Identification of Mycobacterium tuberculosis DnaK substrates – towards inhibiting DnaK as a novel drug target for the treatment of tuberculosis
- Authors: Tonui, Ronald
- Date: 2024-04-05
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/435975 , vital:73217
- Description: Access restricted. Expected release in 2026. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2024
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- Date Issued: 2024-04-05
A model for linking innovation and sustainable growth of immigrant entrepreneurs in the Johannesburg Metropolitan Area, South Africa
- Authors: Mzamo, Ziyanda
- Date: 2022-08
- Subjects: Immigrant business enterprises -- Technological innovations -- South Africa , Business Management -- South Africa , Industrial management -- South Africa
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10353/28828 , vital:75130
- Description: South Africa experienced hard times during the apartheid era. This led to some of the South African nationals seeking solace and hiding in neighbouring African countries. Post 1994, this situation has largely changed. Other African countries have not been as privileged to recover from the political turmoil nations have experienced and have left civilians stranded with no comfort or job security. It is for this reason that immigrants from other African countries track to South Africa for the hope and promise of a better future. While this is the case and hope, South Africa is dealing with its own issues of high unemployment rate, violence and crime, poverty, lack of quality education, drug and substance abuse, unstable political issues and influx of immigrants who have no plans or ways of survival. This makes things even harder for the government to accommodate everyone as the focus and priority is seen to be given to its citizens. Entrepreneurship becomes the most feasible and practical way of survival for the immigrants. Some of these businesses have stood the test of time, are making strides and thriving. Their growth journeys may even be better than those of citizens due to these businesses primarily being characterized by survival tactics. This study was hence conducted to predominantly formulate a model for linking the innovation and sustainable business growth of immigrant entrepreneurs. The secondary objective was to gauge if there is a significant relationship between innovation (incremental, radical, and technological) and sustainable business growth of immigrant entrepreneurs in the Johannesburg Metropolitan Area. A mixed approach was used to achieve these objectives. The population of the study targeted immigrant entrepreneurs from the African continent who are running small and medium (SME) businesses in the Johannesburg Metropolitan area. The data was gathered using semi-structured interviews and a survey. Seventeen (17) interviews were held, and one hundred and two (102) surveys were collected, totalling one hundred and nineteen (119) research study participants. The participants were selected using convenience sampling and snowballing due to the population of immigrant entrepreneurs being unknown in Johannesburg. Descriptive and inferential statistics were applied to analyse the data. The findings revealed that innovation played a major role in sustainable business growth of the immigrant entrepreneurs. The research study showed the typical measures of innovation (incremental, radical and technological) as well as business growth may not be reflective and applicable to the SME space due to the businesses being survival businesses. The research study recommends that development of immigrant entrepreneurship focused programs for coaching, support, funding, and handholding be of absolute government focus. Internal collaborative innovation agendas are key for businesses to balance incremental and radical innovation. This will minimise the reliance on business owners or leadership to drive innovation, but rather, for innovation to be a way of working for all in the business. Growth and sustainability rides on shared innovation as opposed to individually led or an isolated agenda. Education, change management and training of citizens and safety officials is recommended to understand the benefits of immigrant owned businesses as an economic driver and as a point of embracing fellow Africans. This will eliminate the stereotypes that make immigrant entrepreneurs exposed and uncomfortable in their business journeys. , Thesis (DBA) -- Faculty of Management and Commerce, 2022
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- Date Issued: 2022-08
Synthesis and biolgical screening of potential plasmodium falciparum DXR inhibitors
- Authors: Adeyemi, Christiana Modupe
- Date: 2017-04
- Subjects: Plasmodium falciparum , Enzyme inhibitors , Malaria , Antimalarials , Drug development , Malaria -- Chemotherapy , Isopentenoids -- Synthesis , Fosmidomycin , 1-Deoxy-D-xylulose 5-phosphate
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/61790 , vital:28060
- Description: The non-mevalonate isoprenoid pathway, also known as the 1-deoxy-D-xylulose-5- phosphate DXP pathway, is absent in humans, but present in the anopheles mosquito responsible for the transmission of malaria. DXP reductoisomerase - a key enzyme in the DXP pathway in Plasmodium falciparum (PfDXR) has been identified as a target for the design of novel anti-malarial drugs. Fosmidomycin and its acetyl analogue (FR900098) are known to be inhibitors of PfDXR and, in this study, synthetic variations of the fosmidomycin scaffold have led to four series of novel analogues. Particular attention has been centred on the introduction of various substituted benzyl groups in each of these series in order to occupy a recently discovered vacant pocket in the PfDXR active-site and thus enhance ligand-enzyme binding. In the process 160 ligands and precursors have been prepared, no less than 119 of them novel. Fistly, a series of C-benzylated phosphonate esters and phosphonic acids were synthesised, in which the fosmidomycin hydroxamate Mg2+- coordinating moiety was replaced by an amide funtionality and the number of methylene groups in the “hydrophobic patch” between the phosphonate and the hydroxamate moiety was decreased from two to one. Several approaches were explored for this series, the most successful involving reaction of 3- substituted anilines with a-bromo propanoic acid in the presence of the coupling agent 1,1'- carbonyldiimidazole (CDI), followed by Michaelis-Arbuzov phosphonation using triethyl phosphite. Reaction of the resulting chiral phosphonate esters with bromotrimethylsilane gave the corresponding phosphonic acids in good yields. In order to obviate chirality issues, a second series of potential “reverse” fosmidomycin analogues was synthesised by replacing the methylene group adjacent to the the phosphonate moiety with a nitrogen atom. Deprotonation, alkylation and phosphorylation of various amines gave diethyl #-benzylphosphoramidate ester intermediate. Aza-Michael addition of these intermediates, followed by hydrolysis gave the corresponding carboxylic acids which could be reacted with different hydroxylamine hydrochloride derivatives to afford the novel hydroxamic acid derivatives in good yields. Thirdly, a series of a novel #-benzylated phosphoramidate derivatives were prepared as aza- FR900098 analogues. Alkylation of different amines using bromoacetalde-hyde diethylacetal gave a series of N-benzyl-2,2-diethoxyethylamine compounds, which were then elaborated via a futher six steps to afford novel #-benzylated phosphoramidate derivatives. Finally, in order to ensure syn-orientation of the donor atoms in the Mg - coordinating group and, at the same time, introduce conformational constraints in the ligand, the hydrophobic patch and the hydroxamate moiety were replaced by cyclic systems. Several approaches towards the synthesis of such conformationally constrained phosphoramidate analogues from maleic anhydride led to the unexpected isolation of an unprecedented acyclic furfuryl compound, and 1H NMR and DFT-level theoretical studies have been initiated to explore the reaction sequence. A series of #-benzylated phosphoramidate derivatives containing dihydroxy aromatic rings (as the conformationally constrained groups) to replace the hydroxamate moiety, were successfully obtained in six steps from the starting material, 3,4-dihydroxylbenzaldehyde. While in vitro assays have been conducted on all of the synthesised compounds, and some of the ligands show promising anti-malarial inhibitory activity - most especially the conformationally constrained cyclic #-benzylated phosphoramidate series. Interestingly, a number of these compounds has also shown activity against T.brucei - the causative agent of sleeping sickness. In silico docking studies of selected compounds has revealed the capacity of some of the ligands to bind effectively in the PfDXR active-site with the newly introduced benzyl group occupying the adjacent vacant pocket. The physico-chemical properties of these ligands were also explored in order to predict the oral-bioavailability. Most of the ligands obeyed the Lipinski rule of 5, while QSAR methods have been used in an attempt to correlate structural variations and calculated molecular properties with the bioassay data. , Thesis (PhD) -- Faculty of Science, Chemistry, 2017
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- Date Issued: 2017-04