Genotypic and phenotypic characterization of enterococci from cow dung and environmental water sources in three selected dairy farms in Amathole District
- Authors: Tanih, Godfred Ngu
- Date: 2016
- Subjects: Enterobacteriaceae Water -- Microbiology Enterococcus faecalis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10353/2348 , vital:27755
- Description: Enterococcus species are integral members of the gastrointestinal microfloral of humans, animals, birds, as well as insects. Their presence in water and food has been greatly associated with faecal contamination. This study was aimed at evaluating the incidence of Enterococcus species in cow dung and environmental water sources in three commercial dairy farms. In addition, their antibiotic profiles were determined as well as resistance and virulence genes. Furthermore, the genetic relatedness of the isolates was determined by molecular typing method (RAPD PCR). Three hundred and thirty four water and faecal samples consisting of 117, 116 and 101 were collected from Seven Star Middle Drift and Fort Hare Dairy trusts respectively. Of the 334 samples collected, 289 were of faecal origin and 45 from water sources within the farms. All samples were screened for enterococci using culture base growth media and molecular methods targeting the tuf gene. Speciation was done using species-specific primers and the incidences of various species within the farms determined. Furthermore resistance to antibiotics and multidrug-resistant phenotypes were established using the disk diffusion method. Genes coding for virulence and resistance were also determined. From the samples collected, 313 (289 faecal and 24 water) presumptive enteroccocci were isolated, 305 of 313 (97.45 percent) were confirmed as Enterococcus of which 239 of 305 (78.38 percent) were identified as E. hirae, 15 of 305 (4.92 percent) as E. faecium, 12/305 (3.93 percent) as E. durans, 6 of 305 (1.97 percent) as E. faecalis and 33 of 305 (10.82 percent) were unidentified. Out of the five virulence genes that were targeted in the study only gelE (71.80 percent of 219/305) and ace (27.2 percent 83/305) were present in the isolates. Phenotypic resistance to antibiotics was observed is in all twelve antibiotics tested with multidrug resistance phenotypes detected in some enterococcal isolates most predominant in Seven Star and Middledrift dairy trust. Finally RAPD profiles of the isolates showed high relatedness between the strains from water and cow dung sources in all three commercial dairy farms suggesting possible contamination from cow dung to the water sources or vice versa.
- Full Text:
- Date Issued: 2016
- Authors: Tanih, Godfred Ngu
- Date: 2016
- Subjects: Enterobacteriaceae Water -- Microbiology Enterococcus faecalis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10353/2348 , vital:27755
- Description: Enterococcus species are integral members of the gastrointestinal microfloral of humans, animals, birds, as well as insects. Their presence in water and food has been greatly associated with faecal contamination. This study was aimed at evaluating the incidence of Enterococcus species in cow dung and environmental water sources in three commercial dairy farms. In addition, their antibiotic profiles were determined as well as resistance and virulence genes. Furthermore, the genetic relatedness of the isolates was determined by molecular typing method (RAPD PCR). Three hundred and thirty four water and faecal samples consisting of 117, 116 and 101 were collected from Seven Star Middle Drift and Fort Hare Dairy trusts respectively. Of the 334 samples collected, 289 were of faecal origin and 45 from water sources within the farms. All samples were screened for enterococci using culture base growth media and molecular methods targeting the tuf gene. Speciation was done using species-specific primers and the incidences of various species within the farms determined. Furthermore resistance to antibiotics and multidrug-resistant phenotypes were established using the disk diffusion method. Genes coding for virulence and resistance were also determined. From the samples collected, 313 (289 faecal and 24 water) presumptive enteroccocci were isolated, 305 of 313 (97.45 percent) were confirmed as Enterococcus of which 239 of 305 (78.38 percent) were identified as E. hirae, 15 of 305 (4.92 percent) as E. faecium, 12/305 (3.93 percent) as E. durans, 6 of 305 (1.97 percent) as E. faecalis and 33 of 305 (10.82 percent) were unidentified. Out of the five virulence genes that were targeted in the study only gelE (71.80 percent of 219/305) and ace (27.2 percent 83/305) were present in the isolates. Phenotypic resistance to antibiotics was observed is in all twelve antibiotics tested with multidrug resistance phenotypes detected in some enterococcal isolates most predominant in Seven Star and Middledrift dairy trust. Finally RAPD profiles of the isolates showed high relatedness between the strains from water and cow dung sources in all three commercial dairy farms suggesting possible contamination from cow dung to the water sources or vice versa.
- Full Text:
- Date Issued: 2016
The woman who accused Zwelinzima Vavi of rape :a media analysis of eight South African newspapers
- Authors: Timse, Tabelo Veronica
- Date: 2016
- Subjects: Rape -- South Africa -- Case studies Sexual abuse victims -- South Africa , Mass media criticism
- Language: English
- Type: Thesis , Masters , MA
- Identifier: http://hdl.handle.net/10948/45311 , vital:38569
- Description: The focal point of this study is to examine the print and online media representations of Jacqueline Phooko,a woman who accused former Cosatu General Secretary Zwelinzima Vavi of rape. Data for this study was obtained from eight South African newspapers and their websites. The study investigates whether the articles under review, including commentary and discussion online, focused on the incident itself or on the political landscape of South Africa. A content analysis was used to examine the data revelaling that Phooko was underrepresented and that most articles focused on Vavi’s political career. The research will use a feminist perspective to show that Phooko was under-represented in the media, in comparison to Vavi and his supporters who gained greater coverage, specifically in a political context. The significance of the findings is that although there are some strides achieved to have more women voices in the media however women are still under-represented.
- Full Text:
- Date Issued: 2016
- Authors: Timse, Tabelo Veronica
- Date: 2016
- Subjects: Rape -- South Africa -- Case studies Sexual abuse victims -- South Africa , Mass media criticism
- Language: English
- Type: Thesis , Masters , MA
- Identifier: http://hdl.handle.net/10948/45311 , vital:38569
- Description: The focal point of this study is to examine the print and online media representations of Jacqueline Phooko,a woman who accused former Cosatu General Secretary Zwelinzima Vavi of rape. Data for this study was obtained from eight South African newspapers and their websites. The study investigates whether the articles under review, including commentary and discussion online, focused on the incident itself or on the political landscape of South Africa. A content analysis was used to examine the data revelaling that Phooko was underrepresented and that most articles focused on Vavi’s political career. The research will use a feminist perspective to show that Phooko was under-represented in the media, in comparison to Vavi and his supporters who gained greater coverage, specifically in a political context. The significance of the findings is that although there are some strides achieved to have more women voices in the media however women are still under-represented.
- Full Text:
- Date Issued: 2016
The dynamics of police regulation of sexual abuse of children in South Africa: the case of Grahamstown, Eastern Cape
- Authors: Van Blerk, Natasha
- Date: 2016
- Language: English
- Type: Thesis , Masters , MSocSc
- Identifier: http://hdl.handle.net/10962/3828 , vital:20546
- Description: This thesis investigates the current legislation and police protocols set in South Africa, specifically regarding their adequacy in protecting the country’s children from sexual abuse. It focuses on relevant legislative provisions and protocols, on sexual abuse of children and on an empirical study conducted amongst a variety of officials who represent the South African legislation at different levels. Trends, developments and problems are analysed and brought forward to raise an awareness on the severity of the issue of child sexual abuse. In addition, this thesis explores how the diversity within the community of Grahamstown, South Africa, should be considered to a higher degree in the legislation. There is a clear indication of a prevalent patriarchal hierarchy within the community which, in reality, makes women and children more vulnerable to sexual abuse. The methods used in this thesis involves purposive sampling, which led to one on one interviews between the researcher and participant. Thisthesis concludes with confirmation of the hypothesis whereby the South African legislation is not adequately protecting the rights of children in regards to sexual abuse. However, to fully adapt the legislation and make it as versatile and as effective the State hopes it to be, it is necessary to understand the society’s perception on women and children and to rectify it. As difficult as this may sound, it all begins with a strong and influential government.
- Full Text:
- Date Issued: 2016
- Authors: Van Blerk, Natasha
- Date: 2016
- Language: English
- Type: Thesis , Masters , MSocSc
- Identifier: http://hdl.handle.net/10962/3828 , vital:20546
- Description: This thesis investigates the current legislation and police protocols set in South Africa, specifically regarding their adequacy in protecting the country’s children from sexual abuse. It focuses on relevant legislative provisions and protocols, on sexual abuse of children and on an empirical study conducted amongst a variety of officials who represent the South African legislation at different levels. Trends, developments and problems are analysed and brought forward to raise an awareness on the severity of the issue of child sexual abuse. In addition, this thesis explores how the diversity within the community of Grahamstown, South Africa, should be considered to a higher degree in the legislation. There is a clear indication of a prevalent patriarchal hierarchy within the community which, in reality, makes women and children more vulnerable to sexual abuse. The methods used in this thesis involves purposive sampling, which led to one on one interviews between the researcher and participant. Thisthesis concludes with confirmation of the hypothesis whereby the South African legislation is not adequately protecting the rights of children in regards to sexual abuse. However, to fully adapt the legislation and make it as versatile and as effective the State hopes it to be, it is necessary to understand the society’s perception on women and children and to rectify it. As difficult as this may sound, it all begins with a strong and influential government.
- Full Text:
- Date Issued: 2016
Professional behaviour among nursing students at a college in the Eastern Cape
- Authors: Magopeni, Sibongile Nomvuyo
- Date: 2016
- Subjects: Nursing students -- South Africa -- Eastern Cape Nursing -- Study and teaching -- South Africa -- Eastern Cape Nursing -- Psychological aspects
- Language: English
- Type: Thesis , Masters , MCur
- Identifier: http://hdl.handle.net/10353/2566 , vital:27896
- Description: The focus of the study was to explore and describe reasons for poor professional behaviour among nursing students at a public nursing college in the Eastern Cape. The objectives of the study were to explore and describe the reasons for poor professional behaviour among nursing students and to describe strategies to improve poor professional behaviour. The study has significance for the college management, staff, nursing students, registered nurses and everyone involved in professional development of nursing students. The population for this study consisted of third-year nursing students following the four-year comprehensive basic course for registration leading to the Diploma in Nursing (General, Community & Psychiatry) and Midwifery at a public nursing college. The research questions were: What do you understand by professional behaviour? What are the reasons for poor professional behaviour among nursing students? What could be done to improve professionalism among college nursing students? A qualitative, explorative, descriptive and contextual design was used as a framework for the study. Permission to conduct the study was obtained from the University of Fort Hare ethics committee and other relevant authorities as indicated in the study. Ethical principles were maintained and informed consent obtained. Data collection was done using focus groups and an audiotape with a purposefully sampling of 30 third-year nursing students at the public college of nursing. Data were analysed using Tesch’s method of analysis for qualitative research. Three major themes emerged: students’ understanding of professional behaviour, reasons for poor professional behaviour and methods to improve poor professional behaviour. It was concluded that poor professional behaviour has an effect on professionalism and it should be addressed and corrected for protecting the professional image. Recommendations: Policies regarding inappropriate professional behaviour at the college should be in place and easily accessible to every staff member and nursing student. Department of Health should conduct reflective courses and seminars on professionalism and these should begin at the same time as the academic programme.
- Full Text:
- Date Issued: 2016
- Authors: Magopeni, Sibongile Nomvuyo
- Date: 2016
- Subjects: Nursing students -- South Africa -- Eastern Cape Nursing -- Study and teaching -- South Africa -- Eastern Cape Nursing -- Psychological aspects
- Language: English
- Type: Thesis , Masters , MCur
- Identifier: http://hdl.handle.net/10353/2566 , vital:27896
- Description: The focus of the study was to explore and describe reasons for poor professional behaviour among nursing students at a public nursing college in the Eastern Cape. The objectives of the study were to explore and describe the reasons for poor professional behaviour among nursing students and to describe strategies to improve poor professional behaviour. The study has significance for the college management, staff, nursing students, registered nurses and everyone involved in professional development of nursing students. The population for this study consisted of third-year nursing students following the four-year comprehensive basic course for registration leading to the Diploma in Nursing (General, Community & Psychiatry) and Midwifery at a public nursing college. The research questions were: What do you understand by professional behaviour? What are the reasons for poor professional behaviour among nursing students? What could be done to improve professionalism among college nursing students? A qualitative, explorative, descriptive and contextual design was used as a framework for the study. Permission to conduct the study was obtained from the University of Fort Hare ethics committee and other relevant authorities as indicated in the study. Ethical principles were maintained and informed consent obtained. Data collection was done using focus groups and an audiotape with a purposefully sampling of 30 third-year nursing students at the public college of nursing. Data were analysed using Tesch’s method of analysis for qualitative research. Three major themes emerged: students’ understanding of professional behaviour, reasons for poor professional behaviour and methods to improve poor professional behaviour. It was concluded that poor professional behaviour has an effect on professionalism and it should be addressed and corrected for protecting the professional image. Recommendations: Policies regarding inappropriate professional behaviour at the college should be in place and easily accessible to every staff member and nursing student. Department of Health should conduct reflective courses and seminars on professionalism and these should begin at the same time as the academic programme.
- Full Text:
- Date Issued: 2016
Potential benefits and experienced challenges of small household biogas-digesters for rural households
- Authors: Langley, Kyle Anthony
- Date: 2016
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4789 , http://hdl.handle.net/10962/d1021268
- Description: Access to renewable energy supplies is a critical foundation for sustainable development and poverty alleviation. Anaerobic biogas-digesters also referred to as bio-digesters, have been identified as one of the leading technologies with regards to assisting in improving energy access for remote rural areas that still remain dependent upon biomass usage. This thesis assesses the potential feasibility of bio-digesters for rural households in South Africa by focusing on the experiences of a remote and rural community in Eastern Cape. A standardised survey was used to capture household details and energy use patterns of households with 180 interviews being conducted. Field observations were also conducted on the five bio-digesters installed in the community over a three month period. Despite the predominance of electrification in the community, households were heavily reliant upon biomass in the form of fuelwood and cattle dung to supplement their energy needs. Households supplemented their energy usage with alternative energy sources such as LPG gas and paraffin, especially during periods when electricity was unavailable or deemed too expensive. Initial knowledge of bio-digester technology in the community was non-existent, however with the installation of bio-digesters within the targeted villages, social learning was observed. Despite low temperatures bio-digesters continued to function throughout the study period, though malfunctions did occur and gas production did not reach optimal levels. Primary challenges encountered were the lack of financial subsidies for wide-spread adoption; the limited technical capacity of the community to conduct repairs and minimal gas production due to a build-up of ligneous materials within the gas chamber of the bio-digesters. Bio-digesters were found to provide significant benefits for households and further studies into maximising their effectiveness for rural South African households are recommended.
- Full Text:
- Date Issued: 2016
- Authors: Langley, Kyle Anthony
- Date: 2016
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4789 , http://hdl.handle.net/10962/d1021268
- Description: Access to renewable energy supplies is a critical foundation for sustainable development and poverty alleviation. Anaerobic biogas-digesters also referred to as bio-digesters, have been identified as one of the leading technologies with regards to assisting in improving energy access for remote rural areas that still remain dependent upon biomass usage. This thesis assesses the potential feasibility of bio-digesters for rural households in South Africa by focusing on the experiences of a remote and rural community in Eastern Cape. A standardised survey was used to capture household details and energy use patterns of households with 180 interviews being conducted. Field observations were also conducted on the five bio-digesters installed in the community over a three month period. Despite the predominance of electrification in the community, households were heavily reliant upon biomass in the form of fuelwood and cattle dung to supplement their energy needs. Households supplemented their energy usage with alternative energy sources such as LPG gas and paraffin, especially during periods when electricity was unavailable or deemed too expensive. Initial knowledge of bio-digester technology in the community was non-existent, however with the installation of bio-digesters within the targeted villages, social learning was observed. Despite low temperatures bio-digesters continued to function throughout the study period, though malfunctions did occur and gas production did not reach optimal levels. Primary challenges encountered were the lack of financial subsidies for wide-spread adoption; the limited technical capacity of the community to conduct repairs and minimal gas production due to a build-up of ligneous materials within the gas chamber of the bio-digesters. Bio-digesters were found to provide significant benefits for households and further studies into maximising their effectiveness for rural South African households are recommended.
- Full Text:
- Date Issued: 2016
The phytogeography of Southern Mistbelt Forests of the Eastern Cape, South Africa
- Authors: Matiwane, Aviwe
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/3224 , vital:20393
- Description: In the Eastern Cape, a moisture gradient (from west to east) exists along the Escarpment where patches of Southern Mistbelt Forests (SMF) occur. There is a notable profusion of plants in these forests, but the factors that drive plant species composition and abundance in these patches is poorly understood and such knowledge is critical if we are to address or mitigate the problems imposed by global change. Many of our ideas on plant community assembly are based on the premise that species differ in their environmental requirements for successful regeneration, especially when young. The aims of this study were to document the floristic diversity of poorly known patches of Southern Mistbelt Forests in the Eastern Cape and identify the environmental factors that influence plant community composition in these forest patches. Twenty six forest patches across the Eastern Cape were sampled. In each forest 400m2 circular plots were constructed. The diameter at breast height and stem counts for the tree species was taken and the % cover of the herbaceous species was recorded. General collections were also made to supplement the plot data in order to obtain a comprehensive flora for each forest patch. All sampling was done during the summer season of 2013 and 2014. Using plot data, Hierarchal Cluster Analysis and Multidimensional Scaling Analysis were done to compare similarities between patches. Plots from the same forest patch clustered which indicated that the species composition in each forest patch was unique. However, this pattern went down when only tree species were considered. Plant diversity also varied between patches; with those located in the east being generally more diverse than those in the west are. Clustering patterns in fragmented communities and differences in species diversity indicate evidence of species “nestedness”. Analysis of nestedness indicated that these forest patches were significantly nested. To identify which environmental variables might be correlated with both species diversity and nestedness, twelve environmental variables was selected for analysis using Canonical Correspondence Analysis and Principal Component Analysis. Results show that Mean Annual Precipitation, Mean Annual Potential Evapotranspiration, and percentage of Organic Matter of the soil were most strongly correlated with the patterns of diversity observed in these forest patches. Regression analysis indicated that Mean Annual Precipitation accounted for most of the variation in species diversity, especially for the herbaceous species. The herbaceous species thus show a greater sensitivity to “climate filtering” as a consequence of rainfall gradients. With the implementation of suitable monitoring programs, changes in abundance or even local extinction of these species can act as an early warning indicator of the possible long-term effects of climate change on forest communities.
- Full Text:
- Date Issued: 2016
- Authors: Matiwane, Aviwe
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/3224 , vital:20393
- Description: In the Eastern Cape, a moisture gradient (from west to east) exists along the Escarpment where patches of Southern Mistbelt Forests (SMF) occur. There is a notable profusion of plants in these forests, but the factors that drive plant species composition and abundance in these patches is poorly understood and such knowledge is critical if we are to address or mitigate the problems imposed by global change. Many of our ideas on plant community assembly are based on the premise that species differ in their environmental requirements for successful regeneration, especially when young. The aims of this study were to document the floristic diversity of poorly known patches of Southern Mistbelt Forests in the Eastern Cape and identify the environmental factors that influence plant community composition in these forest patches. Twenty six forest patches across the Eastern Cape were sampled. In each forest 400m2 circular plots were constructed. The diameter at breast height and stem counts for the tree species was taken and the % cover of the herbaceous species was recorded. General collections were also made to supplement the plot data in order to obtain a comprehensive flora for each forest patch. All sampling was done during the summer season of 2013 and 2014. Using plot data, Hierarchal Cluster Analysis and Multidimensional Scaling Analysis were done to compare similarities between patches. Plots from the same forest patch clustered which indicated that the species composition in each forest patch was unique. However, this pattern went down when only tree species were considered. Plant diversity also varied between patches; with those located in the east being generally more diverse than those in the west are. Clustering patterns in fragmented communities and differences in species diversity indicate evidence of species “nestedness”. Analysis of nestedness indicated that these forest patches were significantly nested. To identify which environmental variables might be correlated with both species diversity and nestedness, twelve environmental variables was selected for analysis using Canonical Correspondence Analysis and Principal Component Analysis. Results show that Mean Annual Precipitation, Mean Annual Potential Evapotranspiration, and percentage of Organic Matter of the soil were most strongly correlated with the patterns of diversity observed in these forest patches. Regression analysis indicated that Mean Annual Precipitation accounted for most of the variation in species diversity, especially for the herbaceous species. The herbaceous species thus show a greater sensitivity to “climate filtering” as a consequence of rainfall gradients. With the implementation of suitable monitoring programs, changes in abundance or even local extinction of these species can act as an early warning indicator of the possible long-term effects of climate change on forest communities.
- Full Text:
- Date Issued: 2016
Investigation of α-aryl substituted 3-indolylethanones as potential antiplasmodial agents
- Authors: Svogie, Archibald Lesley
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/55487 , vital:26704
- Description: According to the World Health Organisation (WHO), deaths attributed to Plasmodium falciparum exceeded 584 000 in 2013, with 198 million new cases of malaria being reported. One contributing factor to these alarming figures is the emergence of drug resistance against available antimalarial agents. Therefore, there is a pressing need to develop new therapeutic antimalarial drugs with novel mechanisms of action in order to curb the increasing spread of malaria. The indole scaffold is often associated with biologically active compounds, recently exemplified by the antimalarial agent NITD609, which is currently in phase 1 clinical trials. Based on the biological evaluation of a small series of indolyl-3-amides and esters which showed moderate antimalarial activity, coupled to significant toxicity, we were prompted to investigate the synthesis of a series of indolyl-3-ethanone-α-amines (3.37 and 3.41), ethers (3.39 and 3.44) and thioethers (3.42, 3.43, 3.40, 3.45 – 3.73), where the carbonyl moiety and respective heteroatom were separated by a methine spacer. We further investigated these compounds for in vitro biological activity against P. falciparum and a human HeLa cell line. Our study explored the synthetic pathway of a three-step procedure toward our target compounds, with the initial Friedel-Crafts acetylation of indole, followed by α-bromination of the respective 3-acetylindoles. Finally, the halogen of the α-bromo ketone was substituted with an appropriate nucleophile, to yield our desired compounds. Various reagents were explored to optimise the nucleophilic displacement step, including potassium carbonate and various silver containing compounds. While many of the silver salts were found to assist in nucleophilic substitution, none were superior to the addition of potassium carbonate. The majority of compounds, chiefly the thioethers, displayed promising antimalarial activity, against the chloroquine sensitive 3D7 P. falciparum strain, with two thioethers in particular (3.54 and 3.65) inhibiting P. falciparum in the low nanomolar range. Additionally, active compounds were generally found to be non-toxic against HeLa cells, indicating that indolyl-3-thioethers are selective for the malaria parasite. These findings allowed us to begin hypothesising a structure activity relationship of this class, as well as elucidating the possible pharmacophore. In a speculative attempt to uncover the possible mechanism of action of these active compounds, in silico docking studies were conducted against Staphylococcus aureus HPPK (PDB ID: 4CRJ), which is an enzyme that immediately precedes DHPS in the microbial folate biosynthesis. Inhibition of folate biosynthesis is a validated selective antimalarial pathway and HPPK also exists in P. falciparum. Results from these docking studies suggested that our inhibitors bound well in the HPPK ATP pocket and were supportive of our hypothesized structure activity relationship.
- Full Text:
- Date Issued: 2016
- Authors: Svogie, Archibald Lesley
- Date: 2016
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/55487 , vital:26704
- Description: According to the World Health Organisation (WHO), deaths attributed to Plasmodium falciparum exceeded 584 000 in 2013, with 198 million new cases of malaria being reported. One contributing factor to these alarming figures is the emergence of drug resistance against available antimalarial agents. Therefore, there is a pressing need to develop new therapeutic antimalarial drugs with novel mechanisms of action in order to curb the increasing spread of malaria. The indole scaffold is often associated with biologically active compounds, recently exemplified by the antimalarial agent NITD609, which is currently in phase 1 clinical trials. Based on the biological evaluation of a small series of indolyl-3-amides and esters which showed moderate antimalarial activity, coupled to significant toxicity, we were prompted to investigate the synthesis of a series of indolyl-3-ethanone-α-amines (3.37 and 3.41), ethers (3.39 and 3.44) and thioethers (3.42, 3.43, 3.40, 3.45 – 3.73), where the carbonyl moiety and respective heteroatom were separated by a methine spacer. We further investigated these compounds for in vitro biological activity against P. falciparum and a human HeLa cell line. Our study explored the synthetic pathway of a three-step procedure toward our target compounds, with the initial Friedel-Crafts acetylation of indole, followed by α-bromination of the respective 3-acetylindoles. Finally, the halogen of the α-bromo ketone was substituted with an appropriate nucleophile, to yield our desired compounds. Various reagents were explored to optimise the nucleophilic displacement step, including potassium carbonate and various silver containing compounds. While many of the silver salts were found to assist in nucleophilic substitution, none were superior to the addition of potassium carbonate. The majority of compounds, chiefly the thioethers, displayed promising antimalarial activity, against the chloroquine sensitive 3D7 P. falciparum strain, with two thioethers in particular (3.54 and 3.65) inhibiting P. falciparum in the low nanomolar range. Additionally, active compounds were generally found to be non-toxic against HeLa cells, indicating that indolyl-3-thioethers are selective for the malaria parasite. These findings allowed us to begin hypothesising a structure activity relationship of this class, as well as elucidating the possible pharmacophore. In a speculative attempt to uncover the possible mechanism of action of these active compounds, in silico docking studies were conducted against Staphylococcus aureus HPPK (PDB ID: 4CRJ), which is an enzyme that immediately precedes DHPS in the microbial folate biosynthesis. Inhibition of folate biosynthesis is a validated selective antimalarial pathway and HPPK also exists in P. falciparum. Results from these docking studies suggested that our inhibitors bound well in the HPPK ATP pocket and were supportive of our hypothesized structure activity relationship.
- Full Text:
- Date Issued: 2016
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