Pub Date : 2025-02-16DOI: 10.1016/j.ejmech.2025.117382
Si-jie Qi , Ke-xin Liu , Hao-yu Liu , Gao-qiang Zhang , Hong-bo Zheng , Jia-yu Sun , Bin Sun , Hong-xiang Lou
Resistance to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) of cancer cells is a main obstacle for the chemotherapy. NRH: quinone oxidoreductase 2 (NQO2), known as a chemopreventive target, has emerged as a promising therapeutic target for overcoming TRAIL resistance in non-small cell lung cancer (NSCLC). Here we report the design, synthesis and evaluation of resveratrol analogues as novel selective NQO2 inhibitors, and analogue 20b, with potent NQO2 inhibitory activity (IC50 = 95 nM) and relatively low cytotoxicity, displayed synergistic lethal effects in combination with TRAIL on TRAIL-resistant NSCLC cells. In addition, mechanistic studies revealed that 20b sensitized TRAIL-resistant A549 cells to apoptosis through the generation of reactive oxygen species (ROS) and the upregulation of death receptor 5 (DR5). Furthermore, 20b showed no acute toxicity in the healthy mice at a single dose of 2000 mg/kg. Molecular docking confirmed the binding mode of 20b within the NQO2 active site, highlighting key interactions responsible for its enhanced potency. This study provided novel molecular templates for development of NQO2 inhibitor, and laid a foundation for developing agents against TRAIL-resistant cancers for targeting NQO2.
{"title":"Discovery of potent quinone oxidoreductase 2 inhibitors to overcome TRAIL resistance of non-small cell lung cancer","authors":"Si-jie Qi , Ke-xin Liu , Hao-yu Liu , Gao-qiang Zhang , Hong-bo Zheng , Jia-yu Sun , Bin Sun , Hong-xiang Lou","doi":"10.1016/j.ejmech.2025.117382","DOIUrl":"10.1016/j.ejmech.2025.117382","url":null,"abstract":"<div><div>Resistance to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) of cancer cells is a main obstacle for the chemotherapy. NRH: quinone oxidoreductase 2 (NQO2), known as a chemopreventive target, has emerged as a promising therapeutic target for overcoming TRAIL resistance in non-small cell lung cancer (NSCLC). Here we report the design, synthesis and evaluation of resveratrol analogues as novel selective NQO2 inhibitors, and analogue 20b, with potent NQO2 inhibitory activity (IC<sub>50</sub> = 95 nM) and relatively low cytotoxicity, displayed synergistic lethal effects in combination with TRAIL on TRAIL-resistant NSCLC cells. In addition, mechanistic studies revealed that <strong>20b</strong> sensitized TRAIL-resistant A549 cells to apoptosis through the generation of reactive oxygen species (ROS) and the upregulation of death receptor 5 (DR5). Furthermore, 20b showed no acute toxicity in the healthy mice at a single dose of 2000 mg/kg. Molecular docking confirmed the binding mode of 20b within the NQO2 active site, highlighting key interactions responsible for its enhanced potency. This study provided novel molecular templates for development of NQO2 inhibitor, and laid a foundation for developing agents against TRAIL-resistant cancers for targeting NQO2.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117382"},"PeriodicalIF":6.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426968","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}
Malaria, caused by Plasmodium parasites and transmitted by Anopheles mosquitoes, remains a significant global health challenge, especially in tropical and subtropical regions where the disease is endemic. The complex Plasmodium lifecycle, involving stages in both the liver and bloodstream, leads to symptoms such as high fever, anemia, and, in severe cases, life-threatening complications, particularly P. falciparum infections. While historical treatments such as quinine and modern therapies such as artemisinin-based combination therapies (ACTs) have been effective, the growing issue of drug and insecticide resistance undermines these efforts. This resistance has spurred the need for new antimalarial drugs and strategies. Among the promising areas of research are heterocyclic compounds, which, due to their diverse and versatile chemical structures, are being investigated for their ability to disrupt the Plasmodium lifecycle. These compounds have potential as novel therapeutic agents that could enhance current treatment options. Understanding the mechanisms underlying drug resistance and advancing these therapeutic innovations are crucial for maintaining effective malaria control and treatment, highlighting the importance of on-going research in this field.
{"title":"A Progress Report in Advancements of Heterocyclic Compounds as Novel Antimalarial Agents over the Last 5 Years","authors":"Sumit Tahlan, Sucheta Singh, Meenakshi Kaira, Hrithik Dey, Kailash C. Pandey","doi":"10.1016/j.ejmech.2025.117393","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117393","url":null,"abstract":"Malaria, caused by Plasmodium parasites and transmitted by Anopheles mosquitoes, remains a significant global health challenge, especially in tropical and subtropical regions where the disease is endemic. The complex Plasmodium lifecycle, involving stages in both the liver and bloodstream, leads to symptoms such as high fever, anemia, and, in severe cases, life-threatening complications, particularly <em>P. falciparum</em> infections. While historical treatments such as quinine and modern therapies such as artemisinin-based combination therapies (ACTs) have been effective, the growing issue of drug and insecticide resistance undermines these efforts. This resistance has spurred the need for new antimalarial drugs and strategies. Among the promising areas of research are heterocyclic compounds, which, due to their diverse and versatile chemical structures, are being investigated for their ability to disrupt the <em>Plasmodium</em> lifecycle. These compounds have potential as novel therapeutic agents that could enhance current treatment options. Understanding the mechanisms underlying drug resistance and advancing these therapeutic innovations are crucial for maintaining effective malaria control and treatment, highlighting the importance of on-going research in this field.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418152","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}
Pub Date : 2025-02-15DOI: 10.1016/j.ejmech.2025.117396
Yuan-Yuan Wang , Bao-Zhang Luo , Chang-Ming Li , Jian-Long Liang , Zheng Liu , Wei-Min Chen , Jia-Liang Guo
Chronic infections by Pseudomonas aeruginosa (P. aeruginosa) are frequently complicated due to its ability to form biofilm, which also effectively enhance its resistance to antibiotics. Bacteria-specific antibiotic delivery could locally increase drug concentration to break antimicrobial resistance and reduce the drug's peripheral side effects. The standard-of-care drug ciprofloxacin suffers from severe systemic side effects and was therefore chosen for this approach. It has been identified that 3-hydroxypyridin-4(1H)-one as siderophore mimics could be utilized by P. aeruginosa, and reduced bacterial biofilm formation. In this work, ciprofloxacin was conjugated to 3-hydroxypyridin-4(1H)-one by cleavable linkers to yield prodrugs, which were strategically designed and synthesized to function as dual antibacterial and antibiofilm agents against P. aeruginosa. Conjugate 5c was identified and has the best minimum inhibitory concentrations of 1.07 μM against P. aeruginosa PAO1, and reduced 61.7 % of biofilm formation. In addition, 5c destroyed 75.7 % of mature biofilms. Further studies on the uptake mechanisms showed that the bacterial siderophore-dependent iron transport system was involved in the uptake of the conjugates. Conjugate 5c interfered with iron uptake by bacteria, inhibited their motilities and reduced the production of virulence. Furthermore, prodrug 5c reduced toxicity in vivo and in vitro and showed a positive therapeutic effect in the treatment of Caenorhabditis elegans (C. elegans) infected by P. aeruginosa. These results demonstrate that 3-hydroxypyridin-4(1H)-ones-ciprofloxacin prodrugs are potent in the treatment of biofilm-associated drug-resistant P. aeruginosa infections.
{"title":"Discovery of 3-hydroxypyridin-4(1H)-ones ester of ciprofloxacin as prodrug to combat biofilm-associated Pseudomonas aeruginosa","authors":"Yuan-Yuan Wang , Bao-Zhang Luo , Chang-Ming Li , Jian-Long Liang , Zheng Liu , Wei-Min Chen , Jia-Liang Guo","doi":"10.1016/j.ejmech.2025.117396","DOIUrl":"10.1016/j.ejmech.2025.117396","url":null,"abstract":"<div><div>Chronic infections by <em>Pseudomonas aeruginosa</em> (<em>P. aeruginosa</em>) are frequently complicated due to its ability to form biofilm, which also effectively enhance its resistance to antibiotics. Bacteria-specific antibiotic delivery could locally increase drug concentration to break antimicrobial resistance and reduce the drug's peripheral side effects. The standard-of-care drug ciprofloxacin suffers from severe systemic side effects and was therefore chosen for this approach. It has been identified that 3-hydroxypyridin-4(1<em>H</em>)-one as siderophore mimics could be utilized by <em>P. aeruginosa</em>, and reduced bacterial biofilm formation. In this work, ciprofloxacin was conjugated to 3-hydroxypyridin-4(1<em>H</em>)-one by cleavable linkers to yield prodrugs, which were strategically designed and synthesized to function as dual antibacterial and antibiofilm agents against <em>P. aeruginosa</em>. Conjugate <strong>5c</strong> was identified and has the best minimum inhibitory concentrations of 1.07 μM against <em>P. aeruginosa</em> PAO1, and reduced 61.7 % of biofilm formation. In addition, <strong>5c</strong> destroyed 75.7 % of mature biofilms. Further studies on the uptake mechanisms showed that the bacterial siderophore-dependent iron transport system was involved in the uptake of the conjugates. Conjugate <strong>5c</strong> interfered with iron uptake by bacteria, inhibited their motilities and reduced the production of virulence. Furthermore, prodrug <strong>5c</strong> reduced toxicity <em>in vivo</em> and <em>in vitro</em> and showed a positive therapeutic effect in the treatment of <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) infected by <em>P. aeruginosa</em>. These results demonstrate that 3-hydroxypyridin-4(1<em>H</em>)-ones-ciprofloxacin prodrugs are potent in the treatment of biofilm-associated drug-resistant <em>P. aeruginosa</em> infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117396"},"PeriodicalIF":6.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418190","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}
Pub Date : 2025-02-15DOI: 10.1016/j.ejmech.2025.117385
Ki-Kwang Oh, Sang-Jun Yoon, Jung-A Eom, Kyeong Jin Lee, Goo-Hyun Kwon, Dong Joon Kim, Ki-Tae Suk
Non-alcoholic fatty liver disease (NAFLD) is implicated in steatohepatitis (NASH), liver cirrhosis (LC) to hepatocellular carcinoma (HCC), sequentially. Herein, our aim was to unravel the nuanced key components (compounds, and targets) to deter the progressive severity concerning hepatocellular diseases. We incorporated rigor bioinformatics and computational screening tools to decode effector(s) against NAFLD, NASH, LC, and HCC. The corresponding ligands of PDX1 (transcription factor of INS; one agonist), and IL6 (thirty-two antagonists) were identified by Selleckchem. Molecular docking test (MDT) revealed that PDX1- BRD7552 conformer (−12.1 kcal/mol), and IL6- Forsythoside B (−11.4 kcal/mol) conformer formed most stable complex. In parallel, DFT proposed that BRD7552, and Forsythoside B had significant chemical properties to react the targets, respectively. In conclusion, we decoded causatives of the progressive liver disease with web-based tools in drug repositioning theory. BRD7552 as PDX1 agonist, and Forsythoside B as IL6 antagonist were attributed to synergistic efficacy against NAFLD-derived HCC.
{"title":"The assembled decoders to prepare for “bioactive X″ against progressive deterioration of liver disease: From NAFLD to HCC","authors":"Ki-Kwang Oh, Sang-Jun Yoon, Jung-A Eom, Kyeong Jin Lee, Goo-Hyun Kwon, Dong Joon Kim, Ki-Tae Suk","doi":"10.1016/j.ejmech.2025.117385","DOIUrl":"10.1016/j.ejmech.2025.117385","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is implicated in steatohepatitis (NASH), liver cirrhosis (LC) to hepatocellular carcinoma (HCC), sequentially. Herein, our aim was to unravel the nuanced key components (compounds, and targets) to deter the progressive severity concerning hepatocellular diseases. We incorporated rigor bioinformatics and computational screening tools to decode effector(s) against NAFLD, NASH, LC, and HCC. The corresponding ligands of PDX1 (transcription factor of INS; one agonist), and IL6 (thirty-two antagonists) were identified by Selleckchem. Molecular docking test (MDT) revealed that PDX1- BRD7552 conformer (−12.1 kcal/mol), and IL6- Forsythoside B (−11.4 kcal/mol) conformer formed most stable complex. In parallel, DFT proposed that BRD7552, and Forsythoside B had significant chemical properties to react the targets, respectively. In conclusion, we decoded causatives of the progressive liver disease with web-based tools in drug repositioning theory. BRD7552 as PDX1 agonist, and Forsythoside B as IL6 antagonist were attributed to synergistic efficacy against NAFLD-derived HCC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117385"},"PeriodicalIF":6.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418153","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}
Pub Date : 2025-02-15DOI: 10.1016/j.ejmech.2025.117397
Chiara Bosetti , Dionysis Kampasis , Shoshy A. Brinch , Albert Galera-Prat , Maria Karelou , Saurabh S. Dhakar , Juho Alaviuhkola , Jo Waaler , Lari Lehtiö , Ioannis K. Kostakis
Human diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially in oncology, and a vast number of inhibitors have already been successfully developed. These inhibitors typically occupy the nicotinamide binding site and extend along the NAD+ binding groove of the catalytic domain. Quinazolin-4-ones have been explored as compelling scaffolds for such inhibitors and we have identified a new position within the catalytic domain that has not been extensively studied yet. In this study, we investigate larger substituents at the C-8 position and, using X-ray crystallography, we demonstrate that nitro- and diol-substituents engage in new interactions with TNKS2, improving both affinity and selectivity. Both diol- and nitro-substituents exhibit intriguing inhibition of TNKS2, with the diol-based compound EXQ-1e displaying a pIC50 of 7.19, while the nitro-based compound EXQ-2d's pIC50 value is 7.86. Both analogues impact and attenuate the tankyrase-controlled WNT/β-catenin signaling with sub-micromolar IC50. When tested against a wider panel of enzymes, the nitro-based compound EXQ-2d displayed high selectivity towards tankyrases, whereas the diol-based compound EXQ-1e also inhibited other PARPs. Compound EXQ-2d displays in vitro cell growth inhibition of the colon cancer cell line COLO 320DM, while compound EXQ-1e displays nonspecific cell toxicity. Collectively, the results offer new insights for inhibitor development targeting tankyrases and PARPs by focusing on the subsite between a mobile active site loop and the canonical nicotinamide binding site.
{"title":"Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors","authors":"Chiara Bosetti , Dionysis Kampasis , Shoshy A. Brinch , Albert Galera-Prat , Maria Karelou , Saurabh S. Dhakar , Juho Alaviuhkola , Jo Waaler , Lari Lehtiö , Ioannis K. Kostakis","doi":"10.1016/j.ejmech.2025.117397","DOIUrl":"10.1016/j.ejmech.2025.117397","url":null,"abstract":"<div><div>Human diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially in oncology, and a vast number of inhibitors have already been successfully developed. These inhibitors typically occupy the nicotinamide binding site and extend along the NAD<sup>+</sup> binding groove of the catalytic domain. Quinazolin-4-ones have been explored as compelling scaffolds for such inhibitors and we have identified a new position within the catalytic domain that has not been extensively studied yet. In this study, we investigate larger substituents at the C-8 position and, using X-ray crystallography, we demonstrate that nitro- and diol-substituents engage in new interactions with TNKS2, improving both affinity and selectivity. Both diol- and nitro-substituents exhibit intriguing inhibition of TNKS2, with the diol-based compound <strong>EXQ-1e</strong> displaying a pIC<sub>50</sub> of 7.19, while the nitro-based compound <strong>EXQ-2d</strong>'s pIC<sub>50</sub> value is 7.86. Both analogues impact and attenuate the tankyrase-controlled WNT/β-catenin signaling with sub-micromolar IC<sub>50</sub>. When tested against a wider panel of enzymes, the nitro-based compound <strong>EXQ-2d</strong> displayed high selectivity towards tankyrases, whereas the diol-based compound <strong>EXQ-1e</strong> also inhibited other PARPs. Compound <strong>EXQ-2d</strong> displays <em>in vitro</em> cell growth inhibition of the colon cancer cell line COLO 320DM, while compound <strong>EXQ-1e</strong> displays nonspecific cell toxicity. Collectively, the results offer new insights for inhibitor development targeting tankyrases and PARPs by focusing on the subsite between a mobile active site loop and the canonical nicotinamide binding site.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117397"},"PeriodicalIF":6.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418193","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}
Pub Date : 2025-02-14DOI: 10.1016/j.ejmech.2025.117346
Richa Singh , Vinita Kushwaha , Sumit K. Rastogi , Prashant Rai , Santosh Kumar , Nilesh Khandelwal , Sanchita Gupta , Amol Chhatrapati Bisen , Salil Varshney , Astha Singh , Vishal M. Balaramnavar , Rabi Sankar Bhatta , Ravindra Kumar , Anil N. Gaikwad , Arun K. Sinha
Obesity has emerged as the root cause for various metabolic disorders worldwide and hence demands for urgent attention. In the same stride, a series of quinoline carboxylic acid-based styryl/alkyne hybrids were designed, synthesized, and evaluated for their anti-adipogenic activity. Based on the structure-activity relationship, functional groups and essential substituents to potentiate the anti-adipogenic activity were identified. The potent compound (E)-6-fluoro-2-(4-(4-methylstyryl)phenyl)quinoline-4-carboxylic acid (5m) suppresses the adipogenesis with IC50 value of 0.330 μM. In vitro studies in 3T3-L1 preadipocytes cell line show that compound 5m prevents adipogenesis by stopping the cell cycle at the early phase of differentiation, which is caused by stimulation of the Wnt3a/β-catenin pathway. Further compound 5m improves the blood lipid profile and reduces adipogenic marker proteins in the epididymal white adipose tissue (eWAT) of dyslipidemic hamster at 100 mg/kg/day oral dose. Treatment with compound 5m reduces the hypertrophied adipose tissue along with the decrease in the levels of adipogenic marker proteins such as PPARγ and CEBPα. The pharmacokinetic result establishes the molecule 5m to be stable with significant oral bioavailability. Henceforth, the present study provides a unique insight into the anti-adipogenic/anti-dyslipidemic properties of a novel styryl-quinoline carboxylic acid scaffold with a scope to enhance the anti-adipogenic potency for therapeutic intervention of obesity.
{"title":"Design, synthesis, and biological evaluation of novel quinoline carboxylic acid based styryl/alkyne hybrid molecule as a potent anti-adipogenic and antidyslipidemic agent via activation of Wnt/β-catenin pathway","authors":"Richa Singh , Vinita Kushwaha , Sumit K. Rastogi , Prashant Rai , Santosh Kumar , Nilesh Khandelwal , Sanchita Gupta , Amol Chhatrapati Bisen , Salil Varshney , Astha Singh , Vishal M. Balaramnavar , Rabi Sankar Bhatta , Ravindra Kumar , Anil N. Gaikwad , Arun K. Sinha","doi":"10.1016/j.ejmech.2025.117346","DOIUrl":"10.1016/j.ejmech.2025.117346","url":null,"abstract":"<div><div>Obesity has emerged as the root cause for various metabolic disorders worldwide and hence demands for urgent attention. In the same stride, a series of quinoline carboxylic acid-based styryl/alkyne hybrids were designed, synthesized, and evaluated for their anti-adipogenic activity. Based on the structure-activity relationship, functional groups and essential substituents to potentiate the anti-adipogenic activity were identified. The potent compound (<em>E</em>)-6-fluoro-2-(4-(4-methylstyryl)phenyl)quinoline-4-carboxylic acid (<strong>5m</strong>) suppresses the adipogenesis with IC<sub>50</sub> value of 0.330 μM. <em>In vitro</em> studies in 3T3-L1 preadipocytes cell line show that compound <strong>5m</strong> prevents adipogenesis by stopping the cell cycle at the early phase of differentiation, which is caused by stimulation of the Wnt3a/β-catenin pathway. Further compound <strong>5m</strong> improves the blood lipid profile and reduces adipogenic marker proteins in the epididymal white adipose tissue (eWAT) of dyslipidemic hamster at 100 mg/kg/day oral dose. Treatment with compound <strong>5m</strong> reduces the hypertrophied adipose tissue along with the decrease in the levels of adipogenic marker proteins such as PPARγ and CEBPα. The pharmacokinetic result establishes the molecule <strong>5m</strong> to be stable with significant oral bioavailability. Henceforth, the present study provides a unique insight into the anti-adipogenic/anti-dyslipidemic properties of a novel styryl-quinoline carboxylic acid scaffold with a scope to enhance the anti-adipogenic potency for therapeutic intervention of obesity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117346"},"PeriodicalIF":6.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418192","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}
Pub Date : 2025-02-14DOI: 10.1016/j.ejmech.2025.117395
Hugo Roux , Franck Touret , Antonio Coluccia , Pietro Scio , Hawa Sophia Bouzidi , Carole di Giorgio , Florence Gattacceca , Omar Khoumeri , Romano Silvestri , Patrice Vanelle , Manon Roche
The Enterovirus genus contains two major subgroups: rhinovirus (RV) species A-C and enterovirus (EV) ones A-D. While RV only infects the respiratory system, the EV can cause a wide variety of diseases, ranging from non-specific febrile illness to severe neurologic complications. To date, no curative treatments are commercially available. Our research team had recently developed EV-A71 inhibitors. To improve their activity and broaden their spectrum, we performed optimization of the structure following an iterative cycle of chemical modulations. As a result, we obtained two broad-spectrum inhibitors with micromolar activity against these 3 types of viruses (OM1260: EC50 (MRC-5, EV-A71) = 1.15 μM; EC50 (RD, EV-A71) = 4.38 μM; EC50 (MRC-5, E30) = 0.41 μM; EC50 (MRC-5, CVA24) = 1.15 μM; HR-568: EC50 (MRC-5, EV-A71) = 3.25 μM; EC50 (RD, EV-A71) = 1.53 μM; EC50 (MRC-5, E30) = 0.40 μM; EC50 (MRC-5, CVA24) = 1.22 μM). Docking studies shed light on structure-activity relationships, while time-of-drug addition assays confirmed their intervention during the early step of viral replication. Eventually, some pharmacokinetic modelling has been carried out to evaluate their druggability. All these results showed that OM1260 and HR-568 are promising candidates for further development.
{"title":"Design and synthesis of novel thioether analogs as promising antiviral agents: In vitro activity against enteroviruses of interest","authors":"Hugo Roux , Franck Touret , Antonio Coluccia , Pietro Scio , Hawa Sophia Bouzidi , Carole di Giorgio , Florence Gattacceca , Omar Khoumeri , Romano Silvestri , Patrice Vanelle , Manon Roche","doi":"10.1016/j.ejmech.2025.117395","DOIUrl":"10.1016/j.ejmech.2025.117395","url":null,"abstract":"<div><div>The <em>Enterovirus</em> genus contains two major subgroups: rhinovirus (RV) species A-C and enterovirus (EV) ones A-D. While RV only infects the respiratory system, the EV can cause a wide variety of diseases, ranging from non-specific febrile illness to severe neurologic complications. To date, no curative treatments are commercially available. Our research team had recently developed EV-A71 inhibitors. To improve their activity and broaden their spectrum, we performed optimization of the structure following an iterative cycle of chemical modulations. As a result, we obtained two broad-spectrum inhibitors with micromolar activity against these 3 types of viruses (<strong>OM1260</strong>: EC<sub>50</sub> (MRC-5, EV-A71) = 1.15 μM; EC<sub>50</sub> (RD, EV-A71) = 4.38 μM; EC<sub>50</sub> (MRC-5, E30) = 0.41 μM; EC<sub>50</sub> (MRC-5, CVA24) = 1.15 μM; <strong>HR-568</strong>: EC<sub>50</sub> (MRC-5, EV-A71) = 3.25 μM; EC<sub>50</sub> (RD, EV-A71) = 1.53 μM; EC<sub>50</sub> (MRC-5, E30) = 0.40 μM; EC<sub>50</sub> (MRC-5, CVA24) = 1.22 μM). Docking studies shed light on structure-activity relationships, while time-of-drug addition assays confirmed their intervention during the early step of viral replication. Eventually, some pharmacokinetic modelling has been carried out to evaluate their druggability. All these results showed that <strong>OM1260</strong> and <strong>HR-568</strong> are promising candidates for further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117395"},"PeriodicalIF":6.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418195","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}
Pub Date : 2025-02-14DOI: 10.1016/j.ejmech.2025.117383
Yanhong Wei , Fuqiang Zheng , Lirong Guo , Wenxuan Chen , Hexiang Wang , Longzhu Bao , Zhaoyuan Wu , Ying Li , W. Alateng , Jianglong Su , Mengmeng Kong , Shaoyong Ke
As viral infectious diseases increasingly threaten global health, antiviral drug research has become a focus in the medicinal chemistry. Enterovirus has always been an important virus causing infections disease with a high incidence in summer and autumn, such as Enterovirus 71 (EV71) and Coxsackievirus B3 (CVB3). Currently, no specific antiviral drugs are available for EV71 and CVB3. So, we designed and synthesized a novel series of quinazolinone derivatives based on the natural pyrrolo[1,2-a]quinazolinone scaffold, which were fully characterized and identified as potential anti-enterovirus agents. Among them, compound B9 exhibited potent anti-CVB3 activity with an EC50 value of 17.4 ± 3.62 μM, and compound B5 exhibited potent anti-EV71 activity with an EC50 value of 14.8 ± 2.18 μM as confirmed by determining the cytopathic effects, progeny virus titers, viral nucleic acid and protein levels. The potential antiviral mechanisms of compound B5 were also explored. The compound B5 exhibited a powerful therapeutic effect primarily by blocking the post-attachment stage of viral infection. Further experiments demonstrated that compound B5 didn't inhibit the activities of the EV71 2Apro and 3Dpol. Modelling of the molecular binding of the 3Cpro-compound complex revealed that the compound B5 could insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and possibly inhibiting EV71 3Cpro activity. These researches may provide evidence for the development of these novel pyrrolo[1,2-a]quinazolinone derivatives derived from natural products as potential antiviral agents.
{"title":"Natural pyrrolo[1,2-a]quinazolinone derivatives: Design, synthesis, characterization, and bio-evaluation as novel antiviral agents","authors":"Yanhong Wei , Fuqiang Zheng , Lirong Guo , Wenxuan Chen , Hexiang Wang , Longzhu Bao , Zhaoyuan Wu , Ying Li , W. Alateng , Jianglong Su , Mengmeng Kong , Shaoyong Ke","doi":"10.1016/j.ejmech.2025.117383","DOIUrl":"10.1016/j.ejmech.2025.117383","url":null,"abstract":"<div><div>As viral infectious diseases increasingly threaten global health, antiviral drug research has become a focus in the medicinal chemistry. Enterovirus has always been an important virus causing infections disease with a high incidence in summer and autumn, such as Enterovirus 71 (EV71) and Coxsackievirus B3 (CVB<sub>3</sub>). Currently, no specific antiviral drugs are available for EV71 and CVB<sub>3</sub>. So, we designed and synthesized a novel series of quinazolinone derivatives based on the natural pyrrolo[1,2-<em>a</em>]quinazolinone scaffold, which were fully characterized and identified as potential anti-enterovirus agents. Among them, compound <strong>B9</strong> exhibited potent anti-CVB<sub>3</sub> activity with an EC<sub>50</sub> value of 17.4 ± 3.62 μM, and compound <strong>B5</strong> exhibited potent anti-EV71 activity with an EC<sub>50</sub> value of 14.8 ± 2.18 μM as confirmed by determining the cytopathic effects, progeny virus titers, viral nucleic acid and protein levels. The potential antiviral mechanisms of compound <strong>B5</strong> were also explored. The compound <strong>B5</strong> exhibited a powerful therapeutic effect primarily by blocking the post-attachment stage of viral infection. Further experiments demonstrated that compound <strong>B5</strong> didn't inhibit the activities of the EV71 2Apro and 3Dpol. Modelling of the molecular binding of the 3Cpro-compound complex revealed that the compound <strong>B5</strong> could insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and possibly inhibiting EV71 3Cpro activity. These researches may provide evidence for the development of these novel pyrrolo[1,2-<em>a</em>]quinazolinone derivatives derived from natural products as potential antiviral agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117383"},"PeriodicalIF":6.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418194","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}
Pub Date : 2025-02-13DOI: 10.1016/j.ejmech.2025.117384
Ziquan Zhao , Hongjin Lu , Junjie Wang , Tingting Wu , Shicheng Xu , Yuxin Ge , Qidong You , Zhengyu Jiang , Mengchen Lu
The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense system against oxidative insults. Directly inhibiting the Kelch-like ECH-associated protein 1 (Keap1)−Nrf2 protein−protein interaction (PPI) has emerged as a promising approach to activate Nrf2 for the treatment of diseases associated with oxidative stress. Herein, we identified β-amino acids as privileged structural fragments for designing novel naphthalene sulfonamide-based Keap1−Nrf2 PPI inhibitors. Comprehensive structure−activity relationship (SAR) exploration identified compound 19 as the optimal inhibitor with an IC50 of 0.55 μM for disrupting the Keap1−Nrf2 interaction and a Kd of 0.50 μM for binding to Keap1. Further studies demonstrated that 19 effectively activated the Nrf2-regulated cytoprotective system and provided protective effects against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in both in vitro and in vivo models. These findings highlight the potential of β-amino acid substituted naphthalene sulfonamide Keap1−Nrf2 inhibitor 19 as a prospective therapeutic agent for UC via Keap1 targeting.
{"title":"Discovery of β-amino acid substituted naphthalene sulfonamide derivatives as potent Kelch-like ECH-associated protein 1−nuclear factor erythroid 2-related factor 2 (Keap1−Nrf2) protein−protein interaction inhibitors for ulcerative colitis management","authors":"Ziquan Zhao , Hongjin Lu , Junjie Wang , Tingting Wu , Shicheng Xu , Yuxin Ge , Qidong You , Zhengyu Jiang , Mengchen Lu","doi":"10.1016/j.ejmech.2025.117384","DOIUrl":"10.1016/j.ejmech.2025.117384","url":null,"abstract":"<div><div>The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense system against oxidative insults. Directly inhibiting the Kelch-like ECH-associated protein 1 (Keap1)−Nrf2 protein−protein interaction (PPI) has emerged as a promising approach to activate Nrf2 for the treatment of diseases associated with oxidative stress. Herein, we identified β-amino acids as privileged structural fragments for designing novel naphthalene sulfonamide-based Keap1−Nrf2 PPI inhibitors. Comprehensive structure−activity relationship (SAR) exploration identified compound <strong>19</strong> as the optimal inhibitor with an IC<sub>50</sub> of 0.55 μM for disrupting the Keap1−Nrf2 interaction and a <em>K</em><sub>d</sub> of 0.50 μM for binding to Keap1. Further studies demonstrated that <strong>19</strong> effectively activated the Nrf2-regulated cytoprotective system and provided protective effects against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in both <em>in vitro</em> and <em>in vivo</em> models. These findings highlight the potential of β-amino acid substituted naphthalene sulfonamide Keap1−Nrf2 inhibitor <strong>19</strong> as a prospective therapeutic agent for UC via Keap1 targeting.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117384"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401886","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}
The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of β-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound K27 significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC50 = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The in vitro studies indicated that compound K27 distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound K27 was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound K27 and PTX exhibited potent tumor suppression in vivo without generating toxicity. These results demonstrated that β-carboline compounds represented by compound K27 may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.
{"title":"Design, synthesis, and biological evaluation of β-carboline derivatives as ABCB1 inhibitors for reversing multidrug resistance","authors":"Yuanyuan Wang , Nanjin Ding , Yunpeng Zhao, Fengqing Wang, Wen Liu, Zhe Chen, Weiguang Sun, Lianghu Gu, Yonghui Zhang","doi":"10.1016/j.ejmech.2025.117390","DOIUrl":"10.1016/j.ejmech.2025.117390","url":null,"abstract":"<div><div>The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of <em>β</em>-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound <strong>K27</strong> significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC<sub>50</sub> = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The <em>in vitro</em> studies indicated that compound <strong>K27</strong> distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound <strong>K27</strong> was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound <strong>K27</strong> and PTX exhibited potent tumor suppression <em>in vivo</em> without generating toxicity. These results demonstrated that <em>β</em>-carboline compounds represented by compound <strong>K27</strong> may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117390"},"PeriodicalIF":6.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401885","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}
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