{"title":"Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus.","authors":"Cong Wu, Qi Jiang, Hui Zhong, Xudong Zhou, Leping Liu, Tong Pan, Chao Liu, Wei Wang, Wenbing Sheng","doi":"10.1080/14756366.2024.2390909","DOIUrl":"https://doi.org/10.1080/14756366.2024.2390909","url":null,"abstract":"<p><p>An oxidising and substituting one-pot reaction strategy has been developed to synthesise dihydromyricetin derivatives with the aim of enhancing the inhibitory activity of dihydromyricetin against SARS-CoV-2. Different <i>ω</i>-methoxy-<i>ω</i>-oxeylkyl was introduced in C<sub>7</sub>-OH site and yielded eight analogs, all of them showed good inhibitory activity against SARS-CoV-2 3CL<sup>pro</sup> with IC<sub>50</sub> values ranging from 0.72 to 2.36 μM. In the Vero E6-cell, compound <b>3</b> has a good activity of anti-SARS-CoV-2 virus (Omicron virus BA.5) in the prevention model, with an EC<sub>50</sub> of 15.84 μM, and so do compound <b>10</b> in the therapeutic model, with an EC<sub>50</sub> of 11.52 μM. The results suggest that the introduction of long chain <i>ω</i>-oxeylkyl at C<sub>7</sub>-OH facilitate the inhibition of viral replication in the therapeutic model, which is consistent with the binding energies predicted from molecular docking conclusions. It implies that dihydromyricetin derivatives have the potential to become effective inhibitors of SARS-CoV-2 Omicron and other viruses.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2390909"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108024","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}
Yong-Sung Choi, Yoon-Jung Kim, Yeram Jeon, Jong Soon Kang, Juhee Lee, Eunmi Hong, Young-Hoon Park, Wantae Kim, Boksik Cha, Raok Jeon
{"title":"Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives.","authors":"Yong-Sung Choi, Yoon-Jung Kim, Yeram Jeon, Jong Soon Kang, Juhee Lee, Eunmi Hong, Young-Hoon Park, Wantae Kim, Boksik Cha, Raok Jeon","doi":"10.1080/14756366.2024.2419925","DOIUrl":"10.1080/14756366.2024.2419925","url":null,"abstract":"<p><p>Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2419925"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568641","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":"Computational fragment-based drug design of potential Glo-I inhibitors.","authors":"Roaa S Bibars, Qosay A Al-Balas","doi":"10.1080/14756366.2024.2301758","DOIUrl":"10.1080/14756366.2024.2301758","url":null,"abstract":"<p><p>In this study, a fragment-based drug design approach, particularly <i>de novo</i> drug design, was implemented utilising three different crystal structures in order to discover new privileged scaffolds against glyoxalase-I enzyme as anticancer agents. The fragments were evoluted to indicate potential inhibitors with high receptor affinities. The resulting compounds were served as a benchmark for choosing similar compounds from the ASINEX® database by applying different computational ligand-based drug design techniques. Afterwards, the selection of potential hits was further aided by various structure-based approaches. Then, 14 compounds were purchased, and tested <i>in vitro</i> against Glo-I enzyme. Of the tested 14 hits, the biological screening results showed humble activities where the percentage of Glo-I inhibition ranged from 0-18.70 %. Compound <b>19</b> and compound <b>28</b>, whose percentage of inhibitions are 18.70 and 15.80%, respectively, can be considered as hits that need further optimisation in order to be converted into lead-like compounds.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2301758"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10810659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139512636","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":"Identification of potential inhibitors against <i>Staphylococcus aureus</i> shikimate dehydrogenase through virtual screening and susceptibility test.","authors":"Mengfan Zhu, Jinfeng Qu, Qi Deng","doi":"10.1080/14756366.2024.2301768","DOIUrl":"10.1080/14756366.2024.2301768","url":null,"abstract":"<p><p><i>Staphylococcus aureus</i> shikimate dehydrogenase (SaSDH) plays a crucial role in the growth of <i>Staphylococcus aureus</i> (<i>S. aureus</i>), but absent in mammals and therefore a potential target for antibacterial drugs to treat drug-resistant <i>S. aureus</i> infection. In this study, a 3D model of SaSDH was constructed by homology modelling and inhibitors of SaSDH were screened through virtual screening. (-)-Gallocatechin gallate and rhodiosin were identified as inhibitors with K<sub>i</sub>s of 2.47 μM and 73.38 μM, respectively. Molecular docking and isothermal titration calorimetry showed that both inhibitors interact with SaSDH with a K<sub>D</sub> of 44.65 μM for (-)-gallocatechin gallate and 16.45 μM for rhodiosin. Both inhibitors had antibacterial activity, showing MICs of 50 μg/mL for (-)-gallocatechin gallate and 250 μg/mL for rhodiosin against <i>S. aureus</i>. The current findings have the potential for identification of drugs to treat <i>S. aureus</i> infections by targeting SaSDH.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2301768"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10798293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485389","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}
Viviana De Luca, Simone Giovannuzzi, Claudiu T Supuran, Clemente Capasso
{"title":"A comprehensive investigation of the anion inhibition profile of a β-carbonic anhydrase from <i>Acinetobacter baumannii</i> for crafting innovative antimicrobial treatments.","authors":"Viviana De Luca, Simone Giovannuzzi, Claudiu T Supuran, Clemente Capasso","doi":"10.1080/14756366.2024.2372731","DOIUrl":"10.1080/14756366.2024.2372731","url":null,"abstract":"<p><p>This study refers to the intricate world of <i>Acinetobacter baumannii</i>, a resilient pathogenic bacterium notorious for its propensity at antibiotic resistance in nosocomial infections. Expanding upon previous findings that emphasised the bifunctional enzyme PaaY, revealing unexpected γ-carbonic anhydrase (CA) activity, our research focuses on a different class of CA identified within the <i>A. baumannii</i> genome, the β-CA, designated as 𝛽-AbauCA (also indicated as CanB), which plays a crucial role in the resistance mechanism mediated by AmpC beta-lactamase. Here, we cloned, expressed, and purified the recombinant 𝛽-AbauCA, unveiling its distinctive kinetic properties and inhibition profile with inorganic anions (classical CA inhibitors). The exploration of 𝛽-AbauCA not only enhances our understanding of the CA repertoire of <i>A. baumannii</i> but also establishes a foundation for targeted therapeutic interventions against this resilient pathogen, promising advancements in combating its adaptability and antibiotic resistance.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2372731"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC467105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620102","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}
Pierre Popczyk, Alina Ghinet, Clovis Bortolus, Laure Kamus, Marc F Lensink, Jérôme de Ruyck, Boualem Sendid, Faustine Dubar
{"title":"Antifungal and anti-biofilm effects of hydrazone derivatives on <i>Candida</i> spp.","authors":"Pierre Popczyk, Alina Ghinet, Clovis Bortolus, Laure Kamus, Marc F Lensink, Jérôme de Ruyck, Boualem Sendid, Faustine Dubar","doi":"10.1080/14756366.2024.2429109","DOIUrl":"10.1080/14756366.2024.2429109","url":null,"abstract":"<p><p>Worldwide, invasive candidiasis are a burden for the health system due to difficulties to manage patients, to the increasing of the resistance of the current therapeutics and the emergence of naturally resistant species of <i>Candida</i>. In this context, the development of innovative antifungal drugs is urgently needed. During invasive candidiasis, yeast is submitted to many stresses (oxidative, thermic, osmotic) in the human host. In order to resist in this context, yeast develops different strategy, especially the biosynthesis of trehalose. Starting from the 3D structural data of TPS2, an enzyme implicated in trehalose biosynthesis, we identified hydrazone as an interesting scaffold to design new antifungal drugs. Interestingly, our hydrazone derivatives which demonstrate antifungal and anti-biofilm effects on <i>Candida spp</i>., are non-toxic in <i>in vitro</i> and <i>in vivo</i> models (<i>Galleria mellonella</i>).</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2429109"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11600518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716373","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}
Mohammad Abdel-Halim, Dalia S El-Gamil, Mennatallah A Hammam, Mohamed El-Shazly, Yi-Hsuan Wang, Po-Hsiung Kung, Yu-Cheng Chen, Michal Korinek, Ashraf H Abadi, Matthias Engel, Tsong-Long Hwang
{"title":"Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways.","authors":"Mohammad Abdel-Halim, Dalia S El-Gamil, Mennatallah A Hammam, Mohamed El-Shazly, Yi-Hsuan Wang, Po-Hsiung Kung, Yu-Cheng Chen, Michal Korinek, Ashraf H Abadi, Matthias Engel, Tsong-Long Hwang","doi":"10.1080/14756366.2024.2402988","DOIUrl":"10.1080/14756366.2024.2402988","url":null,"abstract":"<p><p>Targeting neutrophil function has gained attention as a propitious therapeutic strategy for diverse inflammatory diseases. Accordingly, a series of enone-based derivatives were developed to inhibit neutrophil-mediated inflammation, showing promise for treating inflammatory diseases. These compounds fall into two clusters with distinct effects: one inhibits neutrophilic superoxide (SO) anion production and elastase release triggered by N-formyl-Met-Leu-Phe (fMLF), with compound <b>6a</b> being most effective (IC<sub>50</sub> values of 1.23 and 1.37 μM, respectively), affecting c-Jun N-terminal kinase (JNK) and Akt phosphorylation. The second cluster suppresses formation of SO anion without affecting elastase levels, surpassed by compound <b>26a</b> (IC<sub>50</sub> of 1.56 μM), which attenuates various mitogen-activated protein kinases (MAPKs) with minimal Akt impact. Notably, none of the tested compounds showed cytotoxicity in human neutrophils, underscoring their potential as therapeutic agents against inflammatory diseases.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2402988"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288898","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":"Synthesis and biological evaluation of <i>ortho</i>-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases.","authors":"Kai-Cheng Hsu, Yun-Yi Huang, Jung-Chun Chu, Yu-Wen Huang, Jing-Lan Hu, Tony Eight Lin, Shih-Chung Yen, Jing-Ru Weng, Wei-Jan Huang","doi":"10.1080/14756366.2024.2406025","DOIUrl":"10.1080/14756366.2024.2406025","url":null,"abstract":"<p><p>Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid <b>LH4f</b> as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the <i>ortho</i>-phenyl group from the selective HDAC7 inhibitor <b>1</b> is incorporated into <i>ortho</i> position of the phenylhydroxamic acid in <b>LH4f</b>. Compared to <b>LH4f</b>, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound <b>7 g</b> exhibited the strongest HDAC9 inhibition with an IC<sub>50</sub> value of 40 nM. Molecular modelling further identified the key interactions of compound <b>7 g</b> bound to HDAC9. Compound <b>7 g</b> significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2406025"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307872","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}
Keren Xu, Leyi Ying, Titi Ying, Qihao Wu, Lin Du, Yanlei Yu, Youmin Ying, Bin Wei, Hong Wang, Zhikun Yang
{"title":"Design, synthesis, and biological evaluation of (thio)urea derivatives as potent <i>Escherichia coli β</i>-glucuronidase inhibitors.","authors":"Keren Xu, Leyi Ying, Titi Ying, Qihao Wu, Lin Du, Yanlei Yu, Youmin Ying, Bin Wei, Hong Wang, Zhikun Yang","doi":"10.1080/14756366.2024.2387415","DOIUrl":"10.1080/14756366.2024.2387415","url":null,"abstract":"<p><p>EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that <b>E-9</b> (IC<sub>50</sub> = 2.68 μM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC<sub>50</sub> = 45.8 μM). Additionally, the inhibitory kinetic study indicated that <b>E-9</b> (K<sub>i</sub> = 1.64 μM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the <i>para</i>-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that <b>E-9</b> has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that <b>E-9</b> could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2387415"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975775","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}
Tingting Wu, Hu Cheng, Lijie Sima, Zhongyuan Wang, Weiwei Ouyang, Jianta Wang, Yunlei Hou, Dongsheng Zhao, Weike Liao, Chujiao Hu
{"title":"Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and <i>in vitro</i> characterisation.","authors":"Tingting Wu, Hu Cheng, Lijie Sima, Zhongyuan Wang, Weiwei Ouyang, Jianta Wang, Yunlei Hou, Dongsheng Zhao, Weike Liao, Chujiao Hu","doi":"10.1080/14756366.2024.2353711","DOIUrl":"10.1080/14756366.2024.2353711","url":null,"abstract":"<p><p>The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds. In this study, we employed multistage virtual screening methods to screen multiple compound databases to predict new PD-1/PD-L1 ligands. 35 compounds were proposed by combined analysis of fitness scores, interaction pattern and MM-GBSA binding affinities. Enzymatic assay confirmed that 10 out of 35 ligands were potential PD-L1 inhibitors, with inhibitory rate higher than 50% at the concentration of 30 µM. Among them, <b>ZDS20</b> was identified as the most effective inhibitor with low micromolar activity (IC<sub>50</sub> = 3.27 μM). Altogether, <b>ZDS20</b> carrying novel scaffold was identified and could serve as a lead for the development of new classes of PD-L1 inhibitors.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2353711"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419415","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}