺酶的优先次序。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-03-15 DOI: 10.1080/14756366.2024.2318830

Jung Hun Lee, Sang-Gyu Kim, Kyung-Min Jang, Kyoungmin Shin, Hyeonku Jin, Dae-Wi Kim, Byeong Chul Jeong, Sang Hee Lee

{"title":"Elucidation of critical chemical moieties of metallo-β-lactamase inhibitors and prioritisation of target metallo-β-lactamases.","authors":"Jung Hun Lee, Sang-Gyu Kim, Kyung-Min Jang, Kyoungmin Shin, Hyeonku Jin, Dae-Wi Kim, Byeong Chul Jeong, Sang Hee Lee","doi":"10.1080/14756366.2024.2318830","DOIUrl":"10.1080/14756366.2024.2318830","url":null,"abstract":"The urgent demand for effective countermeasures against metallo-β-lactamases (MBLs) necessitates development of novel metallo-β-lactamase inhibitors (MBLIs). This study is dedicated to identifying critical chemical moieties within previously developed MBLIs, and critical MBLs should serve as the target in MBLI evaluations. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a systematic literature analysis was conducted, and the NCBI RefSeq genome database was exploited to access the abundance profile and taxonomic distribution of MBLs and their variant types. Through the implementation of two distinct systematic approaches, we elucidated critical chemical moieties of MBLIs, providing pivotal information for rational drug design. We also prioritised MBLs and their variant types, highlighting the imperative need for comprehensive testing to ensure the potency and efficacy of the newly developed MBLIs. This approach contributes valuable information to advance the field of antimicrobial drug discovery.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2318830"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Investigation of the inhibitory properties of azo-dyes on chorismate synthase from Paracoccidioides brasiliensis. 偶氮染料对巴西副球虫氯酸酯合成酶抑制性能的研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-12-10 DOI: 10.1080/14756366.2024.2427175

Katharina Fuchs, Massimo G Totaro, Marina Toplak, Aleksandar Bijelic, Peter Macheroux

{"title":"Investigation of the inhibitory properties of azo-dyes on chorismate synthase from Paracoccidioides brasiliensis.","authors":"Katharina Fuchs, Massimo G Totaro, Marina Toplak, Aleksandar Bijelic, Peter Macheroux","doi":"10.1080/14756366.2024.2427175","DOIUrl":"10.1080/14756366.2024.2427175","url":null,"abstract":"The efficient inhibition of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) by the broad-spectrum herbicide glyphosate validates the shikimate pathway as a promising target for developing antimicrobial, fungicidal and herbicidal agents. The last enzyme of this pathway, chorismate synthase (CS), catalyses an unusual reaction, making it an attractive target for novel inhibitors. Therefore, we tested a series of azo-dyes for their inhibitory potential against CS from the pathogenic fungus Paracoccidioides brasiliensis (PbCS) and identified the azo-dye PH011669 that exhibits a dissociation (Kd) and 50% inhibitory constant (IC50) of 1.1 ± 0.1 and 10 ± 1 µM, respectively. Molecular docking and MD simulations provided insight into the mode of inhibition, showing that PH011669 binds to the enzyme's active site primarily through electrostatic interactions. Thus, our study is the first to integrate structural and computational methods to guide future efforts towards designing the next generation of CS inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2427175"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11633415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis. 1,2,3-三唑-苯并恶唑的新型杂交化合物：利用荧光测定法和计算分析设计、合成和评估 DprE1 酶抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-27 DOI: 10.1080/14756366.2024.2403744

Manisha Singh, Sarah M Batt, Christian S C Canales, Fernando R Pavan, Sethu Arun Kumar, Handattu S Akshatha, Meduri Bhagyalalitha, Karthik G Pujar, Durgesh Bidye, Gurubasavaraj V Pujar, Gurdyal S Besra

{"title":"Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis.","authors":"Manisha Singh, Sarah M Batt, Christian S C Canales, Fernando R Pavan, Sethu Arun Kumar, Handattu S Akshatha, Meduri Bhagyalalitha, Karthik G Pujar, Durgesh Bidye, Gurubasavaraj V Pujar, Gurdyal S Besra","doi":"10.1080/14756366.2024.2403744","DOIUrl":"10.1080/14756366.2024.2403744","url":null,"abstract":"Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2403744"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11441021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 selective ACAT2 antagonist via a combination strategy based on deep docking, pharmacophore modelling, and molecular dynamics simulation. 通过基于深度对接、药理模型和分子动力学模拟的组合策略发现选择性 ACAT2 拮抗剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-24 DOI: 10.1080/14756366.2024.2403736

Yanfeng Liu, Feng Ding, Liangying Deng, Shuran Zhang, Lixing Wu, Huangjin Tong

{"title":"Discovery of selective ACAT2 antagonist via a combination strategy based on deep docking, pharmacophore modelling, and molecular dynamics simulation.","authors":"Yanfeng Liu, Feng Ding, Liangying Deng, Shuran Zhang, Lixing Wu, Huangjin Tong","doi":"10.1080/14756366.2024.2403736","DOIUrl":"https://doi.org/10.1080/14756366.2024.2403736","url":null,"abstract":"Acyl-CoA: cholesterol acyltransferase (ACAT), a pivotal enzyme in the absorption and metabolism of cholesterol, is primarily responsible for intracellular esterification. ACAT inhibition is expected to diminish plasma lipid levels by impeding intestinal cholesterol absorption, thereby preventing the progression of atherosclerotic lesions. A previous study shows that selective inhibition of ACAT2 significantly mitigated hypercholesterolaemia and atherosclerosis in mouse models. Therefore, the need for ACAT2 selective inhibitors becomes particularly urgent. In this study, we established a multilayer virtual screening workflow and subjected biologically evaluated representative compounds to enzyme inhibitory assays. The experimental results indicated that the two compounds, STL565001 (inhibition rate at 25 μM: 75.7 ± 27.8%, selectivity = 6) and STL528213 (inhibition rate at 25 μM: 87.8 ± 12.4%, selectivity = 13), demonstrated robust activity against ACAT2, displaying greater selectivity for ACAT2 than for ACAT1. The molecular mechanisms governing the inhibitory activities of the selected compounds were systematically elucidated using computational approaches. In addition, hotspot residues in ACAT2 that are crucial for ligand binding were successfully identified. In summary, we devised a multilayer screening scheme to expeditiously and efficiently identify compounds with enzyme inhibitory activity, offering novel scaffolds for subsequent drug design centred on ACAT2 targets.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2403736"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovering a novel dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor and its impact on tau phosphorylation and amyloid-β formation. 发现新型双特异性酪氨酸磷酸化调节激酶 1A (DYRK1A) 抑制剂及其对 tau 磷酸化和淀粉样蛋白-β形成的影响

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-04 DOI: 10.1080/14756366.2024.2418470

Huang-Ju Tu, Min-Wu Chao, Cheng-Chung Lee, Chao-Shiang Peng, Yi-Wen Wu, Tony Eight Lin, Yu-Wei Chang, Shih-Chung Yen, Kai-Cheng Hsu, Shiow-Lin Pan, Wei-Chun HuangFu

{"title":"Discovering a novel dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor and its impact on tau phosphorylation and amyloid-β formation.","authors":"Huang-Ju Tu, Min-Wu Chao, Cheng-Chung Lee, Chao-Shiang Peng, Yi-Wen Wu, Tony Eight Lin, Yu-Wei Chang, Shih-Chung Yen, Kai-Cheng Hsu, Shiow-Lin Pan, Wei-Chun HuangFu","doi":"10.1080/14756366.2024.2418470","DOIUrl":"10.1080/14756366.2024.2418470","url":null,"abstract":"Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's disease. Although the development of DYRK1A inhibitors has significantly advanced in recent years, the selectivity of these drugs remains a critical challenge, potentially impeding further progress. In this study, we utilised structure-based virtual screening (SBVS) from NCI library to discover novel DYRK1A inhibitors. The top-ranked compounds were then validated through enzymatic assays to assess their efficacy towards DYRK1A. Among them, NSC361563 emerged as a potent and selective DYRK1A inhibitor. It was shown to decrease tau phosphorylation at multiple sites, thereby enhancing tubulin stability. Moreover, NSC361563 diminished the formation of amyloid β and offered neuroprotective benefits against amyloid β-induced toxicity. Our research highlights the critical role of selective DYRK1A inhibitors in treating neurodegenerative diseases and presents a promising starting point for the development of targeted therapies.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2418470"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Isolation, structure modification, and anti-rheumatoid arthritis activity of isopimarane-type diterpenoids from Orthosiphon aristatus. 从Orthosiphon aristatus中分离、改造结构并研究其抗类风湿关节炎活性。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-17 DOI: 10.1080/14756366.2023.2296355

Yong-Xin Luo, Xu Gong, Zhi-Cheng Su, Jin-Feng Mo, Dong-Li Li, Ri-Hui Wu, Jing-Wei Jin, Ming Lang, Jin-Ping Wang, Xue-Tao Xu, Li-She Gan

{"title":"Isolation, structure modification, and anti-rheumatoid arthritis activity of isopimarane-type diterpenoids from Orthosiphon aristatus.","authors":"Yong-Xin Luo, Xu Gong, Zhi-Cheng Su, Jin-Feng Mo, Dong-Li Li, Ri-Hui Wu, Jing-Wei Jin, Ming Lang, Jin-Ping Wang, Xue-Tao Xu, Li-She Gan","doi":"10.1080/14756366.2023.2296355","DOIUrl":"10.1080/14756366.2023.2296355","url":null,"abstract":"Orthosiphon aristatus is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids (1-8), including a new one with a rarely occurring α,β-unsaturated diketone C-ring, were isolated from O. aristatus. Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives (9-15). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound 10 showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1β, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that 10 could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2296355"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10798283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof. 发现新的胸腺酚-3,4-二取代噻唑杂环作为 COX-2/5-LOX 双重抑制剂，并在体内进行了验证。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-30 DOI: 10.1080/14756366.2024.2309171

Mostafa M M El-Miligy, Ahmed K Al-Kubeisi, Rasha A Nassra, Saad R El-Zemity, Aly A Hazzaa

{"title":"Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof.","authors":"Mostafa M M El-Miligy, Ahmed K Al-Kubeisi, Rasha A Nassra, Saad R El-Zemity, Aly A Hazzaa","doi":"10.1080/14756366.2024.2309171","DOIUrl":"10.1080/14756366.2024.2309171","url":null,"abstract":"New thymol-3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC50= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC50= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a-l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a-f, 6i-l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h-l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2309171"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10833116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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