Synthesis and conformational studies of 5-bromo-1-[(N-substituted-carbamoyl) methyl]-7-azabenzimidazoles
- 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 of 2, 3-dihydroxy-3-(N-substituted carbamoyl) propylphosphonic acid derivatives as hybrid DOXP-fosmidomycin analogues
- 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:
- Date Issued: 2022
Synthesis, stereochemistry and in vitro STD NMR and in silico HIV-1 PR enzyme-binding potential of MBH-derived inhibitors
- 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.
- Full Text:
- Date Issued: 2022
Rational design and regioselective synthesis of conformationally restricted furan-derived ligands as potential anti-malarial agents
- 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:
- Date Issued: 2020
Synthesis and anti-parasitic activity of N-benzylated phosphoramidate Mg2+-chelating ligands
- 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 and biological evaluation of bis-N2, N2′-(4-hydroxycoumarin-3-yl) ethylidene]-2, 3-dihydroxysuccinodihydrazides
- Authors: Manyeruke, Meloddy H , Tshiwawa, Tendamudzimu , Hoppe, Heinrich C , Isaacs, Michelle , Seldon, Ronnett , Warner, Digby F , Krause, Rui W M , Kaye, Perry T
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/193430 , vital:45331 , xlink:href="https://doi.org/10.1016/j.bmcl.2019.126911"
- Description: A series of N2,N2′-bis[4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccino-hydrazides, containing 4-hydroxycoumarin, hydrazine and tartaric acid moieties, have been prepared and examined for possible biological activity. Several of these compounds exhibit promising HIV-1 integrase inhibition (IC50 = 3.5 μM), and anti-T. brucei (32% viability) and anti-mycobacterial (Visual MIC90 = 15.63 μM) activity.
- Full Text:
- Date Issued: 2020
Synthesis of N-Substituted phosphoramidic acid esters as “reverse” fosmidomycin analogues
- 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
- 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
1H NMR-based kinetic and theoretical studies of the simultaneous formation of two discrete rotameric systems of a novel difenchyl sulfite ester
- 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.
- Full Text:
- Date Issued: 2017
Application of the Morita-Baylis-Hillman reaction in the synthesis of 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones as potential HIV-1 integrase inhibitors
- Authors: Sekgota, Khethobole C , Majumder, Swarup , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Khanye, Setshaba D , Kriel, Frederik H , Coates, Judy , Kaye, Perry T
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66178 , vital:28913 , https://doi.org/10.1016/j.bioorg.2017.09.015
- Description: publisher version , A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.
- Full Text: false
- Date Issued: 2017
Synthesis and anti-parasitic activity of C-benzylated (N-arylcarbamoyl) alkylphosphonate esters
- 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
Application of Baylis-Hillman methodology in the direct construction of chromone derivatives
- Authors: Faridoon, H , Olomola, Temitope O , Klein, Rosalyn , Kaye, Perry T
- Date: 2016
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/442488 , vital:73992 , https://doi.org/10.1016/j.tet.2015.11.039
- Description: Pyridinium chlorochromate oxidation of Baylis-Hillman-derived tert-butyl 2H-chromene-3-carboxylates affords chromone-3-carboxylate esters, providing the first application of Baylis-Hillman methodology in a direct and convenient three-step synthesis of chromone derivatives.
- Full Text:
- Date Issued: 2016
Elucidating Latent Mechanistic Complexity in Competing Acid-Catalyzed Reactions of Salicylaldehyde-Derived Baylis–Hillman Adducts
- Authors: Olomola, Temitope O , Klein, Rosalyn , Caira, Mino, R , Kaye, Perry T
- Date: 2016
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/442596 , vital:74010 , https://doi.org/10.1021/acs.joc.5b02372
- Description: 1H NMR-based kinetic studies have revealed the latent mechanistic complexity of deceptively simple hydrochloric acid-catalyzed reactions of salicylaldehyde-derived Baylis–Hillman adducts. Reactions conducted at 0 °C afforded 2-(chloromethyl)cinnamic acid derivatives as the major products and the corresponding 3-(chloromethyl)coumarin derivatives as the minor products. In reactions conducted in refluxing acetic acid, however, the 3-(chloromethyl)coumarin derivatives are the sole products. Variable-temperature 1H NMR analysis permitted the determination of the rate constants and kinetic parameters involved in the pseudo-first-order formation of (Z)-2-(chloromethyl)-3-(2-hydroxyphenyl)-2-propenoic acid. The kinetic data clearly preclude the operation of classical kinetic versus thermodynamic control and indicate the operation of three independent reaction pathways. Theoretical studies of these pathways undertaken at the B3LYP/6-31G(d) level permitted rationalization of the experimental data and provided insights into the possible mechanism of the enzymic E–Z isomerization and cyclization of (E)-cinnamic acid analogues to afford coumarins.
- Full Text:
- Date Issued: 2016
Supplementary Material Synthesis and biological evaluation of (E)-cinnamic acid,(E)-2-styrylthiazole and (E)-2-[2-(naphthalen-1-yl) vinyl] thiazole derivatives
- Authors: Olawode, Emmanuel O , Tandlich, Roman , Prinsloo, Earl , Isaacs, Michelle , Hoppe, Heinrich C , Seldon, Ronnett , Warner, Digby F , Steenkamp, Vanessa , Kaye, Perry T
- Date: 2016
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/431778 , vital:72803 , xlink:href=" https://www.arkat-usa.org/get-file/59868/"
- Description: The screening was conducted using multi-well plates which are suited for HeLa cells in the log phase of growth with final cell density > 10 cells/cm. Each experiment normally includes a blank control, containing medium without the cells.28,45 Non-contaminated HeLa cells (6.57 x 105 cells per well) in media were allowed to grow in the incubator under an atmosphere of 5% CO2 at 37 0C for 24 h. To each well was dispensed 200 µL of HeLa culture, containing 6.57 x 105 cells under LabEAir laminar flow hood (Vivid Air, South Africa); 20 µL of resazurin dye (Sigma TOX-8) and test compound (50 µL) were added, which were then incubated in the presence of 5% CO2 at 37 0C for 24 hours in a shaker, to enhance the distribution of the dye. The absorbance of each well was measured with Bio-tek Power Wave X fluorometer (Beijing, China), and increases in fluorescence was monitored at a wavelength of 590 nm, using an excitation wavelength of 560 nm.
- Full Text:
- Date Issued: 2016
Synthesis and evaluation of substituted 4-(N-benzylamino)cinnamate esters as potential anti-cancer agents and HIV-1 integrase inhibitors
- Authors: Faridoon, H , Edkins, Adrienne L , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66289 , vital:28929 , https://doi.org/10.1016/j.bmcl.2016.05.023
- Description: publisher version , Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50 ⩾ 3.0 μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50 ⩾ 9.6 μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
- Full Text: false
- Date Issued: 2016
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
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
DBU-Mediated cleavage of aryl-and heteroaryl disulfides
- 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.
- Full Text:
- Date Issued: 2012
1H NMR-based kinetic and mechanistic study of unusual skeletal rearrangements of a spirobornyl tosylate derivative
- 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.
- Full Text:
- Date Issued: 2011