Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

{"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":"<p><p>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 <i>in vitro</i> 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, <i>in vitro</i> 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.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2351861"},"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}

{"title":"Crystal structure of dihydroneopterin aldolase from <i>Mycobacterium tuberculosis</i> associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, <i>in vitro</i> 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":"<p><p>The crystallographic structure of the FolB enzyme from <i>Mycobacterium tuberculosis</i> (<i>Mt</i>FolB), 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 <i>in vitro</i> inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of <i>Mt</i>FolB. 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 <i>M. tuberculosis</i> H37Rv strain were evaluated. Compound <b>3e</b> exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound <b>3e</b> showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting <i>Mt</i>FolB, an attractive molecular target for TB drug development.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2388207"},"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}

{"title":"<i>Bacillus</i> 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":"<p><p><i>Bacillus</i> lipopeptides have been reported to display anti-obesity effects. In the present study, Lipopeptides from <i>Bacillus velezensis</i> 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.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2417915"},"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}

{"title":"Structure-guided discovery of novel dUTPase inhibitors with anti-<i>Nocardia</i> 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":"<p><p>The zoonosis caused by <i>Nocardia</i> is increasing seriously. But commonly used antibiotic drugs often lead to resistance. <i>N. seriolae</i> dUTPase (<i>Ns</i>dUTPase) plays a key role in the proliferation of <i>Nocardia</i>, and was regarded as a potent drug target. However, there was little report about the <i>Ns</i>dUTPase inhibitors. In this study, we discovered a series of novel <i>Ns</i>dUTPase inhibitors to fight against <i>Nocardia</i>. The first crystal structure of <i>Ns</i>dUTPase was released, and a structure-based computational design was performed. Compounds <b>4b</b> and <b>12b</b> exhibited promising activities towards <i>Ns</i>dUTPase (IC₅₀ = 0.99 μM and 0.7 μM). In addition, they showed satisfied anti-<i>Nocardia</i> 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 <i>Ns</i>dUTPase inhibitors might be a useful way to repress <i>Nocardia</i>.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2411573"},"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}

{"title":"A multidisciplinary approach to the antioxidant and hepatoprotective activities of <i>Arbutus pavarii</i> Pampan fruit; <i>in vitro</i> and <i>in Vivo</i> biological evaluations, and <i>in silico</i> investigations.","authors":"Fatma A Elshibani, Abdullah D Alamami, Hamdoon A Mohammed, Rabab Ahmed Rasheed, Radwa M El Sabban, Mohamed A Yehia, Sherif S Abdel Mageed, Taghreed A Majrashi, Eslam B Elkaeed, Mahmoud A El Hassab, Wagdy M Eldehna, Mohamed K El-Ashrey","doi":"10.1080/14756366.2023.2293639","DOIUrl":"10.1080/14756366.2023.2293639","url":null,"abstract":"<p><p>The Libyan Strawberry, <i>Arbutus pavarii</i> Pampan (ARB), is an endemic Jebel Akhdar plant used for traditional medicine. This study presents the antioxidant and hepatoprotective properties of ARB fruit-extract. ARB phytochemical analysis indicated the presence of 354.54 GAE and 36.2 RE of the phenolics and flavonoids. LC-MS analysis identified 35 compounds belonging to phenolic acids, procyanidins, and flavonoid glycosides. Gallic acid, procyanidin dimer B3, β-type procyanidin trimer C, and quercetin-3-O-glucoside were the major constituents of the plant extract. ARB administration to paracetamol (PAR)-intoxicated rats reduced serum ALT, AST, bilirubin, hepatic tissue MDA and proinflammatory markers; TNF-α and IL-6 with an increase in tissue GSH level and SOD activity. Histological and immunohistochemical studies revealed that ARB restored the liver histology and significantly reduced the tissue expression of caspase 3, IL-1B, and NF-KB in PAR-induced liver damage. Docking analysis disclosed good binding affinities of some compounds with XO, COX-1, 5-LOX, and PI3K.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2293639"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139048862","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}

{"title":"Imparting aromaticity to 2-pyridone derivatives by <i>O</i>-alkylation resulted in new competitive and non-competitive PIM-1 kinase inhibitors with caspase-activated apoptosis.","authors":"Marwa E Abdelaziz, Mostafa M M El-Miligy, Salwa M Fahmy, Marwa M Abu-Serie, Aly A Hazzaa, Mona A Mahran","doi":"10.1080/14756366.2024.2304044","DOIUrl":"10.1080/14756366.2024.2304044","url":null,"abstract":"<p><p>New aromatic <i>O</i>-alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. <b>4c</b> and <b>4f</b> showed potent <i>in vitro</i> anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, <b>4c</b> and <b>4f</b> induced apoptosis in the four tested cancer cell lines with high percentage. In addition, <b>4c</b> and <b>4f</b> significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, <b>4c</b> and <b>4f</b> showed potent PIM-1 kinase inhibitory activity with IC₅₀ = 0.110, 0.095 µM, respectively. Kinetic studies indicated that <b>4c</b> and <b>4f</b> were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, <i>in silico</i> prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that <b>4c</b> and <b>4f</b> could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2304044"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10795791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478512","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}

{"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":"<p><p>Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds <b>(1a-c, 2a-c, 3a-c, 4a-r</b> and <b>5a-c)</b> were evaluated for <i>in vitro</i> anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound <b>1c</b> showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound <b>1c</b> 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 <b>1c</b> 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 <b>1c</b> treated HL60 cells as well as from 1.51% to 4.72% in compound <b>1c</b> treated leukaemia SR cells. Also, compound <b>1c</b> triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl₂. Moreover, <b>1c</b> revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound <b>1c</b> in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative <b>1c</b> might serve as a model for designing novel anticancer drugs in the future.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2304625"},"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}

{"title":"New natural protein tyrosine phosphatase 1B inhibitors from <i>Gynostemma pentaphyllum</i>.","authors":"Xianting Wang, Yidan Deng, Jianmei Wang, Lin Qin, Yimei Du, Qianru Zhang, Di Wu, Xingdong Wu, Jian Xie, Yuqi He, Daopeng Tan","doi":"10.1080/14756366.2024.2360063","DOIUrl":"10.1080/14756366.2024.2360063","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. <i>Gynostemma pentaphyllum</i> is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from <i>G. pentaphyllum</i>, and their structures were elucidated by spectroscopic methods including HR-ESI-MS,¹H and ¹³C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds <b>7</b>∼<b>10</b> were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2360063"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11182071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317384","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}

{"title":"Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors.","authors":"Mater H Mahnashi, Mohammed Nahari, Hassan Almasoudi, Abdulaziz Alhasaniah, Sara Elgazwi, Mahrous A Abou-Salim","doi":"10.1080/14756366.2024.2358934","DOIUrl":"10.1080/14756366.2024.2358934","url":null,"abstract":"<p><p>Novel series of nitric oxide-releasing thiazolidine-2,4-diones (<b>NO-TZD-3a-d,5,6</b>) and 3,4,5-trimethoxychalcone-based multifunctional 1,4-dihydropyrimidines (<b>CDHPM-10a-g</b>) have been designed and synthesised as potent broad-spectrum anticancer agents with potential VEGFR-2 inhibition. The designed analogs were evaluated for their anticancer activities towards a full panel of NCI-60 tumour cell lines and <b>CDHPM-10a-g</b> emerged mean %inhibitions ranging from 76.40 to 147.69%. Among them, <b>CDHPM-10e</b> and <b>CDHPM-10f</b> demonstrated the highest MGI% of 147.69 and 140.24%, respectively. Compounds <b>CDHPM-10a,b,d-f</b> showed higher mean %inhibitory activity than the reference drug sorafenib (MGI% = 105.46%). Superiorly, the hybrid <b>CDHPM-10e</b> displayed the highest potencies towards all the herein tested subpanels of nine types of cancer with MGI₅₀ of 1.83 µM. Also, it revealed potent cytostatic single-digit micromolar activity towards the herein examined cancer cell lines. The designed compounds <b>CDHPM-10a-g</b> were exposed as potent non-selective broad-spectrum anticancer agents over all NCI subpanels with an SI range of 0.66-1.97. In addition, the target analog <b>CDHPM-10e</b> revealed potency towards VEGFR-2 kinase comparable to that of sorafenib with a sub-micromolar IC₅₀ value of 0.11 µM. Also, <b>CDHPM-10e</b> could effectively induce Sub-G1-phase arrest and prompt apoptosis <i>via</i> caspase and p53-dependent mechanisms. Furthermore, <b>CDHPM-10e</b> revealed significant anti-metastatic activity as detected by wound healing assay. The modelling study implies that <b>CDHPM-10e</b> overlaid well with sorafenib and formed a strong H-bond in the DFG binding domain. The ADMET studies hinted out that <b>CDHPM-10e</b> met Pfizer's drug-likeness criteria. The presented novel potent anticancer agent merits further devotion as a new lead product in developing more chalcone-based VEGFR-2 inhibitors.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2358934"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC467104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432072","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}

{"title":"Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia.","authors":"Zhuoying Chen, Quan Wang, Yao Yao Yan, Dalong Jin, Yumeng Wang, Xing Xing Zhang, Xin Hua Liu","doi":"10.1080/14756366.2024.2305852","DOIUrl":"10.1080/14756366.2024.2305852","url":null,"abstract":"<p><p>It has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound <b>12</b> (<i>3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide</i>) showed the most potent inhibiting activity against CDK8 with an IC₅₀ value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC₅₀ = 0.02 ± 0.01 <i>μ</i>M, MV4-11 GC₅₀ = 0.03 ± 0.01 <i>μ</i>M). Mechanistic studies revealed that this compound <b>12</b> could inhibit the phosphorylation of STAT-1 and STAT-5. Importantly, compound <b>12</b> showed relative good bioavailability (<i>F</i> = 38.80%) and low toxicity <i>in vivo</i>. This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2305852"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10810651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139521031","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}