Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第6页

Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers. 新型 6-氨基-5-氰基-2-噻吩嘧啶衍生物的设计、合成、分子建模和生物学评价，作为抗白血病的强效抗癌剂和细胞凋亡诱导剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-02-13 DOI: 10.1080/14756366.2024.2304625

Naglaa M Ahmed, Mosaad S Mohamed, Samir M Awad, Rania H Abd El-Hameed, Neama A Abd El-Tawab, Mohamed S Gaballah, Ahmed M Said

{"title":"Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers.","authors":"Naglaa M Ahmed, Mosaad S Mohamed, Samir M Awad, Rania H Abd El-Hameed, Neama A Abd El-Tawab, Mohamed S Gaballah, Ahmed M Said","doi":"10.1080/14756366.2024.2304625","DOIUrl":"10.1080/14756366.2024.2304625","url":null,"abstract":"Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 μM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722892","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

Exploring of N-phthalimide-linked 1,2,3-triazole analogues with promising -anti-SARS-CoV-2 activity: synthesis, biological screening, and molecular modelling studies. 探索具有良好抗 SARS-CoV-2 活性的 N-邻苯二甲酰亚胺连接的 1,2,3-三唑类似物：合成、生物筛选和分子建模研究。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-06-07 DOI: 10.1080/14756366.2024.2351861

Ateyatallah Aljuhani, Mosa Alsehli, Mohamed A Seleem, Shaya Y Alraqa, Hany E A Ahmed, Nadjet Rezki, Mohamed R Aouad

{"title":"Exploring of N-phthalimide-linked 1,2,3-triazole analogues with promising -anti-SARS-CoV-2 activity: synthesis, biological screening, and molecular modelling studies.","authors":"Ateyatallah Aljuhani, Mosa Alsehli, Mohamed A Seleem, Shaya Y Alraqa, Hany E A Ahmed, Nadjet Rezki, Mohamed R Aouad","doi":"10.1080/14756366.2024.2351861","DOIUrl":"10.1080/14756366.2024.2351861","url":null,"abstract":"In this study, a library of phthalimide Schiff base linked to 1,4-disubstituted-1,2,3-triazoles was designed, synthesised, and characterised by different spectral analyses. All analogues have been introduced for in vitro assay of their antiviral activity against COVID-19 virus using Vero cell as incubator with different concentrations. The data revealed most of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with no or weak cytotoxic effect on Vero cells. Furthermore, in vitro assay was done against this enzyme for all analogues and the results showed two of them have IC50 data by 90 µM inhibitory activity. An extensive molecular docking simulation was run to analyse their antiviral mechanism that found the proper non-covalent interaction within the Mpro protease enzyme. Finally, we profiled two reversible inhibitors, COOH and F substituted analogues that might be promising drug candidates for further development have been discovered.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283872","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 natural anthraquinones as potent inhibitors against pancreatic lipase: structure-activity relationships and inhibitory mechanism. 发现可作为胰脂肪酶强效抑制剂的天然蒽醌类化合物：结构-活性关系和抑制机制。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-02 DOI: 10.1080/14756366.2024.2398561

Zi-Qiang Chen, Wen-Yao He, Si-Yuan Yang, Hong-Hong Ma, Jing Zhou, Hao Li, Ya-Di Zhu, Xing-Kai Qian, Li-Wei Zou

{"title":"Discovery of natural anthraquinones as potent inhibitors against pancreatic lipase: structure-activity relationships and inhibitory mechanism.","authors":"Zi-Qiang Chen, Wen-Yao He, Si-Yuan Yang, Hong-Hong Ma, Jing Zhou, Hao Li, Ya-Di Zhu, Xing-Kai Qian, Li-Wei Zou","doi":"10.1080/14756366.2024.2398561","DOIUrl":"10.1080/14756366.2024.2398561","url":null,"abstract":"Obesity is acknowledged as a significant risk factor for various metabolic diseases, and the inhibition of human pancreatic lipase (hPL) can impede lipid digestion and absorption, thereby offering potential benefits for obesity treatment. Anthraquinones is a kind of natural and synthetic compounds with wide application. In this study, the inhibitory effects of 31 anthraquinones on hPL were evaluated. The data shows that AQ7, AQ26, and AQ27 demonstrated significant inhibitory activity against hPL, and exhibited selectivity towards other known serine hydrolases. Then the structure-activity relationship between anthraquinones and hPL was further analysed. AQ7 was found to be a mixed inhibition of hPL through inhibition kinetics, while AQ26 and AQ27 were effective non-competitive inhibition of hPL. Molecular docking data revealed that AQ7, AQ26, and AQ27 all could associate with the site of hPL. Developing hPL inhibitors for obesity prevention and treatment could be simplified with this novel and promising lead compound.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119987","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

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity. 与 8-巯基鸟嘌呤相关的结核分枝杆菌二氢蝶呤醛缩酶的晶体结构，以及作为抑制剂的新型 S8 功能化类似物的开发：合成、酶抑制、体外毒性和抗结核活性。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-14 DOI: 10.1080/14756366.2024.2388207

Alexia de Matos Czeczot, Mauro Neves Muniz, Marcia Alberton Perelló, Éverton Edésio Dinis Silva, Luís Fernando Saraiva Macedo Timmers, Andresa Berger, Laura Calle Gonzalez, Guilherme Arraché Gonçalves, Sidnei Moura, Pablo Machado, Cristiano Valim Bizarro, Luiz Augusto Basso

{"title":"Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.","authors":"Alexia de Matos Czeczot, Mauro Neves Muniz, Marcia Alberton Perelló, Éverton Edésio Dinis Silva, Luís Fernando Saraiva Macedo Timmers, Andresa Berger, Laura Calle Gonzalez, Guilherme Arraché Gonçalves, Sidnei Moura, Pablo Machado, Cristiano Valim Bizarro, Luiz Augusto Basso","doi":"10.1080/14756366.2024.2388207","DOIUrl":"10.1080/14756366.2024.2388207","url":null,"abstract":"The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975774","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

Bacillus lipopeptides inhibit lipase activity and promote 3T3-L1 preadipocyte differentiation. 芽孢杆菌脂肽抑制脂肪酶活性并促进 3T3-L1 前脂肪细胞分化

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: 10.1080/14756366.2024.2417915

Meichun Chen, Deju Chen, Rongfeng Xiao, Xuefang Zheng, Bo Liu, Jieping Wang

{"title":"Bacillus lipopeptides inhibit lipase activity and promote 3T3-L1 preadipocyte differentiation.","authors":"Meichun Chen, Deju Chen, Rongfeng Xiao, Xuefang Zheng, Bo Liu, Jieping Wang","doi":"10.1080/14756366.2024.2417915","DOIUrl":"10.1080/14756366.2024.2417915","url":null,"abstract":"Bacillus lipopeptides have been reported to display anti-obesity effects. In the present study, Lipopeptides from Bacillus velezensis FJAT-45028 that consisted of iturin, fengycin and surfactin were reported. The lipopeptides exhibited a strong lipase inhibition activity in a concentration-dependent manner with a half maximal inhibitory concentration of 0.012 mg/mL, and the inhibition mechanism and type were reversible and competitive, respectively. Results of CCK8 assay showed that 3T3-L1 preadipocyte cells were completely viable under treatment of 0.050-0.2 mg/mL lipopeptides for 24 or 48 h. It was found that the lipopeptides could increase lipid droplets in the differentiated 3T3-L1 adipocytes in tested concentration and suppress the expression of peroxisome proliferator-activated receptor gamma (PPARγ). These results indicated the potential anti-obesity mechanism of the tested lipopeptides might be to inhibit lipase activity but not to suppress lipid accumulation in the adipocytes. Moreover, the lipopeptides could elevate glucose utilisation by 14.43%-33.81% in the differentiated 3T3-L1 adipocytes.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467262","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

Structure-guided discovery of novel dUTPase inhibitors with anti-Nocardia activity by computational design. 通过计算设计，在结构指导下发现具有抗诺卡氏菌活性的新型 dUTP 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: 2024-10-10 DOI: 10.1080/14756366.2024.2411573

Zhi-Zheng Wang, Jun Weng, Jing Qi, Xin-Xin Fu, Ban-Bin Xing, Yang Hu, Chun-Hsiang Huang, Chin-Yu Chen, Zigong Wei

{"title":"Structure-guided discovery of novel dUTPase inhibitors with anti-Nocardia activity by computational design.","authors":"Zhi-Zheng Wang, Jun Weng, Jing Qi, Xin-Xin Fu, Ban-Bin Xing, Yang Hu, Chun-Hsiang Huang, Chin-Yu Chen, Zigong Wei","doi":"10.1080/14756366.2024.2411573","DOIUrl":"10.1080/14756366.2024.2411573","url":null,"abstract":"The zoonosis caused by Nocardia is increasing seriously. But commonly used antibiotic drugs often lead to resistance. N. seriolae dUTPase (NsdUTPase) plays a key role in the proliferation of Nocardia, and was regarded as a potent drug target. However, there was little report about the NsdUTPase inhibitors. In this study, we discovered a series of novel NsdUTPase inhibitors to fight against Nocardia. The first crystal structure of NsdUTPase was released, and a structure-based computational design was performed. Compounds 4b and 12b exhibited promising activities towards NsdUTPase (IC50 = 0.99 μM and 0.7 μM). In addition, they showed satisfied anti-Nocardia activity (MIC value ranges from 0.5 to 2 mg/L) and low cytotoxicity, which were better than approved drugs oxytetracycline and florfenicol. Molecular modelling study indicated that hydrophobic interaction might be the main contribution for ligand binding. Our results suggested that NsdUTPase inhibitors might be a useful way to repress Nocardia.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400472","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

Statement of Retraction: Dihydroartemisinin enhances the anti-tumor effect of photodynamic therapy by targeting PKM2-mediated glycolysis in esophageal cancer cell. 撤回声明：双氢青蒿素通过靶向PKM2介导的食管癌细胞糖酵解增强光动力疗法的抗肿瘤效果

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-09 DOI: 10.1080/14756366.2024.2385783

引用次数: 0

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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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