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Hélène Munier-lehmann - One of the best experts on this subject based on the ideXlab platform.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents
European Journal of Medicinal Chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Savvas Savvides, Helena I. BoshoffAbstract:As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.
European journal of medicinal chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Helena I. BoshoffAbstract:Abstract As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of Medicinal Chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Martijn Risseeuw, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of medicinal chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the eff...
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The design and synthesis of inhibitors of Mycobacterium tuberculosis Thymidylate Kinase (MtTMPK)
2016Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Serge Van CalenberghAbstract:Thymidylate Kinase (TMPK) phosphorylates thymidine 5’-monophosphate (dTMP) to thymidine 5’-diphosphate (dTDP) and has been proposed as an attractive anti-tubercular target. By mimicking the structure of the substrate (dTMP), we have previously discovered different series of nucleoside analogues with Mycobacterium tuberculosis (Mt) TMPK inhibitory activities in the micromolar range. Based on recently reported potent piperidin-3-yl-thymine inhibitors of Gram-positive bacterial TMPK, we report a series of isomeric N-benzyl-substituted piperidin-4-yl-thymine analogues, some of which demonstrate very promising MtTMPK inhibitory potency. This poster will discuss the synthesis, MtTMPK inhibitory activity, as well as structural data on how these new inhibitors interact with the target enzyme.
Fabian Hulpia - One of the best experts on this subject based on the ideXlab platform.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents
European Journal of Medicinal Chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Savvas Savvides, Helena I. BoshoffAbstract:As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.
European journal of medicinal chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Helena I. BoshoffAbstract:Abstract As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of Medicinal Chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Martijn Risseeuw, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of medicinal chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the eff...
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
2018Co-Authors: Lijun Song, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Paul Cos, Begoña Gracia, Ainhoa Lucía Quintana, José A. Aínsa, Hélène Munier-lehmann, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
Romain Merceron - One of the best experts on this subject based on the ideXlab platform.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents
European Journal of Medicinal Chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Savvas Savvides, Helena I. BoshoffAbstract:As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.
European journal of medicinal chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Helena I. BoshoffAbstract:Abstract As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of Medicinal Chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Martijn Risseeuw, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of medicinal chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the eff...
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
2018Co-Authors: Lijun Song, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Paul Cos, Begoña Gracia, Ainhoa Lucía Quintana, José A. Aínsa, Hélène Munier-lehmann, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
Martijn Dp Risseeuw - One of the best experts on this subject based on the ideXlab platform.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents
European Journal of Medicinal Chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Savvas Savvides, Helena I. BoshoffAbstract:As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.
European journal of medicinal chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Helena I. BoshoffAbstract:Abstract As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of medicinal chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the eff...
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
2018Co-Authors: Lijun Song, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Paul Cos, Begoña Gracia, Ainhoa Lucía Quintana, José A. Aínsa, Hélène Munier-lehmann, Savvas N. SavvidesAbstract:In recent years, Thymidylate Kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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Elaboration of a proprietary Thymidylate Kinase inhibitor motif towards anti-tuberculosis agents
'Elsevier BV', 2016Co-Authors: Song Lijun, Martijn Dp Risseeuw, Froeyen Mathy, Karalic Izet, Goeman Jan, Cappoen Davie, Van Der Eycken J, Cos Paul, Munier-lehmann Hélène, Van Calenbergh SergeAbstract:We report the design and synthesis of a series of non-nucleoside MtbTMPK inhibitors (1-14) based on the gram-positive bacterial TMPK inhibitor hit compound 1. A practical synthesis was developed to access these analogues. Several compounds show promising MtbTMPK inhibitory potency and allow the establishment of a structure-activity relationship, which is helpful for further optimization.publisher: Elsevier articletitle: Elaboration of a proprietary Thymidylate Kinase inhibitor motif towards anti-tuberculosis agents journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2016.08.041 content_type: article copyright: © 2016 Elsevier Ltd. All rights reserved.status: publishe
Helena I. Boshoff - One of the best experts on this subject based on the ideXlab platform.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents
European Journal of Medicinal Chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Savvas Savvides, Helena I. BoshoffAbstract:As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.
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Endeavors towards transformation of M. tuberculosis Thymidylate Kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.
European journal of medicinal chemistry, 2020Co-Authors: Yanlin Jian, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Steven De Munck, He Eun Forbes, Kristof Van Hecke, Helena I. BoshoffAbstract:Abstract As the last enzyme in nucleotide synthesis as precursors for DNA replication, Thymidylate Kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.