Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N-heteroarylcarboxamides as DXR inhibitors
- 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:
- Date Issued: 2013
1H NMR-based kinetic-mechanistic study of the intramolecular trans-esterification of 2-exo-3-exo-dihydroxybornane monoacrylate esters
- 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.
- Full Text:
- Date Issued: 2013
Dual-Catalyst Acceleration of Tandem Disulfide Cleavage and Baylis–Hillman Synthesis of 2 H-1-Benzothiopyran Derivatives
- 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.
- Full Text:
- Date Issued: 2013