Repurposing a polymer precursor scaffold for medicinal application: Synthesis, characterization and biological evaluation of ferrocenyl 1,3-benzoxazine derivatives as potential antiprotozoal and anticancer agents
- Authors: Mbaba, Mziyanda
- Date: 2020
- Subjects: Uncatalogued
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/164502 , vital:41124 , DOI 10.21504/10962/164502
- Description: The benzoxazines are a prominent class of heterocyclic compounds that possess a multitude of properties. To this end, benzoxazine derivatives have been used as versatile compounds for various utilities ranging from biological applications to the fabrication of polymers. Particularly, the 1,3-benzoxazine scaffold has featured in several bioactive compounds showing antimalarial, anticancer and antibacterial activities. Traditionally, it has been employed as a substrate in the synthesis of polymers with appealing physical and chemical properties. Due to the increasing interest in the polymer application of 1,3-benzoxazines, research of the 1,3-benzoxazine motif for polymer synthesis has been prioritized over other applications including its medicinal potential. The continuous development of resistance to clinical anticancer and antimalarial drugs has necessitated the need for the search of innovative bioactive compounds as potential alternative medicinal agents. To address this, the field of medicinal chemistry is adapting new approaches to counter resistance by incorporating nonconventional chemical moieties such as organometallic complexes, like ferrocene, into bioactive chemical motifs to serve as novel compounds with medicinal benefits. Incorporation of ferrocene into known bioactive chemical moieties has been shown to impart beneficial biological effects into the resultant compounds, which include the introduction of novel, and sometimes varied, mechanistic modalities and enhanced potency. Presented with the benefits of this strategy, the current work aims to design and evaluate the pharmaceutical capacity of novel derivatives containing 1,3-benzoxazine scaffold (traditionally applied in polymer synthesis) hybridized with the organometallic ferrocene unit as bioactive agents. Using a combination of expedient synthetic procedures such as the Burke three-component Mannich-type condensation, Vilsmeier-Haack formylation and reductive amination, four series of ferrocenyl 1,3-benzoxazine derivatives were synthesized and their structures confirmed by common spectroscopic techniques: nuclear magnetic resonance (NMR), infrared spectroscopy (IR) and high-resolution mass spectrometry (HRMS). The target compounds were evaluated in vitro for potential antimalarial and anticancer activities against strains of the malaria parasite (Plasmodium falciparum 3D7 and Dd2) and the triple-negative breast cancer cell line HCC70. Compounds exhibited higher potency towards the Plasmodium falciparum strains with IC50 values in the low and sub-micromolar range in comparison to the breast cancer cell line against for which mid-molar activities were observed. To gain insight into the possible mode of action of ferrocenyl 1,3-benzoxazines, representative compounds showing most efficacy from each series were assessed for DNA binding affinity by employing UV-Vis and fluorescence DNA titration experiments. The selected compounds were found to interact with the DNA by binding to the minor groove, and these findings were confirmed by in silico ligand docking studies using a B-DNA structure as the receptor. Compound 3.16c (IC50: 0.261 μM [3D7], 0.599 μM [Dd2], 11.0 μM [HCC70]), which emerged as the most promising compound, was found to induce DNA damage in HCC70 cancer cells when investigated for effects of DNA interaction. Additionally, compound 3.16c displayed a higher binding constant (Kb) against DNA isolated from 3D7 Plasmodium falciparum trophozoites (Kb = 1.88×106 M-1) than the mammalian DNA (Kb = 6.33×104 M-1) from calf thymus, thus explaining the preferred selectivity of the compounds for the malaria parasite. Moreover, the investigated compounds demonstrated binding affinity for synthetic hemozoin, β-hematin. Collectively, these data suggest that the compounds possess a dual mode of action for antimalarial activity involving DNA interaction and hemozoin inhibition. , Thesis (PhD) -- Faculty of Science, Chemistry, 2020
- Full Text:
- Date Issued: 2020
- Authors: Mbaba, Mziyanda
- Date: 2020
- Subjects: Uncatalogued
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/164502 , vital:41124 , DOI 10.21504/10962/164502
- Description: The benzoxazines are a prominent class of heterocyclic compounds that possess a multitude of properties. To this end, benzoxazine derivatives have been used as versatile compounds for various utilities ranging from biological applications to the fabrication of polymers. Particularly, the 1,3-benzoxazine scaffold has featured in several bioactive compounds showing antimalarial, anticancer and antibacterial activities. Traditionally, it has been employed as a substrate in the synthesis of polymers with appealing physical and chemical properties. Due to the increasing interest in the polymer application of 1,3-benzoxazines, research of the 1,3-benzoxazine motif for polymer synthesis has been prioritized over other applications including its medicinal potential. The continuous development of resistance to clinical anticancer and antimalarial drugs has necessitated the need for the search of innovative bioactive compounds as potential alternative medicinal agents. To address this, the field of medicinal chemistry is adapting new approaches to counter resistance by incorporating nonconventional chemical moieties such as organometallic complexes, like ferrocene, into bioactive chemical motifs to serve as novel compounds with medicinal benefits. Incorporation of ferrocene into known bioactive chemical moieties has been shown to impart beneficial biological effects into the resultant compounds, which include the introduction of novel, and sometimes varied, mechanistic modalities and enhanced potency. Presented with the benefits of this strategy, the current work aims to design and evaluate the pharmaceutical capacity of novel derivatives containing 1,3-benzoxazine scaffold (traditionally applied in polymer synthesis) hybridized with the organometallic ferrocene unit as bioactive agents. Using a combination of expedient synthetic procedures such as the Burke three-component Mannich-type condensation, Vilsmeier-Haack formylation and reductive amination, four series of ferrocenyl 1,3-benzoxazine derivatives were synthesized and their structures confirmed by common spectroscopic techniques: nuclear magnetic resonance (NMR), infrared spectroscopy (IR) and high-resolution mass spectrometry (HRMS). The target compounds were evaluated in vitro for potential antimalarial and anticancer activities against strains of the malaria parasite (Plasmodium falciparum 3D7 and Dd2) and the triple-negative breast cancer cell line HCC70. Compounds exhibited higher potency towards the Plasmodium falciparum strains with IC50 values in the low and sub-micromolar range in comparison to the breast cancer cell line against for which mid-molar activities were observed. To gain insight into the possible mode of action of ferrocenyl 1,3-benzoxazines, representative compounds showing most efficacy from each series were assessed for DNA binding affinity by employing UV-Vis and fluorescence DNA titration experiments. The selected compounds were found to interact with the DNA by binding to the minor groove, and these findings were confirmed by in silico ligand docking studies using a B-DNA structure as the receptor. Compound 3.16c (IC50: 0.261 μM [3D7], 0.599 μM [Dd2], 11.0 μM [HCC70]), which emerged as the most promising compound, was found to induce DNA damage in HCC70 cancer cells when investigated for effects of DNA interaction. Additionally, compound 3.16c displayed a higher binding constant (Kb) against DNA isolated from 3D7 Plasmodium falciparum trophozoites (Kb = 1.88×106 M-1) than the mammalian DNA (Kb = 6.33×104 M-1) from calf thymus, thus explaining the preferred selectivity of the compounds for the malaria parasite. Moreover, the investigated compounds demonstrated binding affinity for synthetic hemozoin, β-hematin. Collectively, these data suggest that the compounds possess a dual mode of action for antimalarial activity involving DNA interaction and hemozoin inhibition. , Thesis (PhD) -- Faculty of Science, Chemistry, 2020
- Full Text:
- Date Issued: 2020
Sedimentology, reservoir properties and hydrocarbon potential of the southern Bredasdorp Basin, offshore of the Western Cape Province, South Africa
- Authors: Baiyegunhi, Temitope Love
- Date: 2021-05
- Subjects: Sediments (Geology) , Hydrocarbon reservoirs
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10353/20753 , vital:46546
- Description: The Bredasdorp Basin has become the focus for exploration activity (i.e., seismic exploration and drilling) since the discovery of gas-condensate and oil reservoirs in the early 1980s. The basin has proven hydrocarbon reserves and potential for future discoveries. However, uncertainty about the sedimentological and petrographic characteristics, reservoir qualities, thermal maturity and hydrocarbon potential of the source/reservoir rocks has hindered further exploration, particularly in the southern part of the basin. To date, this part of the basin remains unexplored and partially understood with respect to petroleum systems evolution when compared to the central and northern parts of the basin. To fill the research gaps, exploration wells E-AH1, E-AJ1, E-BA1, E-BB1 and E-D3 were investigated so as to unravel the petrographic characteristics, depositional processes and paleoenvironment, tectonic provenance, paleoweathering, hydrocarbon potential, thermal maturity, diagenetic characterisitcs and reservoir qualities of the southern Bredasdorp Basin. The grain size textural parameters revealed that the southern Bredasdorp Basin sandstones are unimodal, predominantly fine-grained, moderately well sorted, mesokurtic and near-symmetrical. The bivariate plots of grain size textural parameters indicate that the depositional environments had been influenced mainly by river/beach/coastal dune conditions. The linear discriminate functions (LDF) diagrams show that the sediments are turbidity current deposits in a shallow marine environment. The Passega diagram revealed that the studied sandstones were mainly deposited by traction currents and beach process. In addition, the grain size log-probability curves and Passega diagram show the predominance of saltation and suspension modes of sediment transportation. Based on the inter-relationship of the various statistical parameters, it is deduced that the southern Bredasdorp Basin are mainly shallow marine deposits with signature of beach and coastal river processes. Based on the lithofacies analysis of the southern Bredasdorp Basin borehole cores, thirteen lithofacies were identified and grouped into six facies associations (FAs). The facies associations are: matrix supported conglomerate and massive sandstone (FA 1), ripple cross laminated, trough cross bedded and bioturbated sandstone (FA 2), massive sandstone with mudstone and shale interbeds (FA 3), alternating laminated to interbedded sandstone/siltstone and mudstone (FA 4), massive mudstone with minor interlamination of clay-rich sandstones and siltstone (FA 5), and carbonaceous laminated shale and mudstone with occasional siltstone laminae (FA 6). Facies associations FA1, FA2, FA3, FA4, FA5 and FA6 are interpreted as submarine channel-fills, submarine channel-levee, submarine sheet lobe, submarine lobe fring/overflow, basin plain deposits and deep sea floor/basin plain deposits, respectively. Sedimentological evidences from lithofacies interpretation revealed shallow marine environment as the main depositional environment, with minor contribution from the deep marine environment. Petrographic studies show that the southern Bredasdorp Basin sandstones chiefly consist of quartz (52.2–68.0percent), feldspar (10.0–18.0percent), and lithic fragments (5.0–10.2percent). The modal composition analysis revealed that the sandstones could be classified as subarkosic arenite and lithic arkose. The provenance ternary diagrams revealed that the rocks are mainly of continental block provenances (stable shields and basement uplifted areas) and complemented by recycled sands from an associated platform. The tectonic provenance studies show that the sandstones are typically rift-derived arenites and have undergone long-distance transport from the source area along the rift. In the regional context of the evolution of the Bredasdorp Basin, the results suggested that the basin developed on a passive rift setting (trailing edge) of the stable continental margins. The provenance discrimination diagrams based on major oxide geochemistry revealed that the sandstones are mainly of quartzose sedimentary provenance, while the mudrocks are of quartzose sedimentary and intermediate igneous provenances. The discrimination diagrams indicate that the southern Bredasdorp Basin sediments were mostly derived from a cratonic interior or recycled orogen. The bivariate plots of TiO2 versus Ni, TiO2 against Zr and La/Th versus Hf as well as the ternary diagrams of V–Ni–Th×10 suggest that the mudrocks and sandstones were derived from felsic igneous rocks. The tectonic setting discrimination diagrams support passive-active continental margin setting of the provenance. Chemical index of alteration (CIA) indices observed in the sandstones suggest that their source area underwent low to moderate degree of chemical weathering. However, the mudrocks have high CIA indices suggesting that the source area underwent more intense chemical weathering, possibly due to climatic and/or tectonic variations. The organic geochemistry results show that these rocks have total organic carbon, TOC contents ranging from 0.14 to 7.03 wt.percent. The hydrogen index (HI), oxygen index (OI), and hydrocarbon index (S2/S3) values vary between 24–263 mg HC/g TOC, 4–78 mg CO2/g TOC, and 0.01–18 mgHC/mgCO2 TOC, respectively, indicating predominantly Type III and IV kerogen with a minor amount of mixed Type II/III kerogen. The mean vitrinite reflectance values vary from 0.60–1.20percent, indicating that the samples are in the oil-generation window. The Tmax and PI values are consistent with the mean vitrinite reflectance values, indicating that the southern Bredasdorp Basin source rocks have entered the oil window and are considered as effective source rocks in the southern Bredasdorp Basin. The hydrocarbon genetic potential (SP), normalized oil content (NOC) and production index (PI) values all indicate poor to fair hydrocarbon generative potential. The main diagenetic processes that have affected the reservoir quality of the southern Bredasdorp Basin rocks are cementation by authigenic clay, carbonate and silica, growth of authigenic glauconite, dissolution of minerals and load compaction. These aforementioned diagenetic processes act differently in each borehole and at different depths. The influence of cementation and compaction is complex with no particular pattern with increasing depth, suggesting that diagenesis is the main challenge to reservoir characterization in the southern Bredasdorp Basin. The clays in the sandstones act as pore choking cement, which reduces porosity and permeability of the reservoir rocks. Reservoir quality of the sandstones has been improved to various extents due to the development of secondary porosity as a result of partial to complete dissolution of early calcite cement and some detrital grains (feldspars) and also affected by grain fracturing. The scattered plots of porosity and permeability versus cement+clays show good inverse correlations, suggesting that the reservoir quality is mainly controlled by cementation and authigenic clays. Based on the diagenetic study, it can be inferred that the potential reservoir quality of the southern Bredasdorp Basin sandstones is poor-moderate. , Thesis (PhD) -- Faculty of Science and Agriculture, 2021
- Full Text:
- Date Issued: 2021-05
- Authors: Baiyegunhi, Temitope Love
- Date: 2021-05
- Subjects: Sediments (Geology) , Hydrocarbon reservoirs
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10353/20753 , vital:46546
- Description: The Bredasdorp Basin has become the focus for exploration activity (i.e., seismic exploration and drilling) since the discovery of gas-condensate and oil reservoirs in the early 1980s. The basin has proven hydrocarbon reserves and potential for future discoveries. However, uncertainty about the sedimentological and petrographic characteristics, reservoir qualities, thermal maturity and hydrocarbon potential of the source/reservoir rocks has hindered further exploration, particularly in the southern part of the basin. To date, this part of the basin remains unexplored and partially understood with respect to petroleum systems evolution when compared to the central and northern parts of the basin. To fill the research gaps, exploration wells E-AH1, E-AJ1, E-BA1, E-BB1 and E-D3 were investigated so as to unravel the petrographic characteristics, depositional processes and paleoenvironment, tectonic provenance, paleoweathering, hydrocarbon potential, thermal maturity, diagenetic characterisitcs and reservoir qualities of the southern Bredasdorp Basin. The grain size textural parameters revealed that the southern Bredasdorp Basin sandstones are unimodal, predominantly fine-grained, moderately well sorted, mesokurtic and near-symmetrical. The bivariate plots of grain size textural parameters indicate that the depositional environments had been influenced mainly by river/beach/coastal dune conditions. The linear discriminate functions (LDF) diagrams show that the sediments are turbidity current deposits in a shallow marine environment. The Passega diagram revealed that the studied sandstones were mainly deposited by traction currents and beach process. In addition, the grain size log-probability curves and Passega diagram show the predominance of saltation and suspension modes of sediment transportation. Based on the inter-relationship of the various statistical parameters, it is deduced that the southern Bredasdorp Basin are mainly shallow marine deposits with signature of beach and coastal river processes. Based on the lithofacies analysis of the southern Bredasdorp Basin borehole cores, thirteen lithofacies were identified and grouped into six facies associations (FAs). The facies associations are: matrix supported conglomerate and massive sandstone (FA 1), ripple cross laminated, trough cross bedded and bioturbated sandstone (FA 2), massive sandstone with mudstone and shale interbeds (FA 3), alternating laminated to interbedded sandstone/siltstone and mudstone (FA 4), massive mudstone with minor interlamination of clay-rich sandstones and siltstone (FA 5), and carbonaceous laminated shale and mudstone with occasional siltstone laminae (FA 6). Facies associations FA1, FA2, FA3, FA4, FA5 and FA6 are interpreted as submarine channel-fills, submarine channel-levee, submarine sheet lobe, submarine lobe fring/overflow, basin plain deposits and deep sea floor/basin plain deposits, respectively. Sedimentological evidences from lithofacies interpretation revealed shallow marine environment as the main depositional environment, with minor contribution from the deep marine environment. Petrographic studies show that the southern Bredasdorp Basin sandstones chiefly consist of quartz (52.2–68.0percent), feldspar (10.0–18.0percent), and lithic fragments (5.0–10.2percent). The modal composition analysis revealed that the sandstones could be classified as subarkosic arenite and lithic arkose. The provenance ternary diagrams revealed that the rocks are mainly of continental block provenances (stable shields and basement uplifted areas) and complemented by recycled sands from an associated platform. The tectonic provenance studies show that the sandstones are typically rift-derived arenites and have undergone long-distance transport from the source area along the rift. In the regional context of the evolution of the Bredasdorp Basin, the results suggested that the basin developed on a passive rift setting (trailing edge) of the stable continental margins. The provenance discrimination diagrams based on major oxide geochemistry revealed that the sandstones are mainly of quartzose sedimentary provenance, while the mudrocks are of quartzose sedimentary and intermediate igneous provenances. The discrimination diagrams indicate that the southern Bredasdorp Basin sediments were mostly derived from a cratonic interior or recycled orogen. The bivariate plots of TiO2 versus Ni, TiO2 against Zr and La/Th versus Hf as well as the ternary diagrams of V–Ni–Th×10 suggest that the mudrocks and sandstones were derived from felsic igneous rocks. The tectonic setting discrimination diagrams support passive-active continental margin setting of the provenance. Chemical index of alteration (CIA) indices observed in the sandstones suggest that their source area underwent low to moderate degree of chemical weathering. However, the mudrocks have high CIA indices suggesting that the source area underwent more intense chemical weathering, possibly due to climatic and/or tectonic variations. The organic geochemistry results show that these rocks have total organic carbon, TOC contents ranging from 0.14 to 7.03 wt.percent. The hydrogen index (HI), oxygen index (OI), and hydrocarbon index (S2/S3) values vary between 24–263 mg HC/g TOC, 4–78 mg CO2/g TOC, and 0.01–18 mgHC/mgCO2 TOC, respectively, indicating predominantly Type III and IV kerogen with a minor amount of mixed Type II/III kerogen. The mean vitrinite reflectance values vary from 0.60–1.20percent, indicating that the samples are in the oil-generation window. The Tmax and PI values are consistent with the mean vitrinite reflectance values, indicating that the southern Bredasdorp Basin source rocks have entered the oil window and are considered as effective source rocks in the southern Bredasdorp Basin. The hydrocarbon genetic potential (SP), normalized oil content (NOC) and production index (PI) values all indicate poor to fair hydrocarbon generative potential. The main diagenetic processes that have affected the reservoir quality of the southern Bredasdorp Basin rocks are cementation by authigenic clay, carbonate and silica, growth of authigenic glauconite, dissolution of minerals and load compaction. These aforementioned diagenetic processes act differently in each borehole and at different depths. The influence of cementation and compaction is complex with no particular pattern with increasing depth, suggesting that diagenesis is the main challenge to reservoir characterization in the southern Bredasdorp Basin. The clays in the sandstones act as pore choking cement, which reduces porosity and permeability of the reservoir rocks. Reservoir quality of the sandstones has been improved to various extents due to the development of secondary porosity as a result of partial to complete dissolution of early calcite cement and some detrital grains (feldspars) and also affected by grain fracturing. The scattered plots of porosity and permeability versus cement+clays show good inverse correlations, suggesting that the reservoir quality is mainly controlled by cementation and authigenic clays. Based on the diagenetic study, it can be inferred that the potential reservoir quality of the southern Bredasdorp Basin sandstones is poor-moderate. , Thesis (PhD) -- Faculty of Science and Agriculture, 2021
- Full Text:
- Date Issued: 2021-05
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