Synthesis and conformational studies of 5-bromo-1-[(N-substituted-carbamoyl) methyl]-7-azabenzimidazoles
- Oluwafemi, Kola A, Klein, Rosalyn, Lobb, Kevin A, Tshiwawa, Tendamudzimu, Isaacs, Michelle, Hoppe, Heinrich C, Kaye, Perry T
- Authors: Oluwafemi, Kola A , Klein, Rosalyn , Lobb, Kevin A , Tshiwawa, Tendamudzimu , Isaacs, Michelle , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452800 , vital:75171 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133811"
- Description: The Cs2CO3-catalysed condensation of 5-bromo-7-azabenzimidazole with a series of bromomethyl ketones has afforded a small library of ten, novel 5-bromo-1-[(N-substututed-carbamoyl)methyl]-7-azabenzimidazoles. Rotamerism in the products, as evidenced by the splitting of 1H- and 13C-NMR signals, is attributed to hindered internal rotation about the amide N-C(=O) bond, and has been explored using dynamic NMR (DNMR) analysis and computational methods at the GIAO B3LYP/6-311+G(2d,p) level of theory. Coalescence temperatures have been obtained for representative examples and rotational barriers determined experimentally and theoretically. A detailed theoretical analysis has been undertaken to explore conformations which may contribute to the relative populations of the s-cis and s-trans rotamers. The products have also been screened for cytotoxicity and activity against two parasitic protozoan strains (Plasmodium falciparum and Trypanosoma brucei).
- Full Text:
- Authors: Oluwafemi, Kola A , Klein, Rosalyn , Lobb, Kevin A , Tshiwawa, Tendamudzimu , Isaacs, Michelle , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452800 , vital:75171 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133811"
- Description: The Cs2CO3-catalysed condensation of 5-bromo-7-azabenzimidazole with a series of bromomethyl ketones has afforded a small library of ten, novel 5-bromo-1-[(N-substututed-carbamoyl)methyl]-7-azabenzimidazoles. Rotamerism in the products, as evidenced by the splitting of 1H- and 13C-NMR signals, is attributed to hindered internal rotation about the amide N-C(=O) bond, and has been explored using dynamic NMR (DNMR) analysis and computational methods at the GIAO B3LYP/6-311+G(2d,p) level of theory. Coalescence temperatures have been obtained for representative examples and rotational barriers determined experimentally and theoretically. A detailed theoretical analysis has been undertaken to explore conformations which may contribute to the relative populations of the s-cis and s-trans rotamers. The products have also been screened for cytotoxicity and activity against two parasitic protozoan strains (Plasmodium falciparum and Trypanosoma brucei).
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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.
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- 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.
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Synthesis, stereochemistry and in vitro STD NMR and in silico HIV-1 PR enzyme-binding potential of MBH-derived inhibitors
- Tukulula, Matshawandile, Olasupo, Idris A, Mugumbate, Grace C, Lobb, Kevin A, Klein, Rosalyn, Sayed, Yasien, Tshiwawa, Tendamudzimu, Kaye, Perry T
- Authors: Tukulula, Matshawandile , Olasupo, Idris A , Mugumbate, Grace C , Lobb, Kevin A , Klein, Rosalyn , Sayed, Yasien , Tshiwawa, Tendamudzimu , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452813 , vital:75172 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133716"
- Description: Aza-Michael reactions of a pyridine-3-carbaldehyde-derived Morita-Baylis-Hillman (MBH) adduct with various amines have afforded a series of 10 diastereomeric products, stereochemical analysis of which has been achieved using a combination of NMR (1D, 2D and NOESY) and computer modelling methods. Saturation Transfer Difference (STD) 1H NMR spectroscopy and in silico molecular docking studies have been used to explore the HIV-1 protease sub-type C enzyme binding potential of these compounds in five different HIV-1 PR enzyme receptors.
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- Authors: Tukulula, Matshawandile , Olasupo, Idris A , Mugumbate, Grace C , Lobb, Kevin A , Klein, Rosalyn , Sayed, Yasien , Tshiwawa, Tendamudzimu , Kaye, Perry T
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452813 , vital:75172 , xlink:href="https://doi.org/10.1016/j.molstruc.2022.133716"
- Description: Aza-Michael reactions of a pyridine-3-carbaldehyde-derived Morita-Baylis-Hillman (MBH) adduct with various amines have afforded a series of 10 diastereomeric products, stereochemical analysis of which has been achieved using a combination of NMR (1D, 2D and NOESY) and computer modelling methods. Saturation Transfer Difference (STD) 1H NMR spectroscopy and in silico molecular docking studies have been used to explore the HIV-1 protease sub-type C enzyme binding potential of these compounds in five different HIV-1 PR enzyme receptors.
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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.
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- 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.
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Synthesis and anti-parasitic activity of N-benzylated phosphoramidate Mg2+-chelating ligands
- Adeyemi, Christiana M, Hoppe, Heinrich C, Isaacs, Michelle, Mnkandhla, Dumisani, Lobb, Kevin A, Klein, Rosalyn, Kaye, Perry T
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Mnkandhla, Dumisani , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451171 , vital:75025 , xlink:href="https://doi.org/10.1016/j.bioorg.2020.104280"
- Description: A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-D-xylulose-5- phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+- chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6–16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 – 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.
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- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Mnkandhla, Dumisani , Lobb, Kevin A , Klein, Rosalyn , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451171 , vital:75025 , xlink:href="https://doi.org/10.1016/j.bioorg.2020.104280"
- Description: A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-D-xylulose-5- phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+- chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6–16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 – 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.
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Synthesis of N-Substituted phosphoramidic acid esters as “reverse” fosmidomycin analogues
- Adeyemi, Christiana M, Hoppe, Heinrich C, Isaacs, Michelle, Klein, Rosalyn, Lobb, Kevin A, Kaye, Perry T
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/443238 , vital:74101 , https://doi.org/10.1016/j.tet.2019.02.003
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
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- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/443238 , vital:74101 , https://doi.org/10.1016/j.tet.2019.02.003
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
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Synthesis of N-Substituted phosphoramidic acid esters as “reverse” fosmidomycin analogues
- Adeyemi, Christiana M, Hoppe, Heinrich C, Isaacs, Michelle, Klein, Rosalyn, Lobb, Kevin A, Kaye, Perry T
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447196 , vital:74591 , xlink:href="https://doi.org/10.1016/j.tet.2019.02.003"
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
- Full Text:
- Authors: Adeyemi, Christiana M , Hoppe, Heinrich C , Isaacs, Michelle , Klein, Rosalyn , Lobb, Kevin A , Kaye, Perry T
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447196 , vital:74591 , xlink:href="https://doi.org/10.1016/j.tet.2019.02.003"
- Description: An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.
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1H NMR-based kinetic and theoretical studies of the simultaneous formation of two discrete rotameric systems of a novel difenchyl sulfite ester
- Singh, Alicia, Kaye, Perry T, Lobb, Kevin A
- Authors: Singh, Alicia , Kaye, Perry T , Lobb, Kevin A
- Date: 2017
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447925 , vital:74684 , xlink:href="https://doi.org/10.1016/j.tet.2017.10.059"
- Description: Attempted repetition of a reported synthesis of fenchene from fenchol has afforded, in high overall yield, a mixture shown by spectroscopic and elemental analysis to comprise a pair of discrete rotameric systems of a novel 2-endo-2′-endo-difenchyl sulfite ester. The kinetics of the formation of these dimeric rotameric systems (I and II) has been explored experimentally, using 1H NMR spectroscopic analysis, and theoretically at molecular and quantum mechanical levels. Construction of a theoretical model has permitted calculation of rate constants for each of the steps, while modelling of the transition state complexes corresponding to the rate-determining steps for the formation of the rotameric systems I and II has revealed their independent access to further sets of interconverting rotamers.
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- Authors: Singh, Alicia , Kaye, Perry T , Lobb, Kevin A
- Date: 2017
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447925 , vital:74684 , xlink:href="https://doi.org/10.1016/j.tet.2017.10.059"
- Description: Attempted repetition of a reported synthesis of fenchene from fenchol has afforded, in high overall yield, a mixture shown by spectroscopic and elemental analysis to comprise a pair of discrete rotameric systems of a novel 2-endo-2′-endo-difenchyl sulfite ester. The kinetics of the formation of these dimeric rotameric systems (I and II) has been explored experimentally, using 1H NMR spectroscopic analysis, and theoretically at molecular and quantum mechanical levels. Construction of a theoretical model has permitted calculation of rate constants for each of the steps, while modelling of the transition state complexes corresponding to the rate-determining steps for the formation of the rotameric systems I and II has revealed their independent access to further sets of interconverting rotamers.
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Synthesis and anti-parasitic activity of C-benzylated (N-arylcarbamoyl) alkylphosphonate esters
- Adeyemi, Christiana Modupe, Isaacs, Michelle, Mnkandhla, Dumisani, Krause, Rui W M, Klein, Rosalyn, Hoppe, Heinrich C, Lobb, Kevin A, Kaye, Perry T
- Authors: Adeyemi, Christiana Modupe , Isaacs, Michelle , Mnkandhla, Dumisani , Krause, Rui W M , Klein, Rosalyn , Hoppe, Heinrich C , Lobb, Kevin A , Kaye, Perry T
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125641 , vital:35803 , https://doi.org/10.1016/j.tet.2017.01.045
- Description: Unexpected substituent-dependent regioselectivty challenges in the synthesis of C-benzylated (N-arylcarbamoyl)phosphonate esters have been resolved. The C-benzylated N-furfurylcarbamoyl derivative showed low micromolar PfLDH inhibition, while one of the C-benzylated N-arylcarbamoyl analogues was active against Nagana Trypanosoma brucei parasites which are responsible for African trypanosomiasis in cattle.
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- Authors: Adeyemi, Christiana Modupe , Isaacs, Michelle , Mnkandhla, Dumisani , Krause, Rui W M , Klein, Rosalyn , Hoppe, Heinrich C , Lobb, Kevin A , Kaye, Perry T
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125641 , vital:35803 , https://doi.org/10.1016/j.tet.2017.01.045
- Description: Unexpected substituent-dependent regioselectivty challenges in the synthesis of C-benzylated (N-arylcarbamoyl)phosphonate esters have been resolved. The C-benzylated N-furfurylcarbamoyl derivative showed low micromolar PfLDH inhibition, while one of the C-benzylated N-arylcarbamoyl analogues was active against Nagana Trypanosoma brucei parasites which are responsible for African trypanosomiasis in cattle.
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1H NMR-based kinetic-mechanistic study of the intramolecular trans-esterification of 2-exo-3-exo-dihydroxybornane monoacrylate esters
- Duggan, Andrew R, Mciteka, Lulama P, Lobb, Kevin A, Kaye, Perry T
- Authors: Duggan, Andrew R , Mciteka, Lulama P , Lobb, Kevin A , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448871 , vital:74767 , xlink:href="https://hdl.handle.net/10520/EJC135616"
- Description: A 1H NMR study of the acid-catalyzed, intramolecular trans-esterification between isomeric 2-exo-3-exo-dihydroxybornane monoacrylate esters has afforded insights into the reaction mechanism and permitted the determination of kinetic and thermodynamic parameters for the pseudo-first-order processes.
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- Authors: Duggan, Andrew R , Mciteka, Lulama P , Lobb, Kevin A , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448871 , vital:74767 , xlink:href="https://hdl.handle.net/10520/EJC135616"
- Description: A 1H NMR study of the acid-catalyzed, intramolecular trans-esterification between isomeric 2-exo-3-exo-dihydroxybornane monoacrylate esters has afforded insights into the reaction mechanism and permitted the determination of kinetic and thermodynamic parameters for the pseudo-first-order processes.
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Dual-Catalyst Acceleration of Tandem Disulfide Cleavage and Baylis–Hillman Synthesis of 2 H-1-Benzothiopyran Derivatives
- Nyoni, Dubekile, Lobb, Kevin A, Kaye, Perry T
- Authors: Nyoni, Dubekile , Lobb, Kevin A , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448898 , vital:74769 , xlink:href="https://doi.org/10.1080/00397911.2012.673449"
- Description: While both 1,8-diazabicyclo[5.4.0]undec-7-ene and triphenylphosphine catalyze tandem Baylis–Hillman reaction/disulfide cleavage of 2,2′-dithiodibenzaldehyde independently, when used together as a dual-catalyst system, the overall yields of the cyclized 2H-1-benzothiopyrans are consistently greater and the reaction time decreases dramatically.
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- Authors: Nyoni, Dubekile , Lobb, Kevin A , Kaye, Perry T
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448898 , vital:74769 , xlink:href="https://doi.org/10.1080/00397911.2012.673449"
- Description: While both 1,8-diazabicyclo[5.4.0]undec-7-ene and triphenylphosphine catalyze tandem Baylis–Hillman reaction/disulfide cleavage of 2,2′-dithiodibenzaldehyde independently, when used together as a dual-catalyst system, the overall yields of the cyclized 2H-1-benzothiopyrans are consistently greater and the reaction time decreases dramatically.
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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.
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- 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.
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DBU-Mediated cleavage of aryl-and heteroaryl disulfides
- Nyoni, Dubekile, Lobb, Kevin A, Kaye, Perry T, Cairab, Mino R
- Authors: Nyoni, Dubekile , Lobb, Kevin A , Kaye, Perry T , Cairab, Mino R
- Date: 2012
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448884 , vital:74768
- Description: The capacity of the nitrogen nucleophile, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to reduce aryl- and heteroaryl disulfides to the corresponding mercaptans is demonstrated. While dicarboxylated disulfide analogues afford the mono-DBU disulfide salts, as confirmed by X-ray crystallography, the corresponding methyl esters are cleaved normally.
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- Authors: Nyoni, Dubekile , Lobb, Kevin A , Kaye, Perry T , Cairab, Mino R
- Date: 2012
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448884 , vital:74768
- Description: The capacity of the nitrogen nucleophile, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to reduce aryl- and heteroaryl disulfides to the corresponding mercaptans is demonstrated. While dicarboxylated disulfide analogues afford the mono-DBU disulfide salts, as confirmed by X-ray crystallography, the corresponding methyl esters are cleaved normally.
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1H NMR-based kinetic and mechanistic study of unusual skeletal rearrangements of a spirobornyl tosylate derivative
- Lobb, Kevin A, Kaye, Perry T
- Authors: Lobb, Kevin A , Kaye, Perry T
- Date: 2011
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448858 , vital:74766 , xlink:href="https://doi.org/10.1002/poc.1699"
- Description: 1H NMR analysis of the kinetics of skeletal rearrangement of optically pure 3,3-xylyl-2-exo-bornyl tosylate in CDCl3 indicates the operation of tandem autocatalytic and pseudo-first-order transformations, leading sequentially to a pairof isomeric camphene derivatives and involving partial racemization. Changing the solvent system has been shown topermit the chemoselective isolation of either of the isomeric camphenes.
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- Authors: Lobb, Kevin A , Kaye, Perry T
- Date: 2011
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448858 , vital:74766 , xlink:href="https://doi.org/10.1002/poc.1699"
- Description: 1H NMR analysis of the kinetics of skeletal rearrangement of optically pure 3,3-xylyl-2-exo-bornyl tosylate in CDCl3 indicates the operation of tandem autocatalytic and pseudo-first-order transformations, leading sequentially to a pairof isomeric camphene derivatives and involving partial racemization. Changing the solvent system has been shown topermit the chemoselective isolation of either of the isomeric camphenes.
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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.
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- 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.
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31P NMR kinetic study of the tandem cleavage of phosphonate esters by bromotrimethylsilane
- Conibear, Anne C, Lobb, Kevin A, Kaye, Perry T
- Authors: Conibear, Anne C , Lobb, Kevin A , Kaye, Perry T
- Date: 2010
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449304 , vital:74810 , xlink:href="https://doi.org/10.1016/j.tet.2010.08.058"
- Description: 1H and 31P NMR methods have been used to access rate constants and activation parameters for each of the consecutive second-order silylation reactions involved in the overall transformation (1a→3a→4a), while computational optimisation of the rate constants obtained from the initial, linear phase of each reaction has permitted an excellent fit with the experimental data for the entire course of the reaction.
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- Authors: Conibear, Anne C , Lobb, Kevin A , Kaye, Perry T
- Date: 2010
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449304 , vital:74810 , xlink:href="https://doi.org/10.1016/j.tet.2010.08.058"
- Description: 1H and 31P NMR methods have been used to access rate constants and activation parameters for each of the consecutive second-order silylation reactions involved in the overall transformation (1a→3a→4a), while computational optimisation of the rate constants obtained from the initial, linear phase of each reaction has permitted an excellent fit with the experimental data for the entire course of the reaction.
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Introducing chemistry students to the “real world” of chemistry
- Brown, Michael E, Cosser, Ronald C, Davies-Coleman, Michael T, Kaye, Perry T, Klein, Rosalyn, Lamprecht, Emmanuel, Lobb, Kevin A, Nyokong, Tebello, Sewry, Joyce D, Tshentu, Zenixole R, van der Zeyde, Tino, Watkins, Gareth M
- Authors: Brown, Michael E , Cosser, Ronald C , Davies-Coleman, Michael T , Kaye, Perry T , Klein, Rosalyn , Lamprecht, Emmanuel , Lobb, Kevin A , Nyokong, Tebello , Sewry, Joyce D , Tshentu, Zenixole R , van der Zeyde, Tino , Watkins, Gareth M
- Date: 2010
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449360 , vital:74814 , xlink:href="https://doi.org/10.1021/ed8001539"
- Description: A majority of chemistry graduates seek employment in a rapidly changing chemical industry. Our attempts to provide the graduates with skills in entrepreneurship and the ability to understand and communicate with their chemical engineering colleagues, in addition to their fundamental knowledge of chemistry, are described. This is done at second-year level with practical projects in which student teams formulate and prepare relatively simple chemical products for marketing, followed a year later by a more advanced study of the feasibility of producing and marketing a fine chemical on a commercial scale.
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- Authors: Brown, Michael E , Cosser, Ronald C , Davies-Coleman, Michael T , Kaye, Perry T , Klein, Rosalyn , Lamprecht, Emmanuel , Lobb, Kevin A , Nyokong, Tebello , Sewry, Joyce D , Tshentu, Zenixole R , van der Zeyde, Tino , Watkins, Gareth M
- Date: 2010
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449360 , vital:74814 , xlink:href="https://doi.org/10.1021/ed8001539"
- Description: A majority of chemistry graduates seek employment in a rapidly changing chemical industry. Our attempts to provide the graduates with skills in entrepreneurship and the ability to understand and communicate with their chemical engineering colleagues, in addition to their fundamental knowledge of chemistry, are described. This is done at second-year level with practical projects in which student teams formulate and prepare relatively simple chemical products for marketing, followed a year later by a more advanced study of the feasibility of producing and marketing a fine chemical on a commercial scale.
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Towards the synthesis of coumarin derivatives as potential dual-action HIV-1 protease and reverse transcriptase inhibitors
- Olomola, Temitope O, Klein, Rosalyn, Lobb, Kevin A, Sayed, Yasien, Kaye, Perry T
- Authors: Olomola, Temitope O , Klein, Rosalyn , Lobb, Kevin A , Sayed, Yasien , Kaye, Perry T
- Date: 2010
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448963 , vital:74774 , xlink:href="https://doi.org/10.1016/j.tetlet.2010.09.121"
- Description: 3-(Chloromethyl)coumarins, obtained via acid-catalysed cyclisation of salicylaldehyde-derived Baylis– Hillman adducts, have been treated with propargylamine; reaction of the resulting 3-alkynylmethylcoumarins with azidothymidine (AZT) in the presence of a Cu(I) catalyst has afforded a series of cycloaddition products for evaluation, in their own right, as potential dual-action HIV-1 protease and non-nucleoside reverse transcriptase inhibitors, and as scaffolds for further structural elaboration.
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- Authors: Olomola, Temitope O , Klein, Rosalyn , Lobb, Kevin A , Sayed, Yasien , Kaye, Perry T
- Date: 2010
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448963 , vital:74774 , xlink:href="https://doi.org/10.1016/j.tetlet.2010.09.121"
- Description: 3-(Chloromethyl)coumarins, obtained via acid-catalysed cyclisation of salicylaldehyde-derived Baylis– Hillman adducts, have been treated with propargylamine; reaction of the resulting 3-alkynylmethylcoumarins with azidothymidine (AZT) in the presence of a Cu(I) catalyst has afforded a series of cycloaddition products for evaluation, in their own right, as potential dual-action HIV-1 protease and non-nucleoside reverse transcriptase inhibitors, and as scaffolds for further structural elaboration.
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Chromone Studies. Part 17. Tricyclic Scaffolds from Reactions of chromone-3-carbaldehydes and methyl vinyl ketone under Baylis–Hillman conditions
- Ganto, Mlungiseleli M, Molefe, Duduzile M, Lobb, Kevin A, Kaye, Perry T
- Authors: Ganto, Mlungiseleli M , Molefe, Duduzile M , Lobb, Kevin A , Kaye, Perry T
- Date: 2009
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449321 , vital:74811 , xlink:href="https://doi.org/10.3184/030823409X4652"
- Description: Reaction of a series of chromone-3-carbaldehydes with methyl vinyl ketone under Baylis–Hillman conditions, using 3-hydroxyquinuclidine in chloroform or DABCO in 1-methyl-2-pyrrolidinone, affords unprecedented tricylic chromone derivatives which, depending on the conditions, may be accompanied by the normal Baylis–Hillman products or their respective tricyclic dimers.
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- Authors: Ganto, Mlungiseleli M , Molefe, Duduzile M , Lobb, Kevin A , Kaye, Perry T
- Date: 2009
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449321 , vital:74811 , xlink:href="https://doi.org/10.3184/030823409X4652"
- Description: Reaction of a series of chromone-3-carbaldehydes with methyl vinyl ketone under Baylis–Hillman conditions, using 3-hydroxyquinuclidine in chloroform or DABCO in 1-methyl-2-pyrrolidinone, affords unprecedented tricylic chromone derivatives which, depending on the conditions, may be accompanied by the normal Baylis–Hillman products or their respective tricyclic dimers.
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Synthesis and structure determination of 8-and 9-iodocamphorquinone bis (ethylene ketal)
- Magqi, Nceba, Lobb, Kevin A, Kaye, Perry T, Caira, Mino R
- Authors: Magqi, Nceba , Lobb, Kevin A , Kaye, Perry T , Caira, Mino R
- Date: 2007
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449399 , vital:74817 , xlink:href="https://doi.org/10.3184/030823407X209"
- Description: The structures of 8- and 9-iodocamphorquinone bis(ethylene ketal) have been confirmed by spectroscopic and single crystal X-ray analysis. The unexpected formation of the latter isomer is attributed to intramolecular rearrangement of the camphor skeleton, the mechanistic details of which have been explored using coset analysis.
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- Authors: Magqi, Nceba , Lobb, Kevin A , Kaye, Perry T , Caira, Mino R
- Date: 2007
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/449399 , vital:74817 , xlink:href="https://doi.org/10.3184/030823407X209"
- Description: The structures of 8- and 9-iodocamphorquinone bis(ethylene ketal) have been confirmed by spectroscopic and single crystal X-ray analysis. The unexpected formation of the latter isomer is attributed to intramolecular rearrangement of the camphor skeleton, the mechanistic details of which have been explored using coset analysis.
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