Synthesis and structure-activity relationship studies of 1,4-naphthoquinone derivatives as potential anti-trypanosomal agents
- Authors: Chakaingesu, Chikomborero
- Date: 2014
- Subjects: African trypanosomiasis , Trypanosoma brucei , Naphthoquinone , Protozoan diseases , Drugs -- Structure-activity relationships , Millennium Development Goals
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3873 , http://hdl.handle.net/10962/d1020959
- Description: Human African Trypanosomiasis (HAT) is an infectious, vector-borne protozoal disease which is amongst the so-called neglected diseases. In 2000, at a summit of the United Nations, eight Millennium Development Goals (MDGs) were set, to be achieved by 2015. MDG 6 states “to combat HIV/AIDS, malaria & other diseases”. With just under 2 years to go before the end of 2015, HAT is still thriving in developing countries. The drugs currently used for the treatment of HAT are in short supply, have severe side effects and those used to treat late stages of the disease are very difficult to administer. The aforementioned challenges call for research into this neglected disease in order to develop new, safe and easy-to-use medicines. Naphthoquinones are a class of compounds shown to possess anti-parasitic activity, amongst a variety of other biological activities, and therefore this pharmacophore was selected for this study. The purpose of this study was to synthesise derivatives of 2,3-dichloro-1,4- naphthoquinone to be tested for anti-trypanosomal activity and thereafter conduct structureactivity relationship studies. A series of reactions were carried out using thiophenol, phenol and aniline nucleophiles to synthesise thioether (-S-), ether (-O-) and amino (-NH-) derivatives of 2,3-dichloro-1,4-naphthoquinone with various halogen or methyl substituents. Purification of the products was carried out by recrystallisation. Nuclear magnetic resonance (NMR), infra-red (IR) and high pressure liquid chromatography coupled to an electro-spray ionisation mass spectrometer (HPLC-ESI-MS) were the analytical methods used for structural confirmation of the products. There were eighteen 1,4-naphthoquinone derivatives that were successfully synthesised using ethanolic solutions. Unfortunately, attempts to synthesise 1,4-naphthoquinones in reactions involving 2-(trifluoro-methyl)aniline and 2-isopropyl-5-methylphenol were unsuccessful, presumably due to steric hindrance by the bulky ortho-substituents. Although the aims of the synthetic procedures were to obtain both mono- and disubstituted products by nucleophilic displacement of the chlorine atom(s) of 2,3-dichloro-1,4- naphthoquinone, only monosubstituted products were obtained from substitution with aniline and phenol nucleophiles. Thiol nucleophiles, however, selectively yielded disubstituted products only. Synthesised naphthoquinone derivatives were tested against Trypanosoma brucei and calculation of the EC₅₀ values from the obtained dose-response curves was carried out using the four parametric equation. All the 1,4-naphthoquinones showed a degree of potency, except compounds 1b, 3c and 3e, which had little or lack of potency. Structure-activity relationship studies (SARs and QSARs) were carried out to determine which structural features or functional group substituents of the naphthoquinone derivatives contribute or take away from the desired anti-trypanosomal activity. It was found that compounds with the best in vitro anti-trypanosomal potencies in the series of analogous 1,4-naphthoquinone derivatives had EC₅₀ values in the range 2.137 to 2.884 μM. The most potent compound in the series was 2-chloro-3-(4-(trifluoromethyl)phenylamino)-1,4- naphthoquinone 1e; but it was 142-fold less potent than the reference standard of melarsoprol.
- Full Text:
- Date Issued: 2014
- Authors: Chakaingesu, Chikomborero
- Date: 2014
- Subjects: African trypanosomiasis , Trypanosoma brucei , Naphthoquinone , Protozoan diseases , Drugs -- Structure-activity relationships , Millennium Development Goals
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3873 , http://hdl.handle.net/10962/d1020959
- Description: Human African Trypanosomiasis (HAT) is an infectious, vector-borne protozoal disease which is amongst the so-called neglected diseases. In 2000, at a summit of the United Nations, eight Millennium Development Goals (MDGs) were set, to be achieved by 2015. MDG 6 states “to combat HIV/AIDS, malaria & other diseases”. With just under 2 years to go before the end of 2015, HAT is still thriving in developing countries. The drugs currently used for the treatment of HAT are in short supply, have severe side effects and those used to treat late stages of the disease are very difficult to administer. The aforementioned challenges call for research into this neglected disease in order to develop new, safe and easy-to-use medicines. Naphthoquinones are a class of compounds shown to possess anti-parasitic activity, amongst a variety of other biological activities, and therefore this pharmacophore was selected for this study. The purpose of this study was to synthesise derivatives of 2,3-dichloro-1,4- naphthoquinone to be tested for anti-trypanosomal activity and thereafter conduct structureactivity relationship studies. A series of reactions were carried out using thiophenol, phenol and aniline nucleophiles to synthesise thioether (-S-), ether (-O-) and amino (-NH-) derivatives of 2,3-dichloro-1,4-naphthoquinone with various halogen or methyl substituents. Purification of the products was carried out by recrystallisation. Nuclear magnetic resonance (NMR), infra-red (IR) and high pressure liquid chromatography coupled to an electro-spray ionisation mass spectrometer (HPLC-ESI-MS) were the analytical methods used for structural confirmation of the products. There were eighteen 1,4-naphthoquinone derivatives that were successfully synthesised using ethanolic solutions. Unfortunately, attempts to synthesise 1,4-naphthoquinones in reactions involving 2-(trifluoro-methyl)aniline and 2-isopropyl-5-methylphenol were unsuccessful, presumably due to steric hindrance by the bulky ortho-substituents. Although the aims of the synthetic procedures were to obtain both mono- and disubstituted products by nucleophilic displacement of the chlorine atom(s) of 2,3-dichloro-1,4- naphthoquinone, only monosubstituted products were obtained from substitution with aniline and phenol nucleophiles. Thiol nucleophiles, however, selectively yielded disubstituted products only. Synthesised naphthoquinone derivatives were tested against Trypanosoma brucei and calculation of the EC₅₀ values from the obtained dose-response curves was carried out using the four parametric equation. All the 1,4-naphthoquinones showed a degree of potency, except compounds 1b, 3c and 3e, which had little or lack of potency. Structure-activity relationship studies (SARs and QSARs) were carried out to determine which structural features or functional group substituents of the naphthoquinone derivatives contribute or take away from the desired anti-trypanosomal activity. It was found that compounds with the best in vitro anti-trypanosomal potencies in the series of analogous 1,4-naphthoquinone derivatives had EC₅₀ values in the range 2.137 to 2.884 μM. The most potent compound in the series was 2-chloro-3-(4-(trifluoromethyl)phenylamino)-1,4- naphthoquinone 1e; but it was 142-fold less potent than the reference standard of melarsoprol.
- Full Text:
- Date Issued: 2014
Propagation and stress physiology of selected Subtropical Thicket species : towards increasing biodiversity at rehabilitation sites
- Authors: Louw, Merika
- Date: 2012
- Subjects: Biodiversity conservation , Plant physiology , Stress (Physiology) , Plant propagation
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10758 , http://hdl.handle.net/10948/d1021115
- Description: Sundays Thicket and Spekboomveld vegetation in the Eastern Cape have experienced intensive and extensive degradation due to over-browsing by domestic stock. The Subtropical Thicket Restoration Project aims to take advantage of the high carbon sequestration potential of Portulacaria afra (Spekboom) and other Thicket species, to rehabilitate degraded Thicket by restoring biodiversity and ecosystem services, create job opportunities and socio-economic upliftment in local communities, and promote the trade of carbon credits generated by planting and „farming‟ with Spekboom truncheons, rather than domestic stock. Plant material (seeds and length of stem) was sourced from the farm Krompoort, outside Uitenhage in the Eastern Cape. The effectiveness of four different rooting media i.e. plain pool filter sand and 1:1 mixtures of pool filter sand with perlite, potting soil and Thicket soil, on the rooting of ten Thicket species, were tested. Species with the greatest percentage strike and mean root length on stem cuttings were succulent species, Crassula ovata (84 percent strike) and Portulacaria afra (97 percent), as was expected. The application of rooting hormone Seradix© No. 3 did not significantly promote cutting strike or increase mean root length in C. ovata and P. afra. Woody canopy shrub species with the greatest cutting strike and mean root length, overall, were Rhigozum obovatum (24 percent), Lycium cinereum and L. oxycarpum (21 percent), and Searsia longispina (19 percent). These species, as well as Grewia robusta (4 percent), are considered „easy-to-root‟ species, or of sufficient functional value in terms of their spinescence, flower and fruit production, and soil-binding capabilities. Very low percentage strike (<1 percent) and mean root length were achieved in Azima tetracantha, Carissa bispinosa and Gymnosporia polyacantha subsp. polyacantha. These species are considered unsuitable for propagation for rehabilitation purposes. Crassula ovata, L. cinereum, L. oxycarpum, P. afra and S. longispina cuttings produced longer roots when planted in Thicket soil, the same having been found in R. obovatum cuttings planted in perlite. Thicket soil was, therefore, best at promoting cutting strike and root growth in „easy-to-root‟ species. Plain pool filter sand was the only medium in which A. tetracantha, C. bispinosa and G. robusta, cuttings rooted, and perlite the only medium in which G. polyacantha subsp. polyacantha cuttings rooted. Potting soil did not promote significant cutting strike or root growth in any of the species tested. Physiological variables i.e. photosynthetic efficiency (chlorophyll a fluorescence, Fv/Fm) and stomatal conductance (mmol H2O m-2 s-1) were measured for ten Thicket species, including Portulacaria afra. Control plants were watered well once a week, and treatment plants were dried out for 30 days, rewatered on the 30th day and their recovery from drought stress monitored for a further 17 days. Species that responded poorly to drought stress were Gymnosporia buxifolia and Putterlickia pyracantha. In addition to Portulacaria afra, species that showed the fastest recovery and resprout after rewatering, were: Crassula ovata, Ehretia rigida, Grewia robusta, Lycium ferocissimum, Rhigozum obovatum and Searsia longispina. These species produced the smallest decline in volumetric moisture content of soil, and had the lowest decline in photosynthetic efficiency and stomatal conductance during simulated drought. Unlike C. ovata and P. afra, which are CAM or C3-CAM switching species, mortality of transplants will most likely be high, if not total, during transplantation, as this study was done at lower light and temperature, and higher humidity levels than experienced at rehabilitation sites. This study has shown that the reintroduction of propagated woody canopy shrubs and trees into degraded Thicket sites does not appear to be a practical or economical method of actively restoring biodiversity to rehabilitation sites. As woody climax species have been shown to return to sites planted with Spekboom truncheons through „natural regeneration‟ within approximately 50 years, future research efforts should focus on optimising restoration site selection and planting techniques in order to maximize carbon sequestration potential of planted truncheons, which will, in the long term, result in an environment that can support regeneration of the biodiversity to something resembling intact Thicket.
- Full Text:
- Date Issued: 2012
- Authors: Louw, Merika
- Date: 2012
- Subjects: Biodiversity conservation , Plant physiology , Stress (Physiology) , Plant propagation
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10758 , http://hdl.handle.net/10948/d1021115
- Description: Sundays Thicket and Spekboomveld vegetation in the Eastern Cape have experienced intensive and extensive degradation due to over-browsing by domestic stock. The Subtropical Thicket Restoration Project aims to take advantage of the high carbon sequestration potential of Portulacaria afra (Spekboom) and other Thicket species, to rehabilitate degraded Thicket by restoring biodiversity and ecosystem services, create job opportunities and socio-economic upliftment in local communities, and promote the trade of carbon credits generated by planting and „farming‟ with Spekboom truncheons, rather than domestic stock. Plant material (seeds and length of stem) was sourced from the farm Krompoort, outside Uitenhage in the Eastern Cape. The effectiveness of four different rooting media i.e. plain pool filter sand and 1:1 mixtures of pool filter sand with perlite, potting soil and Thicket soil, on the rooting of ten Thicket species, were tested. Species with the greatest percentage strike and mean root length on stem cuttings were succulent species, Crassula ovata (84 percent strike) and Portulacaria afra (97 percent), as was expected. The application of rooting hormone Seradix© No. 3 did not significantly promote cutting strike or increase mean root length in C. ovata and P. afra. Woody canopy shrub species with the greatest cutting strike and mean root length, overall, were Rhigozum obovatum (24 percent), Lycium cinereum and L. oxycarpum (21 percent), and Searsia longispina (19 percent). These species, as well as Grewia robusta (4 percent), are considered „easy-to-root‟ species, or of sufficient functional value in terms of their spinescence, flower and fruit production, and soil-binding capabilities. Very low percentage strike (<1 percent) and mean root length were achieved in Azima tetracantha, Carissa bispinosa and Gymnosporia polyacantha subsp. polyacantha. These species are considered unsuitable for propagation for rehabilitation purposes. Crassula ovata, L. cinereum, L. oxycarpum, P. afra and S. longispina cuttings produced longer roots when planted in Thicket soil, the same having been found in R. obovatum cuttings planted in perlite. Thicket soil was, therefore, best at promoting cutting strike and root growth in „easy-to-root‟ species. Plain pool filter sand was the only medium in which A. tetracantha, C. bispinosa and G. robusta, cuttings rooted, and perlite the only medium in which G. polyacantha subsp. polyacantha cuttings rooted. Potting soil did not promote significant cutting strike or root growth in any of the species tested. Physiological variables i.e. photosynthetic efficiency (chlorophyll a fluorescence, Fv/Fm) and stomatal conductance (mmol H2O m-2 s-1) were measured for ten Thicket species, including Portulacaria afra. Control plants were watered well once a week, and treatment plants were dried out for 30 days, rewatered on the 30th day and their recovery from drought stress monitored for a further 17 days. Species that responded poorly to drought stress were Gymnosporia buxifolia and Putterlickia pyracantha. In addition to Portulacaria afra, species that showed the fastest recovery and resprout after rewatering, were: Crassula ovata, Ehretia rigida, Grewia robusta, Lycium ferocissimum, Rhigozum obovatum and Searsia longispina. These species produced the smallest decline in volumetric moisture content of soil, and had the lowest decline in photosynthetic efficiency and stomatal conductance during simulated drought. Unlike C. ovata and P. afra, which are CAM or C3-CAM switching species, mortality of transplants will most likely be high, if not total, during transplantation, as this study was done at lower light and temperature, and higher humidity levels than experienced at rehabilitation sites. This study has shown that the reintroduction of propagated woody canopy shrubs and trees into degraded Thicket sites does not appear to be a practical or economical method of actively restoring biodiversity to rehabilitation sites. As woody climax species have been shown to return to sites planted with Spekboom truncheons through „natural regeneration‟ within approximately 50 years, future research efforts should focus on optimising restoration site selection and planting techniques in order to maximize carbon sequestration potential of planted truncheons, which will, in the long term, result in an environment that can support regeneration of the biodiversity to something resembling intact Thicket.
- Full Text:
- Date Issued: 2012
- «
- ‹
- 1
- ›
- »