Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors. 基于细胞内生物发光共振能量转移（BRET）的检测发现 Ceritinib 和 CA-074 是 SARS-CoV-2 类木瓜蛋白酶抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-20 DOI: 10.1080/14756366.2024.2387417

Mei Li, Zhu-Chun Bei, Yongtian Yuan, Baogang Wang, Dongna Zhang, Likun Xu, Liangliang Zhao, Qin Xu, Yabin Song

{"title":"In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors.","authors":"Mei Li, Zhu-Chun Bei, Yongtian Yuan, Baogang Wang, Dongna Zhang, Likun Xu, Liangliang Zhao, Qin Xu, Yabin Song","doi":"10.1080/14756366.2024.2387417","DOIUrl":"10.1080/14756366.2024.2387417","url":null,"abstract":"Papain-like protease (PLpro) is an attractive anti-coronavirus target. The development of PLpro inhibitors, however, is hampered by the limitations of the existing PLpro assay and the scarcity of validated active compounds. We developed a novel in-cell PLpro assay based on BRET and used it to evaluate and discover SARS-CoV-2 PLpro inhibitors. The developed assay demonstrated remarkable sensitivity for detecting the reduction of intracellular PLpro activity while presenting high reliability and performance for inhibitor evaluation and high-throughput screening. Using this assay, three protease inhibitors were identified as novel PLpro inhibitors that are structurally disparate from those previously known. Subsequent enzymatic assays and ligand-protein interaction analysis based on molecular docking revealed that ceritinib directly inhibited PLpro, showing high geometric complementarity with the substrate-binding pocket in PLpro, whereas CA-074 methyl ester underwent intracellular hydrolysis, exposing a free carboxyhydroxyl group essential for hydrogen bonding with G266 in the BL2 groove, resulting in PLpro inhibition.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2387417"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008884","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

Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors. 作为 ASK1 抑制剂的喹喔啉衍生物的合成和生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-21 DOI: 10.1080/14756366.2024.2414382

Xiaorui Han, Pingping Lan, Qianfeng Chen, Hua Liu, Zhongwen Chen, Tiantian Wang, Zengtao Wang

引用次数: 0

Vitamin B6 inhibits activity of Helicobacter pylori adenylosuccinate synthetase and growth of reference and clinical, antibiotic-resistant H. pylori strains. 维生素 B6 可抑制幽门螺旋杆菌腺苷琥珀酸合成酶的活性以及参考菌株和临床抗生素耐药幽门螺旋杆菌菌株的生长。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-16 DOI: 10.1080/14756366.2024.2372734

Marta Ilona Wojtyś, Weronika Maksymiuk, Marta Narczyk, Ante Bubić, Ivana Leščić Ašler, Paweł Krzyżek, Grażyna Gościniak, Elżbieta Katarzyna Jagusztyn-Krynicka, Agnieszka Bzowska

{"title":"Vitamin B6 inhibits activity of Helicobacter pylori adenylosuccinate synthetase and growth of reference and clinical, antibiotic-resistant H. pylori strains.","authors":"Marta Ilona Wojtyś, Weronika Maksymiuk, Marta Narczyk, Ante Bubić, Ivana Leščić Ašler, Paweł Krzyżek, Grażyna Gościniak, Elżbieta Katarzyna Jagusztyn-Krynicka, Agnieszka Bzowska","doi":"10.1080/14756366.2024.2372734","DOIUrl":"10.1080/14756366.2024.2372734","url":null,"abstract":"The current therapies against gastric pathogen Helicobacter pylori are ineffective in over 20% of patients. Enzymes belonging to the purine salvage pathway are considered as novel drug targets in this pathogen. Therefore, the main aim of the current study was to determine the antibacterial activity of pyridoxal 5'-phosphate (PLP), an active form of vitamin B6, against reference and clinical strains of H. pylori. Using a broad set of microbiological, physicochemical (UV absorption, LC-MS, X-ray analysis) and in silico experiments, we were able to prove that PLP inhibits adenylosuccinate synthetase (AdSS) from H. pylori by the competition with GTP (IC50eq ∼30 nM). This behaviour was attributed to formation of a Schiff base with a lysine residue (a covalent bond with Lys322 in the GTP binding site of AdSS) and was potentiated by the presence of vitamin C. This antibacterial activity of PLP gives hope for its future use against H. pylori.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2372734"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988056","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 anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease. 作为选择性丁酰胆碱酯酶抑制剂治疗阿尔茨海默病的新型抗神经炎吡喃酮-氨基甲酸酯衍生物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-02-16 DOI: 10.1080/14756366.2024.2313682

Chuanyu Yu, Xueyan Liu, Bingxiang Ma, Jiexin Xu, Yiquan Chen, Chaoxian Dai, Huaping Peng, Daijun Zha

{"title":"Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease.","authors":"Chuanyu Yu, Xueyan Liu, Bingxiang Ma, Jiexin Xu, Yiquan Chen, Chaoxian Dai, Huaping Peng, Daijun Zha","doi":"10.1080/14756366.2024.2313682","DOIUrl":"10.1080/14756366.2024.2313682","url":null,"abstract":"Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2313682"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10878344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139741200","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

Correction. 更正。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-07-29 DOI: 10.1080/14756366.2024.2374156

引用次数: 0

Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity. 设计和合成具有广谱抗增殖活性的强效 JAK/HDAC 双抑制剂三唑吡啶衍生物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-08 DOI: 10.1080/14756366.2024.2409771

Zhengshui Xu, Changchun Ye, Xingjie Wang, Ranran Kong, Zilu Chen, Jing Shi, Xin Chen, Shiyuan Liu

引用次数: 0

Evaluation of N-alkyl isatins and indoles as acetylcholinesterase and butyrylcholinesterase inhibitors. n -烷基异黄酮和吲哚作为乙酰胆碱酯酶和丁基胆碱酯酶抑制剂的评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-07 DOI: 10.1080/14756366.2023.2286935

Kaitlyn N Alcorn, Isabelle A Oberhauser, Matthew D Politeski, Todd J Eckroat

{"title":"Evaluation of N-alkyl isatins and indoles as acetylcholinesterase and butyrylcholinesterase inhibitors.","authors":"Kaitlyn N Alcorn, Isabelle A Oberhauser, Matthew D Politeski, Todd J Eckroat","doi":"10.1080/14756366.2023.2286935","DOIUrl":"10.1080/14756366.2023.2286935","url":null,"abstract":"Two series of N-alkyl isatins and N-alkyl indoles varying in size of the alkyl group were synthesised and evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the N-alkyl isatins 4a-j, the addition of the N-alkyl group improved inhibition potency towards AChE and BChE compared to isatin. Selectivity towards inhibition of BChE was observed, and the increase in size of the N-alkyl group positively correlated to improved inhibition potency. The most potent inhibitor for BChE was 4i (IC50 = 3.77 µM, 22-fold selectivity for BChE over AChE). N-alkyl indoles 5a-j showed similar inhibition of AChE, the most potent being 5g (IC50 = 35.0 µM), but 5a-j lost activity towards BChE. This suggests an important role of the 3-oxo group on isatin for BChE inhibition, and molecular docking of 4i with human BChE indicates a key hydrogen bond between this group and Ser198 and His438 of the BChE catalytic triad.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2286935"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation. 通过虚拟筛选和生物学评价鉴定BCKDK的推定变构抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-07 DOI: 10.1080/14756366.2023.2290458

Chunqiong Li, Quanjun Yang, Li Zhang

{"title":"Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation.","authors":"Chunqiong Li, Quanjun Yang, Li Zhang","doi":"10.1080/14756366.2023.2290458","DOIUrl":"10.1080/14756366.2023.2290458","url":null,"abstract":"Abnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by BCAA accumulation. Here, we screened PPHN and POAB as novel putative allosteric inhibitors by integrating allosteric binding site prediction, large-scale ligand database virtual screening, and bioactivity evaluation assays. Both of them showed a high binding affinity to BCKDK, with Kd values of 3.9 μM and 1.86 μM, respectively. In vivo experiments, the inhibitors demonstrated superior kinase inhibitory activity and notable antiproliferative and proapoptotic effects on diverse cancer cells. Finally, bulk RNA-seq analysis revealed that PPHN and POAB suppressed cell growth through a range of signalling pathways. Taken together, our findings highlight two novel BCKDK inhibitors as potent therapeutic candidates for metabolic diseases and cancers associated with BCAA dysfunctional metabolism.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2290458"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies. 与苊烯酮相连的新型咪唑-2-硫酮作为双重 DNA 中间体和拓扑异构酶 II 抑制剂：结构优化、对接和细胞凋亡研究。

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: 10.1080/14756366.2024.2311818

Asmaa H Mohamed, Mohammed B Alshammari, Ashraf A Aly, Kamal U Sadek, Akil Ahmad, Eman A Aziz, Amira F El-Yazbi, Eman J El-Agroudy, Marwa E Abdelaziz

{"title":"New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies.","authors":"Asmaa H Mohamed, Mohammed B Alshammari, Ashraf A Aly, Kamal U Sadek, Akil Ahmad, Eman A Aziz, Amira F El-Yazbi, Eman J El-Agroudy, Marwa E Abdelaziz","doi":"10.1080/14756366.2024.2311818","DOIUrl":"10.1080/14756366.2024.2311818","url":null,"abstract":"In this article, a new series of 2-((3,5-disubstituted-2-thioxo-imidazol-1-yl)imino)acenaphthylen-1(2H)-ones were synthesized. Imidazole-2-thione with acenaphthylen-one gave a hybrid scaffold that integrated key structural elements essential for DNA damage via direct DNA intercalation and inhibition of the topoisomerase II enzyme. All the synthesized compounds were screened to detect their DNA damage using a terbium fluorescent probe. Results demonstrated that 4-phenyl-imidazoles 5b and 5e in addition to 4-(4-chlorophenyl)imidazoles 5h and 5j would induce detectable potent damage in ctDNA. The four most potent compounds as DNA intercalators were further evaluated for their antiproliferative activity against HepG2, MCF-7 and HCT-116 utilizing the MTT assay. The highest anticancer activity was recorded with compounds 5b and 5h against the breast cancer cell line MCF-7 which were 1.5- and 3- folds more active than doxorubicin, respectively. Therefore, imidazole-2-thione tethered acenaphthylenone derivatives can be considered as promising scaffold for the development of effective dual DNA intercalators and topoisomerase II inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2311818"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131586","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

Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition. 开发基于 G-四叉链稳定和碳酸酐酶抑制的多靶点化疗方法。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-18 DOI: 10.1080/14756366.2024.2366236

Alessio Nocentini, Anna Di Porzio, Alessandro Bonardi, Carla Bazzicalupi, Andrea Petreni, Tarita Biver, Silvia Bua, Simona Marzano, Jussara Amato, Bruno Pagano, Nunzia Iaccarino, Stefano De Tito, Stefano Amente, Claudiu T Supuran, Antonio Randazzo, Paola Gratteri

{"title":"Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition.","authors":"Alessio Nocentini, Anna Di Porzio, Alessandro Bonardi, Carla Bazzicalupi, Andrea Petreni, Tarita Biver, Silvia Bua, Simona Marzano, Jussara Amato, Bruno Pagano, Nunzia Iaccarino, Stefano De Tito, Stefano Amente, Claudiu T Supuran, Antonio Randazzo, Paola Gratteri","doi":"10.1080/14756366.2024.2366236","DOIUrl":"10.1080/14756366.2024.2366236","url":null,"abstract":"A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis. The ligands reported feature a berberine G-quadruplex stabiliser scaffold connected to a moiety inhibiting hCAs IX and XII. In vitro experiments showed that our compounds selectively stabilise G-quadruplex structures and inhibit hCAs IX and XII. The crystal structure of a telomeric G-quadruplex in complex with one of these ligands was obtained, shedding light on the ligand/target interaction mode. The most promising ligands showed significant cytotoxicity against CA IX-positive HeLa cancer cells in hypoxia, and the ability to stabilise G-quadruplexes within tumour cells.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2366236"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436968","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