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Claire J. Russell - One of the best experts on this subject based on the ideXlab platform.
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scalable total synthesis and comprehensive Structure Activity Relationship studies of the phytotoxin coronatine
Nature Communications, 2018Co-Authors: Mairi M. Littleson, Christopher M. Baker, Anne J. Dalençon, Elizabeth C. Frye, Craig Jamieson, Alan R. Kennedy, Matthew M. Mclachlan, Kenneth Ling, Mark Montgomery, Claire J. RussellAbstract:Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive Structure–Activity Relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template. Development of comprehensive Structure–Activity Relationships for coronatine has been a major goal in the agrochemical industry. Here, the authors report the gram-scale production and Structure–Activity Relationship of parent coronafacic acid and ultimately rationalise the biological Activity of analogues of this phytotoxin.
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Scalable total synthesis and comprehensive Structure–Activity Relationship studies of the phytotoxin coronatine
Nature Publishing Group, 2018Co-Authors: Mairi M. Littleson, Christopher M. Baker, Anne J. Dalençon, Elizabeth C. Frye, Craig Jamieson, Alan R. Kennedy, Kenneth B. Ling, Matthew M. Mclachlan, Mark G. Montgomery, Claire J. RussellAbstract:Development of comprehensive Structure–Activity Relationships for coronatine has been a major goal in the agrochemical industry. Here, the authors report the gram-scale production and Structure–Activity Relationship of parent coronafacic acid and ultimately rationalise the biological Activity of analogues of this phytotoxin
Sriraghavan Kamaraj - One of the best experts on this subject based on the ideXlab platform.
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Structure Activity Relationship of antischistosomal ozonide carboxylic acids
Journal of Medicinal Chemistry, 2020Co-Authors: Xiaofang Wang, David M Shackleford, Francis C K Chiu, Sriraghavan Kamaraj, Vivek J Bulbule, Cecile Haberli, Eileen Ryan, Alexander I Wallick, Yuxiang DongAbstract:Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial Activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial Structure-Activity Relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal Activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane subStructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal Activity.
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Structure Activity Relationship of the antimalarial ozonide artefenomel oz439
Journal of Medicinal Chemistry, 2017Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Jacques Chollet, Manickam Dhanasekaran, Christopher D HeinAbstract:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the Structure–Activity Relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle subStructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associ...
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Structure–Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
2017Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Jacques Chollet, Manickam Dhanasekaran, Christopher D Hein, Petros Papastogiannidis, Julia MorizziAbstract:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the Structure–Activity Relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle subStructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity
Xiaofang Wang - One of the best experts on this subject based on the ideXlab platform.
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Structure Activity Relationship of antischistosomal ozonide carboxylic acids
Journal of Medicinal Chemistry, 2020Co-Authors: Xiaofang Wang, David M Shackleford, Francis C K Chiu, Sriraghavan Kamaraj, Vivek J Bulbule, Cecile Haberli, Eileen Ryan, Alexander I Wallick, Yuxiang DongAbstract:Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial Activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial Structure-Activity Relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal Activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane subStructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal Activity.
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Structure Activity Relationship of the antimalarial ozonide artefenomel oz439
Journal of Medicinal Chemistry, 2017Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Jacques Chollet, Manickam Dhanasekaran, Christopher D HeinAbstract:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the Structure–Activity Relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle subStructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associ...
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Structure–Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
2017Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Jacques Chollet, Manickam Dhanasekaran, Christopher D Hein, Petros Papastogiannidis, Julia MorizziAbstract:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the Structure–Activity Relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle subStructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity
Christopher D Hein - One of the best experts on this subject based on the ideXlab platform.
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Structure Activity Relationship of the antimalarial ozonide artefenomel oz439
Journal of Medicinal Chemistry, 2017Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Jacques Chollet, Manickam Dhanasekaran, Christopher D HeinAbstract:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the Structure–Activity Relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle subStructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associ...
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Structure–Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
2017Co-Authors: Xiaofang Wang, Sriraghavan Kamaraj, Vivek J Bulbule, Jacques Chollet, Manickam Dhanasekaran, Christopher D Hein, Petros Papastogiannidis, Julia MorizziAbstract:Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the Structure–Activity Relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle subStructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity
Mairi M. Littleson - One of the best experts on this subject based on the ideXlab platform.
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scalable total synthesis and comprehensive Structure Activity Relationship studies of the phytotoxin coronatine
Nature Communications, 2018Co-Authors: Mairi M. Littleson, Christopher M. Baker, Anne J. Dalençon, Elizabeth C. Frye, Craig Jamieson, Alan R. Kennedy, Matthew M. Mclachlan, Kenneth Ling, Mark Montgomery, Claire J. RussellAbstract:Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive Structure–Activity Relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template. Development of comprehensive Structure–Activity Relationships for coronatine has been a major goal in the agrochemical industry. Here, the authors report the gram-scale production and Structure–Activity Relationship of parent coronafacic acid and ultimately rationalise the biological Activity of analogues of this phytotoxin.
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Scalable total synthesis and comprehensive Structure–Activity Relationship studies of the phytotoxin coronatine
Nature Publishing Group, 2018Co-Authors: Mairi M. Littleson, Christopher M. Baker, Anne J. Dalençon, Elizabeth C. Frye, Craig Jamieson, Alan R. Kennedy, Kenneth B. Ling, Matthew M. Mclachlan, Mark G. Montgomery, Claire J. RussellAbstract:Development of comprehensive Structure–Activity Relationships for coronatine has been a major goal in the agrochemical industry. Here, the authors report the gram-scale production and Structure–Activity Relationship of parent coronafacic acid and ultimately rationalise the biological Activity of analogues of this phytotoxin
