Synthesis of 2, 3-dihydroxy-3-(N-substituted carbamoyl) propylphosphonic acid derivatives as hybrid DOXP-fosmidomycin analogues
- Mutorwa, Marius K, Lobb, Kevin A, Klein, Rosalyn, Blatch, Gregory L, Kaye, Perry T
- Authors: Mutorwa, Marius K , Lobb, Kevin A , Klein, Rosalyn , Blatch, Gregory L , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453212 , vital:75231 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.132453"
- Description: A six-step synthetic pathway has been established to access a series of racemic 2,3-dihydroxy-3-(Nsubstituted carbamoyl)propylphosphonic acid derivatives, designed to contain structural features common to both the natural substrate 1-deoxy-D-xylulose 5-phosphate (DOXP) of the Plasmodium falciparum (Pf) DXR enzyme and its known inhibitor, fosmidomycin. Positive STD-NMR and in silico docking data obtained for some of the compounds indicate their capacity to bind to the analogous E.coli DXR enzyme.
- Full Text:
- Authors: Mutorwa, Marius K , Lobb, Kevin A , Klein, Rosalyn , Blatch, Gregory L , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/453212 , vital:75231 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.132453"
- Description: A six-step synthetic pathway has been established to access a series of racemic 2,3-dihydroxy-3-(Nsubstituted carbamoyl)propylphosphonic acid derivatives, designed to contain structural features common to both the natural substrate 1-deoxy-D-xylulose 5-phosphate (DOXP) of the Plasmodium falciparum (Pf) DXR enzyme and its known inhibitor, fosmidomycin. Positive STD-NMR and in silico docking data obtained for some of the compounds indicate their capacity to bind to the analogous E.coli DXR enzyme.
- Full Text:
Synthesis of 2, 3-dihydroxy-3-(N-substituted carbamoyl) propylphosphonic acid derivatives as hybrid DOXP-fosmidomycin analogues
- Mutorwa, Marius K, Lobb, Kevin A, Klein, Rosalyn, Blatch, Gregory L, Kaye, Perry T
- Authors: Mutorwa, Marius K , Lobb, Kevin A , Klein, Rosalyn , Blatch, Gregory L , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/477694 , vital:78112 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.132453"
- Description: A six-step synthetic pathway has been established to access a series of racemic 2,3-dihydroxy-3-(N-substituted carbamoyl) propylphosphonic acid derivatives, designed to contain structural features common to both the natural substrate 1-deoxy-D-xylulose 5-phosphate (DOXP) of the Plasmodium falciparum (Pf) DXR enzyme and its known inhibitor, fosmidomycin. Positive STD-NMR and in silico docking data obtained for some of the compounds indicate their capacity to bind to the analogous E.coli DXR enzyme.
- Full Text:
- Authors: Mutorwa, Marius K , Lobb, Kevin A , Klein, Rosalyn , Blatch, Gregory L , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/477694 , vital:78112 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.132453"
- Description: A six-step synthetic pathway has been established to access a series of racemic 2,3-dihydroxy-3-(N-substituted carbamoyl) propylphosphonic acid derivatives, designed to contain structural features common to both the natural substrate 1-deoxy-D-xylulose 5-phosphate (DOXP) of the Plasmodium falciparum (Pf) DXR enzyme and its known inhibitor, fosmidomycin. Positive STD-NMR and in silico docking data obtained for some of the compounds indicate their capacity to bind to the analogous E.coli DXR enzyme.
- Full Text:
Rational design and regioselective synthesis of conformationally restricted furan-derived ligands as potential anti-malarial agents
- Mutorwa, Marius K, Nokalipa, Iviwe, Tanner, Delia C, Blatch, Gregory L, Lobb, Kevin A, Klein, Rosalyn, Kaye, Perry T
- Authors: Mutorwa, Marius K , Nokalipa, Iviwe , Tanner, Delia C , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447170 , vital:74589 , xlink:href="https://doi.org/10.24820/ark.5550190.p011.281"
- Description: Substituted 3-furanomethyl phosphate esters and their corresponding phosphoric acids have been prepared as conformationally restricted analogues of DOXP, the natural substrate for Plasmodium falciparum 1-deoxyD-xylulose-5-phosphate reductoisomerase (PfDXR), and fosmidomycin, an established inhibitor. Saturation Transfer Difference (STD) NMR analysis and in silico docking data suggest the potential of such compounds as PfDXR inhibitors.
- Full Text:
- Authors: Mutorwa, Marius K , Nokalipa, Iviwe , Tanner, Delia C , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447170 , vital:74589 , xlink:href="https://doi.org/10.24820/ark.5550190.p011.281"
- Description: Substituted 3-furanomethyl phosphate esters and their corresponding phosphoric acids have been prepared as conformationally restricted analogues of DOXP, the natural substrate for Plasmodium falciparum 1-deoxyD-xylulose-5-phosphate reductoisomerase (PfDXR), and fosmidomycin, an established inhibitor. Saturation Transfer Difference (STD) NMR analysis and in silico docking data suggest the potential of such compounds as PfDXR inhibitors.
- Full Text:
Rational design and regioselective synthesis of conformationally restricted furan-derived ligands as potential anti-malarial agents
- Mutorwa, Marius K, Nokalipa, Iviwe C, Tanner, Delia C, Blatch, Gregory L, Lobb, Kevin A, Klein, Rosalyn, Kaye, Perry T
- Authors: Mutorwa, Marius K , Nokalipa, Iviwe C , Tanner, Delia C , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/477650 , vital:78108 , xlink:href="https://doi.org/10.24820/ark.5550190.p011.281"
- Description: Substituted 3-furanomethyl phosphate esters and their corresponding phosphoric acids have been prepared as conformationally restricted analogues of DOXP, the natural substrate for Plasmodium falciparum 1-deoxyD-xylulose-5-phosphate reductoisomerase (PfDXR), and fosmidomycin, an established inhibitor. Saturation Transfer Difference (STD) NMR analysis and in silico docking data suggest the potential of such compounds as PfDXR inhibitors.
- Full Text:
- Authors: Mutorwa, Marius K , Nokalipa, Iviwe C , Tanner, Delia C , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/477650 , vital:78108 , xlink:href="https://doi.org/10.24820/ark.5550190.p011.281"
- Description: Substituted 3-furanomethyl phosphate esters and their corresponding phosphoric acids have been prepared as conformationally restricted analogues of DOXP, the natural substrate for Plasmodium falciparum 1-deoxyD-xylulose-5-phosphate reductoisomerase (PfDXR), and fosmidomycin, an established inhibitor. Saturation Transfer Difference (STD) NMR analysis and in silico docking data suggest the potential of such compounds as PfDXR inhibitors.
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Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N-heteroarylcarboxamides as DXR inhibitors
- Bodill, Taryn, Conibear, Anne C, Mutorwa, Marius K, Goble, Jessica L, Blatch, Gregory L, Lobb, Kevin A, Klein, Rosalyn, Kaye, Perry T
- Authors: Bodill, Taryn , Conibear, Anne C , Mutorwa, Marius K , Goble, Jessica L , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448912 , vital:74770 , xlink:href=""
- Description: DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand–receptor interactions.
- Full Text:
- Authors: Bodill, Taryn , Conibear, Anne C , Mutorwa, Marius K , Goble, Jessica L , Blatch, Gregory L , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448912 , vital:74770 , xlink:href=""
- Description: DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand–receptor interactions.
- Full Text:
Synthesis and evaluation of phosphonated N-heteroarylcarboxamides as DOXP-reductoisomerase (DXR) inhibitors
- Bodill, Taryn, Conibear, Anne C, Blatch, Gregory L, Lobb, Kevin A, Kaye, Perry T
- Authors: Bodill, Taryn , Conibear, Anne C , Blatch, Gregory L , Lobb, Kevin A , Kaye, Perry T
- Date: 2011
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448939 , vital:74772 , xlink:href="https://doi.org/10.1016/j.bmc.2010.11.062"
- Description: The diethyl esters and disodium salts of a range of heteroarylcarbamoylphosphonic acids have been prepared and evaluated as analogues of the highly active DOXP-reductoisomerase (DXR) inhibitor, fosmidomycin. Computer-simulated docking studies, Saturation Transfer Difference (STD) NMR analysis and enzyme inhibition assays have been used to explore enzyme-binding and -inhibition potential, while in silico analysis of the DXR active site has highlighted the importance of including a well-parameterised metal co-factor in docking studies and has revealed the availability of an additional binding pocket to guide future drug design.
- Full Text:
- Authors: Bodill, Taryn , Conibear, Anne C , Blatch, Gregory L , Lobb, Kevin A , Kaye, Perry T
- Date: 2011
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448939 , vital:74772 , xlink:href="https://doi.org/10.1016/j.bmc.2010.11.062"
- Description: The diethyl esters and disodium salts of a range of heteroarylcarbamoylphosphonic acids have been prepared and evaluated as analogues of the highly active DOXP-reductoisomerase (DXR) inhibitor, fosmidomycin. Computer-simulated docking studies, Saturation Transfer Difference (STD) NMR analysis and enzyme inhibition assays have been used to explore enzyme-binding and -inhibition potential, while in silico analysis of the DXR active site has highlighted the importance of including a well-parameterised metal co-factor in docking studies and has revealed the availability of an additional binding pocket to guide future drug design.
- Full Text:
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