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
Wavelet Theory: for Economic & Financial Cycles
- Authors: Mlambo, Farai Fredric
- Date: 2019-12
- Subjects: Wavelets (Mathematics) , Finance -- Mathematical models , Economic forecasting
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/49930 , vital:41861
- Description: Cycles - their nature in existence, their implications on human-kind and the study thereof have sparked some important philosophical debates since the very pre-historic days. Notable contributions by famous, genius philosophers, mathematicians, historians and economists such as Pareto, Deulofeu, Danielewski, Kuznets, Kondratiev, Elliot and many others in itself shows how cycles and their study have been deemed important, through the history and process of scientific and philosophical inquiry. Particularly, the explication of Business, Economic and Financial cycles have seen some significant research and policy attention. Nevertheless, most of the methodologies employed in this space are either purely empirical in nature, time series based or the so-called Regime-Switching Markov model popularized in Economics by James Hamilton. In this work, we develop a Statistical, non-linear model fit based on circle geometry which is applicable for the dating of cycles. This study proposes a scalable, smooth and differentiable quarter-circular wavelet basis for the smoothing and dating of business, economic and financial cycles. The dating then necessitates the forecasting of the cyclical patterns in the evolution of business, economic and financial time series. The practical significance of dating and forecasting business and financial cycles cannot be over-emphasized. The use of wavelet decomposition in explaining cycles can be seen as an critical contribution of spectral methods of statistical modelling to finance and economic policy at large. Being a relatively new method, wavelet analysis has seen some great contribution in geophysical modelling. This study endeavours to widen the use and application of frequency-time decomposition to the economic and financial space. Wavelets are localized in both time and frequency, such that there is no loss of the time resolution. The importance of time resolution in dating of cycles is another motivation behind using wavelets. Moreover, the preservation of time resolution in wavelet analysis is a fundamental strength employed in the dating of cycles. , Thesis (DPhil) -- Faculty of Science, Mathematical Statistics, 2019
- Full Text:
- Date Issued: 2019-12
- Authors: Mlambo, Farai Fredric
- Date: 2019-12
- Subjects: Wavelets (Mathematics) , Finance -- Mathematical models , Economic forecasting
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10948/49930 , vital:41861
- Description: Cycles - their nature in existence, their implications on human-kind and the study thereof have sparked some important philosophical debates since the very pre-historic days. Notable contributions by famous, genius philosophers, mathematicians, historians and economists such as Pareto, Deulofeu, Danielewski, Kuznets, Kondratiev, Elliot and many others in itself shows how cycles and their study have been deemed important, through the history and process of scientific and philosophical inquiry. Particularly, the explication of Business, Economic and Financial cycles have seen some significant research and policy attention. Nevertheless, most of the methodologies employed in this space are either purely empirical in nature, time series based or the so-called Regime-Switching Markov model popularized in Economics by James Hamilton. In this work, we develop a Statistical, non-linear model fit based on circle geometry which is applicable for the dating of cycles. This study proposes a scalable, smooth and differentiable quarter-circular wavelet basis for the smoothing and dating of business, economic and financial cycles. The dating then necessitates the forecasting of the cyclical patterns in the evolution of business, economic and financial time series. The practical significance of dating and forecasting business and financial cycles cannot be over-emphasized. The use of wavelet decomposition in explaining cycles can be seen as an critical contribution of spectral methods of statistical modelling to finance and economic policy at large. Being a relatively new method, wavelet analysis has seen some great contribution in geophysical modelling. This study endeavours to widen the use and application of frequency-time decomposition to the economic and financial space. Wavelets are localized in both time and frequency, such that there is no loss of the time resolution. The importance of time resolution in dating of cycles is another motivation behind using wavelets. Moreover, the preservation of time resolution in wavelet analysis is a fundamental strength employed in the dating of cycles. , Thesis (DPhil) -- Faculty of Science, Mathematical Statistics, 2019
- Full Text:
- Date Issued: 2019-12
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