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:
- Date Issued: 2022
- 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:
- Date Issued: 2022
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.
- Full Text:
- Date Issued: 2020
- 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.
- Full Text:
- Date Issued: 2020
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”.
- Full Text:
- Date Issued: 2019
- 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”.
- Full Text:
- Date Issued: 2019
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:
- Date Issued: 2019
- 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:
- Date Issued: 2019
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.
- Full Text:
- Date Issued: 2017
- 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.
- Full Text:
- Date Issued: 2017
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