In silico substrate-binding profiling for SARS-CoV-2 Main protease (Mpro) using Hexapeptide substrates
- Zabo, Sophakama, Lobb, Kevin A
- Authors: Zabo, Sophakama , Lobb, Kevin A
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452711 , vital:75164 , xlink:href="https://doi.org/10.3390/v15071480"
- Description: The SARS-CoV-2 main protease (Mpro) is essential for the life cycle of the COVID-19 virus. It cleaves the two polyproteins at 11 positions to generate mature proteins for virion formation. The cleavage site on these polyproteins is known to be Leu-Gln↓(Ser/Ala/Gly). A range of hexapeptides that follow the known sequence for recognition and cleavage was constructed using RDKit libraries and complexed with the crystal structure of Mpro (PDB ID 6XHM) through extensive molecular docking calculations. A subset of 131 of these complexes underwent 20 ns molecular dynamics simulations. The analyses of the trajectories from molecular dynamics included principal component analysis (PCA), and a method to compare PCA plots from separate trajectories was developed in terms of encoding PCA progression during the simulations. The hexapeptides formed stable complexes as expected, with reproducible molecular docking of the substrates given the extensiveness of the procedure. Only Lys-Leu-Gln*** (KLQ***) sequence complexes were studied for molecular dynamics. In this subset of complexes, the PCA analysis identified four classifications of protein motions across these sequences. KLQ*** complexes illustrated the effect of changes in substrate on the active site, with implications for understanding the substrate recognition of Mpro and informing the development of small molecule inhibitors.
- Full Text:
- Date Issued: 2023
- Authors: Zabo, Sophakama , Lobb, Kevin A
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452711 , vital:75164 , xlink:href="https://doi.org/10.3390/v15071480"
- Description: The SARS-CoV-2 main protease (Mpro) is essential for the life cycle of the COVID-19 virus. It cleaves the two polyproteins at 11 positions to generate mature proteins for virion formation. The cleavage site on these polyproteins is known to be Leu-Gln↓(Ser/Ala/Gly). A range of hexapeptides that follow the known sequence for recognition and cleavage was constructed using RDKit libraries and complexed with the crystal structure of Mpro (PDB ID 6XHM) through extensive molecular docking calculations. A subset of 131 of these complexes underwent 20 ns molecular dynamics simulations. The analyses of the trajectories from molecular dynamics included principal component analysis (PCA), and a method to compare PCA plots from separate trajectories was developed in terms of encoding PCA progression during the simulations. The hexapeptides formed stable complexes as expected, with reproducible molecular docking of the substrates given the extensiveness of the procedure. Only Lys-Leu-Gln*** (KLQ***) sequence complexes were studied for molecular dynamics. In this subset of complexes, the PCA analysis identified four classifications of protein motions across these sequences. KLQ*** complexes illustrated the effect of changes in substrate on the active site, with implications for understanding the substrate recognition of Mpro and informing the development of small molecule inhibitors.
- Full Text:
- Date Issued: 2023
Insights into the Dynamics and Binding of Two Polyprotein Substrate Cleavage Points in the Context of the SARS-CoV-2 Main and Papain-like Proteases
- Sanusi, Zainab K, Lobb, Kevin A
- Authors: Sanusi, Zainab K , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452773 , vital:75169 , xlink:href="https://doi.org/10.3390/molecules27238251"
- Description: It is well known that vital enzymes in the replication process of the coronavirus are the SARS-CoV-2 PLpro and SARS-CoV-2 3CLpro, both of which are important targets in the search for anti-coronavirus agents. These two enzymes are responsible for cleavage at various polyprotein sites in the SARS-CoV-2 lifecycle. Herein, the dynamics of the polyprotein cleavage sequences for the boundary between non-structural proteins Nsp1 and Nsp2 (CS1) and between Nsp2 and Nsp3 (CS2) in complex with both the papain-like protein PLpro and the main protease 3CLpro were explored using computational methods. The post dynamics analysis reveals that CS1 and CS2 both have greater stability when complexed with PLpro. Of these two, greater stability is observed for the CS1–PLpro complex, while destabilization resulting in loss of CS2 from the PLpro active site is observed for CS2-PLpro, suggesting the rate of exchange by the papain-like protease is faster for CS2 compared to CS1. On the other hand, the 3CLpro main protease also reveals stability for CS1 suggesting that the main protease could also play a potential role in the cleavage at point CS1. However, destabilization occurs early in the simulation for the complex CLpro–CS2 suggesting a poor interaction and non-plausible protease cleavage of the polyprotein at CS2 by the main protease. These findings could be used as a guide in the development and design of potent COVID-19 antiviral inhibitors that mimic the CS1 cleavage site.
- Full Text:
- Date Issued: 2022
- Authors: Sanusi, Zainab K , Lobb, Kevin A
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/452773 , vital:75169 , xlink:href="https://doi.org/10.3390/molecules27238251"
- Description: It is well known that vital enzymes in the replication process of the coronavirus are the SARS-CoV-2 PLpro and SARS-CoV-2 3CLpro, both of which are important targets in the search for anti-coronavirus agents. These two enzymes are responsible for cleavage at various polyprotein sites in the SARS-CoV-2 lifecycle. Herein, the dynamics of the polyprotein cleavage sequences for the boundary between non-structural proteins Nsp1 and Nsp2 (CS1) and between Nsp2 and Nsp3 (CS2) in complex with both the papain-like protein PLpro and the main protease 3CLpro were explored using computational methods. The post dynamics analysis reveals that CS1 and CS2 both have greater stability when complexed with PLpro. Of these two, greater stability is observed for the CS1–PLpro complex, while destabilization resulting in loss of CS2 from the PLpro active site is observed for CS2-PLpro, suggesting the rate of exchange by the papain-like protease is faster for CS2 compared to CS1. On the other hand, the 3CLpro main protease also reveals stability for CS1 suggesting that the main protease could also play a potential role in the cleavage at point CS1. However, destabilization occurs early in the simulation for the complex CLpro–CS2 suggesting a poor interaction and non-plausible protease cleavage of the polyprotein at CS2 by the main protease. These findings could be used as a guide in the development and design of potent COVID-19 antiviral inhibitors that mimic the CS1 cleavage site.
- Full Text:
- Date Issued: 2022
Photo-and thermoresponsive N-salicylideneaniline derivatives: solid-state studies and structural aspects
- Hulushe, Siyabonga T, Malan, Frederick P, Hosten, Eric C, Lobb, Kevin A, Khanye, Setshaba D, Watkins, Gareth M
- Authors: Hulushe, Siyabonga T , Malan, Frederick P , Hosten, Eric C , Lobb, Kevin A , Khanye, Setshaba D , Watkins, Gareth M
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451137 , vital:75021 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2022/nj/d1nj03056f"
- Description: N-Salicylideneaniline (SA) and its derivatives are known to possess chromism upon exposure to external stimuli. Herein, we present mechanochemical synthesis of a series of photo-and thermoresponsive SAderivatives and report on solid-state stabilisation of their tautomeric forms either by change in temperature or by photoirradiation. The influence of UV light on proton transfer between the enol-imine (EI) and keto-amine (KA) forms was investigated at l1 = 254 and l2 = 365 nm. Differential scanning calorimetry (DSC) measurements provided extra information on the thermodynamic relationship between the prototropic tautomers, and their exposition to liquid nitrogen, combined with variable temperature single-crystal X-ray diffraction (VT-SCXRD) and spectroscopic data, ascertained structural reasons for the intrinsic thermo-optical properties of the compounds. A series of structural determinations between 150 and 300 K further shed light on the thermomechanical behaviour exhibited by the thermoresponsive compounds. By virtue of calorimetry we were able to demonstrate proton transfer via the intramolecular ON hydrogen bond over the temperature range 193–453 K. This present work demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the switching behaviour between the EI and KA forms. Furthermore, the assertion that it is predominantly the planarity (j o 251) that determines thermochromaticity is questioned.
- Full Text:
- Date Issued: 2022
- Authors: Hulushe, Siyabonga T , Malan, Frederick P , Hosten, Eric C , Lobb, Kevin A , Khanye, Setshaba D , Watkins, Gareth M
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451137 , vital:75021 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2022/nj/d1nj03056f"
- Description: N-Salicylideneaniline (SA) and its derivatives are known to possess chromism upon exposure to external stimuli. Herein, we present mechanochemical synthesis of a series of photo-and thermoresponsive SAderivatives and report on solid-state stabilisation of their tautomeric forms either by change in temperature or by photoirradiation. The influence of UV light on proton transfer between the enol-imine (EI) and keto-amine (KA) forms was investigated at l1 = 254 and l2 = 365 nm. Differential scanning calorimetry (DSC) measurements provided extra information on the thermodynamic relationship between the prototropic tautomers, and their exposition to liquid nitrogen, combined with variable temperature single-crystal X-ray diffraction (VT-SCXRD) and spectroscopic data, ascertained structural reasons for the intrinsic thermo-optical properties of the compounds. A series of structural determinations between 150 and 300 K further shed light on the thermomechanical behaviour exhibited by the thermoresponsive compounds. By virtue of calorimetry we were able to demonstrate proton transfer via the intramolecular ON hydrogen bond over the temperature range 193–453 K. This present work demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the switching behaviour between the EI and KA forms. Furthermore, the assertion that it is predominantly the planarity (j o 251) that determines thermochromaticity is questioned.
- Full Text:
- Date Issued: 2022
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 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/10962/477672 , vital:78110 , 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/10962/477672 , vital:78110 , 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
Force Field Parameters for Fe2+ 4S2− 4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies
- Tendwa, Maureen B, Chebon-Bore, Lorna, Lobb, Kevin A, Musyoka, Thommas M, Taştan Bishop, Özlem
- Authors: Tendwa, Maureen B , Chebon-Bore, Lorna , Lobb, Kevin A , Musyoka, Thommas M , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451078 , vital:75016 , xlink:href="https://doi.org/10.3390/molecules26102929 "
- Description: The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.
- Full Text:
- Date Issued: 2021
- Authors: Tendwa, Maureen B , Chebon-Bore, Lorna , Lobb, Kevin A , Musyoka, Thommas M , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451078 , vital:75016 , xlink:href="https://doi.org/10.3390/molecules26102929 "
- Description: The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.
- Full Text:
- Date Issued: 2021
Synthesis, characterization, computational studies and DPPH scavenging activity of some triazatetracyclic derivatives
- Odame, Felix, Hosten, Eric C, Betz, Richard, Krause, Jason, Frost, Carminita L, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Krause, Jason , Frost, Carminita L , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451186 , vital:75026 , xlink:href="https://doi.org/10.1007/s13738-021-02158-3"
- Description: Some dihydrobenzo[4,5]imidazo[1,2-c]quinazolines have been synthesized from aldehydes and ketones, using the ketones as both reagents and solvents and tetrahydrofuran (THF) as the solvent for the aldehydes, to yield the triazatetracyclics. The compounds have been characterized with spectroscopy and microanalysis. The crystal structures of 9,9-dimethyl-8,10,17- triazatetracyclo[8.7.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaene (I), 9-butyl-9-methyl-8,10,17-triazatetracyclo[8.7.0.02 , 7 .011,16]heptadeca-(17),2,4,6,11(16),12,14-heptaene (III) and 9-phenyl-8,10,17-triazatetracyclo[8.7.0 02 7.011,16] heptadeca-1(17),2,4,6,11(16),12,14-heptaene (VIII) have been discussed. The computed NMR, IR, molecular electrostatic potential and frontier molecular orbitals of compounds I, III and VIII have been discussed. The M06 functional gave most of its values closest to the experimental values for the bond lengths and bond angles of compounds I and III. For compound VIII, none of the functionals gave values for bond lengths and bond angles that were consistent with the experimental values, but M06 gave values closest to experimental values. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity of the triazatetracyclics showed that compound I exhibits signifcant DPPH scavenging activity with an IC50 of 56.18 µM compared to 2.37 µM for ascorbic acid.
- Full Text:
- Date Issued: 2021
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Krause, Jason , Frost, Carminita L , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451186 , vital:75026 , xlink:href="https://doi.org/10.1007/s13738-021-02158-3"
- Description: Some dihydrobenzo[4,5]imidazo[1,2-c]quinazolines have been synthesized from aldehydes and ketones, using the ketones as both reagents and solvents and tetrahydrofuran (THF) as the solvent for the aldehydes, to yield the triazatetracyclics. The compounds have been characterized with spectroscopy and microanalysis. The crystal structures of 9,9-dimethyl-8,10,17- triazatetracyclo[8.7.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaene (I), 9-butyl-9-methyl-8,10,17-triazatetracyclo[8.7.0.02 , 7 .011,16]heptadeca-(17),2,4,6,11(16),12,14-heptaene (III) and 9-phenyl-8,10,17-triazatetracyclo[8.7.0 02 7.011,16] heptadeca-1(17),2,4,6,11(16),12,14-heptaene (VIII) have been discussed. The computed NMR, IR, molecular electrostatic potential and frontier molecular orbitals of compounds I, III and VIII have been discussed. The M06 functional gave most of its values closest to the experimental values for the bond lengths and bond angles of compounds I and III. For compound VIII, none of the functionals gave values for bond lengths and bond angles that were consistent with the experimental values, but M06 gave values closest to experimental values. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity of the triazatetracyclics showed that compound I exhibits signifcant DPPH scavenging activity with an IC50 of 56.18 µM compared to 2.37 µM for ascorbic acid.
- Full Text:
- Date Issued: 2021
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:
- Date Issued: 2020
- 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
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:
- Date Issued: 2020
- 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:
- Date Issued: 2020
Ultrasound promoted synthesis, characterization and computational studies of some thiourea derivatives
- Odame, Felix, Hosten, Eric C, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451199 , vital:75028 , xlink:href="https://doi.org/10.1016/j.molstruc.2020.128302"
- Description: Synthesis of some thiourea derivatives have been achieved by using ultrasound, the compounds have been characterised using IR, NMR, GC-MS and elemental analysis. The single crystal X-ray structure of N-[(benzyloxy)methanethioyl]benzamide (IV), 1-benzoyl-3-(2-hydroxyethyl)thiourea (V) and 3-benzoyl-1-(1-benzylpiperidin-4-yl)thiourea (VI) has been presented and the bond lengths and bond angles contrasted with computed results. The HOMO and LUMO energy levels as well as the global chemical reactivity descriptors of the compounds have also been computed and discussed. Two comformers were obtained for compounds IV to VI in the molecular Electrostatic potential and the vibrational frequency computations and these have been discussed.
- Full Text:
- Date Issued: 2020
- Authors: Odame, Felix , Hosten, Eric C , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451199 , vital:75028 , xlink:href="https://doi.org/10.1016/j.molstruc.2020.128302"
- Description: Synthesis of some thiourea derivatives have been achieved by using ultrasound, the compounds have been characterised using IR, NMR, GC-MS and elemental analysis. The single crystal X-ray structure of N-[(benzyloxy)methanethioyl]benzamide (IV), 1-benzoyl-3-(2-hydroxyethyl)thiourea (V) and 3-benzoyl-1-(1-benzylpiperidin-4-yl)thiourea (VI) has been presented and the bond lengths and bond angles contrasted with computed results. The HOMO and LUMO energy levels as well as the global chemical reactivity descriptors of the compounds have also been computed and discussed. Two comformers were obtained for compounds IV to VI in the molecular Electrostatic potential and the vibrational frequency computations and these have been discussed.
- Full Text:
- Date Issued: 2020
Establishing computational approaches towards identifying malarial allosteric modulators: a case study of plasmodium falciparum hsp70s
- Amusengeri, Arnold, Astl, Lindy, Lobb, Kevin A, Verkhivker, Gennady M, Tastan Bishop, Özlem
- Authors: Amusengeri, Arnold , Astl, Lindy , Lobb, Kevin A , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163000 , vital:41003 , https://doi.org/10.3390/ijms20225574
- Description: Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks.
- Full Text:
- Date Issued: 2019
- Authors: Amusengeri, Arnold , Astl, Lindy , Lobb, Kevin A , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163000 , vital:41003 , https://doi.org/10.3390/ijms20225574
- Description: Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks.
- Full Text:
- Date Issued: 2019
Iron (iii) porphyrin electrocatalyzed enantioselective carbon-chloride bond cleavage of hexachlorocyclohexanes (HCHs): combined experimental investigation and theoretical calculations
- Liang, Xu, Li, Minzhi, Mack, John, Lobb, Kevin A, Zhu, Weihua
- Authors: Liang, Xu , Li, Minzhi , Mack, John , Lobb, Kevin A , Zhu, Weihua
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447979 , vital:74688 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2018/dt/c8dt02510j"
- Description: Enantioselective electrocatalysis of α-, β-, γ- and δ-hexachlorocyclohexanes (HCHs) by tetrakis-pentafluorophenyl-Fe(III)porphyrin is described. The first example of the combined use of electrochemical measurements and theoretical calculations to determine the mechanism of the enantioselective C–Cl bond cleavage of the electrocatalysis is reported. The electrochemical measurements demonstrate that the reactivity of the HCHs follows the order γ-HCH > α-HCH > δ-HCH > β-HCH. Steric considerations and a molecular orbital theory approach can be used to rationalize the enantioselective nature of the catalysis based on the ease of approach of each Cl atom to the central Fe(I) ion and a consideration of the nodes on the C–Cl bonds that weaken these bonds in a manner that results in bond cleavage and the formation of an Fe–Cl bond.
- Full Text:
- Date Issued: 2018
- Authors: Liang, Xu , Li, Minzhi , Mack, John , Lobb, Kevin A , Zhu, Weihua
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447979 , vital:74688 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2018/dt/c8dt02510j"
- Description: Enantioselective electrocatalysis of α-, β-, γ- and δ-hexachlorocyclohexanes (HCHs) by tetrakis-pentafluorophenyl-Fe(III)porphyrin is described. The first example of the combined use of electrochemical measurements and theoretical calculations to determine the mechanism of the enantioselective C–Cl bond cleavage of the electrocatalysis is reported. The electrochemical measurements demonstrate that the reactivity of the HCHs follows the order γ-HCH > α-HCH > δ-HCH > β-HCH. Steric considerations and a molecular orbital theory approach can be used to rationalize the enantioselective nature of the catalysis based on the ease of approach of each Cl atom to the central Fe(I) ion and a consideration of the nodes on the C–Cl bonds that weaken these bonds in a manner that results in bond cleavage and the formation of an Fe–Cl bond.
- Full Text:
- Date Issued: 2018
Seed extract of Psoralea corylifolia and its constituent bakuchiol impairs AHL-based quorum sensing and biofilm formation in food-and human-related pathogens
- Husain, Fohad M, Ahmad, Iqbal, Khan, Faez I, Al-Shabib, Nasser A, Baig, Mohammad H, Hussain, Afzal, Rehman, Md T, Alajmi, Mohamed F, Lobb, Kevin A
- Authors: Husain, Fohad M , Ahmad, Iqbal , Khan, Faez I , Al-Shabib, Nasser A , Baig, Mohammad H , Hussain, Afzal , Rehman, Md T , Alajmi, Mohamed F , Lobb, Kevin A
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447182 , vital:74590 , xlink:href="https://doi.org/10.3389/fcimb.2018.00351"
- Description: The emergence of multi-drug resistance in pathogenic bacteria in clinical settings as well as food-borne infections has become a serious health concern. The problem of drug resistance necessitates the need for alternative novel therapeutic strategies to combat this menace. One such approach is targeting the quorum-sensing (QS) controlled virulence and biofilm formation. In this study, we first screened different fractions of Psoralea corylifolia (seed) for their anti-QS property in the Chromobacterium violaceum 12472 strain.
- Full Text:
- Date Issued: 2018
- Authors: Husain, Fohad M , Ahmad, Iqbal , Khan, Faez I , Al-Shabib, Nasser A , Baig, Mohammad H , Hussain, Afzal , Rehman, Md T , Alajmi, Mohamed F , Lobb, Kevin A
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447182 , vital:74590 , xlink:href="https://doi.org/10.3389/fcimb.2018.00351"
- Description: The emergence of multi-drug resistance in pathogenic bacteria in clinical settings as well as food-borne infections has become a serious health concern. The problem of drug resistance necessitates the need for alternative novel therapeutic strategies to combat this menace. One such approach is targeting the quorum-sensing (QS) controlled virulence and biofilm formation. In this study, we first screened different fractions of Psoralea corylifolia (seed) for their anti-QS property in the Chromobacterium violaceum 12472 strain.
- Full Text:
- Date Issued: 2018
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
Analysis of non-peptidic compounds as potential malarial inhibitors against plasmodial cysteine proteases via integrated virtual screening workflow
- Musyoka, Thommas M, Kanzi, Aquillah M, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123074 , vital:35403 , https://doi.10.1080/07391102.2015.1108231
- Description: Malaria is an infectious disease caused by a diverse group of erythrocytic protozoan parasites of the genus Plasmodium. It remains an exigent public health problem in the tropical areas of Africa, South America and parts of Asia and continues to take its toll in morbidity and mortality with half of the world’s population under a permanent risk of infection leading to more than half a million deaths annually (WHO, 2013). Five Plasmodium species, namely P. falciparum (Pf ), P. vivax (Pv), P. ovale (Po), P. malariae (Pm) and P. knowlesi (Pk), are known to infect humans with Pf responsible for more than 90% of the malarial fatalities reported in sub-Saharan Africa. The predominance of Pf is attributed to its adaptability (Ashley, McGready, Proux, & Nosten, 2006; Prugnolle et al., 2011). Although the high occurrence of the Duffy negative trait among African populations lowers the threat posed by Pv, it is the most frequent and widely causative agent of benign tertian malaria in other parts of the world (Mendis, Sina, Marchesini, & Carter, 2001). In addition to the listed human malarial parasite forms, several other Plasmodium species, which infect non-human laboratory models, have been identified and are of significant importance in understanding the parasite biology, the host–parasite interactions and in the drug development process (Langhorne et al., 2011).
- Full Text:
- Date Issued: 2016
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123074 , vital:35403 , https://doi.10.1080/07391102.2015.1108231
- Description: Malaria is an infectious disease caused by a diverse group of erythrocytic protozoan parasites of the genus Plasmodium. It remains an exigent public health problem in the tropical areas of Africa, South America and parts of Asia and continues to take its toll in morbidity and mortality with half of the world’s population under a permanent risk of infection leading to more than half a million deaths annually (WHO, 2013). Five Plasmodium species, namely P. falciparum (Pf ), P. vivax (Pv), P. ovale (Po), P. malariae (Pm) and P. knowlesi (Pk), are known to infect humans with Pf responsible for more than 90% of the malarial fatalities reported in sub-Saharan Africa. The predominance of Pf is attributed to its adaptability (Ashley, McGready, Proux, & Nosten, 2006; Prugnolle et al., 2011). Although the high occurrence of the Duffy negative trait among African populations lowers the threat posed by Pv, it is the most frequent and widely causative agent of benign tertian malaria in other parts of the world (Mendis, Sina, Marchesini, & Carter, 2001). In addition to the listed human malarial parasite forms, several other Plasmodium species, which infect non-human laboratory models, have been identified and are of significant importance in understanding the parasite biology, the host–parasite interactions and in the drug development process (Langhorne et al., 2011).
- Full Text:
- Date Issued: 2016
Characterization of some amino acid derivatives of benzoyl isothiocyanate: Crystal structures and theoretical prediction of their reactivity
- Odame, Felix, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447952 , vital:74686 , xlink:href="https://doi.org/10.1016/j.molstruc.2015.05.053"
- Description: The reaction of benzoyl isothiocyanate with L-serine, L-proline, D-methionine and L-alanine gave 2-[(benzoylcarbamothioyl)amino]-3-hydroxypropanoic acid (I), 1-(benzoylcarbamothioyl)pyrrolidine-2-carboxylic acid (II), 2-[(benzoylcarbamothioyl)amino]-4-(methylsulfanyl)butanoic acid (III) and 2-[(benzoylcarbamothioyl)amino]propanoic acid (IV), respectively. The compounds have been characterized by IR, NMR, microanalyses and mass spectrometry. The crystal structures of all the compounds have also been discussed. Compound II showed rotamers in solution. DFT calculations of the frontier orbitals of the compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity of these compounds. The calculations indicated that the carboxylic acid group in these compounds is unreactive hence making the conversion to benzimidazoles via cyclization on the carboxylic acids impractical. This has been further confirmed by the reaction of compounds I–IV, respectively, with o-phenylene diamine which was unsuccessful but gave compound V.
- Full Text:
- Date Issued: 2015
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447952 , vital:74686 , xlink:href="https://doi.org/10.1016/j.molstruc.2015.05.053"
- Description: The reaction of benzoyl isothiocyanate with L-serine, L-proline, D-methionine and L-alanine gave 2-[(benzoylcarbamothioyl)amino]-3-hydroxypropanoic acid (I), 1-(benzoylcarbamothioyl)pyrrolidine-2-carboxylic acid (II), 2-[(benzoylcarbamothioyl)amino]-4-(methylsulfanyl)butanoic acid (III) and 2-[(benzoylcarbamothioyl)amino]propanoic acid (IV), respectively. The compounds have been characterized by IR, NMR, microanalyses and mass spectrometry. The crystal structures of all the compounds have also been discussed. Compound II showed rotamers in solution. DFT calculations of the frontier orbitals of the compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity of these compounds. The calculations indicated that the carboxylic acid group in these compounds is unreactive hence making the conversion to benzimidazoles via cyclization on the carboxylic acids impractical. This has been further confirmed by the reaction of compounds I–IV, respectively, with o-phenylene diamine which was unsuccessful but gave compound V.
- Full Text:
- Date Issued: 2015
SANCDB: a South African natural compound database
- Hatherley, Rowan, Brown, David K, Musyoka, Thommas M, Penkler, David L, Faya, Ngonidzashe, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148337 , vital:38730 , DOI: 10.1186/s13321-015-0080-8
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148337 , vital:38730 , DOI: 10.1186/s13321-015-0080-8
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
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.
- Full Text:
- Date Issued: 2013
- 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
The Formation of 2, 2, 4-Trimethyl-2, 3-dihydro-1 H-1, 5-Benzodiazepine from 1, 2-Diaminobenzene in the Presence of Acetone
- Odame, Felix, Kleyi, Phumelele, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Kleyi, Phumelele , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448952 , vital:74773 , xlink:href="https://doi.org/10.3390/molecules181114293"
- Description: In an attempt to synthesize a 2-substituted benzimidazole from the reaction of o-phenylenediamine and isophthalic acid in the presence of acetone and ethanol under microwave irradiation, a salt of the isophthalate ion and 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepin-5-ium ion was obtained. The condensation of two moles of acetone with the amine groups resulted in the formation of the benzodiazepine which crystallized as an iminium cation forming a salt with the isophthalate anion. The formation of benzodiazepine was also confirmed by performing the reaction of o-phenylenediamine with excess acetone in ethanol under conventional heating conditions. The compounds were characterized by NMR, FTIR, HRMS and microanalysis as well as X-ray crystallography. The reaction mechanism leading to the formation of benzodiazepine is also discussed.
- Full Text:
- Date Issued: 2013
- Authors: Odame, Felix , Kleyi, Phumelele , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2013
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448952 , vital:74773 , xlink:href="https://doi.org/10.3390/molecules181114293"
- Description: In an attempt to synthesize a 2-substituted benzimidazole from the reaction of o-phenylenediamine and isophthalic acid in the presence of acetone and ethanol under microwave irradiation, a salt of the isophthalate ion and 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepin-5-ium ion was obtained. The condensation of two moles of acetone with the amine groups resulted in the formation of the benzodiazepine which crystallized as an iminium cation forming a salt with the isophthalate anion. The formation of benzodiazepine was also confirmed by performing the reaction of o-phenylenediamine with excess acetone in ethanol under conventional heating conditions. The compounds were characterized by NMR, FTIR, HRMS and microanalysis as well as X-ray crystallography. The reaction mechanism leading to the formation of benzodiazepine is also discussed.
- Full Text:
- Date Issued: 2013
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.
- Full Text:
- Date Issued: 2011
- 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