Synthesis, characterisation and biological activity of 2-(methylthiomethyl)anilines, 2-(methylthio)anilines, their Schiff-base derivatives and metal(II) (Co, Ni, Cu) complexes
- Olalekan, Temitope Elizabeth
- Authors: Olalekan, Temitope Elizabeth
- Date: 2013
- Subjects: Aniline , Schiff bases , Ligands , Nuclear magnetic resonance spectroscopy , Chelates , X-ray crystallography , Antimalarials
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4562 , http://hdl.handle.net/10962/d1020868
- Description: A series of 31 sulfur-nitrogen donor ligands and 64 metal(II) complexes have been investigated. The thiomethylated aniline ligands 2–(methylthiomethyl)aniline 2MT and 2–(methylthio)aniline 2MA were synthesized with their substituted derivatives (-Me, -MeO, -Cl, -Br, -NO2) to serve as chelating agents. These ligands behave as bidentate ligands with SN donor group with Co(II), Ni(II) and Cu(II). The Co(II) and Ni(II) complexes have the ML2Cl2 molecular formula while the Cu(II) complexes formed with MLCl2 stoichiometry where L is the bidentate ligand. The ligands and their metal(II) complexes have been characterized by elemental analysis and with spectroscopic techniques. The trend observed in the NMR spectra and IR frequencies of the thiomethylated compounds shows there is a significant difference between the 2MT and 2MA series as a result of sulfur lone pairs extending the conjugation of the aromatic ring in the case of the latter. The effect of the position and electronic nature of ring substituent on the NMR shifts of the amine protons is discussed. The 6- and 5-membered chelate complexes formed by the 2MT and 2MA ligands respectively do not show significant diversity in their spectroscopic properties. From the elemental analysis for the Co(II) and Ni(II) complexes, their compositions reveal 1:2 M:L stoichiometry with 2 chlorine atoms from the respective metal salts. In addition, the spectroscopic data are largely indicative of tetragonally distorted structures for these solid complexes. The X-ray crystallography data reveal the Cu(II) complexes exist as square pyramidal dimers and with long Cu–Cl equitorial bonds fit into the tetragonally distorted octahedral structure. The electrolytic nature of Co(II) and Cu(II) complexes in DMF were found to be similar, they behave as non electrolytes in contrast to Ni(II) complexes which are 1:1 electrolytes. The electronic spectra of these metal(II) complexes were found to be different for both their solid forms and in solutions of DMF and DMSO and this has been discussed. The thiomethylated aniline ligands possess the amine and thioether groups which are present in many known biologically active compounds, hence the biological activity of the ligands and their metal complexes were tested against three strains of bacteria and one fungus. The methoxy-substituted derivatives were found to possess better inhibitory activity and this was similarly reflected in the metal(II) complexes. The activity of the complexes can be said to be in the order, Cu(II) > Co(II) > Ni(II). The Schiff-base derivatives were prepared from the ligands and para-methoxysalicylaldehyde and their Cu(II) complexes were synthesized in order to determine their biological activity. The Schiff-base ligands were found to be less active than their parent ligands. The Cu(II) complexes are not soluble in water, DMSO or DMF, as a result and could not be evaluated for their biological activity. Based on the good results from the antimicrobial evaluation, the antiplasmodial activity of some of the Co(II), Ni(II) and Cu(II) complexes of the thiomethylated ligands against Plasmodium falciparum (FCR-3) was determined. At 50 μM concentration level, the Cu(II) complexes show activity equal or better than the prophylactic chloroquine. The Cu(II) complexes with the methoxy-substituted demonstrated exceptional activity but their Co(II) and Ni(II) analogues did not show any activity. The cytotoxicity of the active Cu(II) complexes at 50 μM concentration was determined against the breast cancer cell line (MDA-MB-231). The compounds destroyed the cancer cell in the range of 28–40%, thus showing their preferred activity against the parasitic cell instead of the cancer cell. The selectivity demonstrated by these compounds have shown them to be potential antimalarial agents and this could be further investigated.
- Full Text:
- Authors: Olalekan, Temitope Elizabeth
- Date: 2013
- Subjects: Aniline , Schiff bases , Ligands , Nuclear magnetic resonance spectroscopy , Chelates , X-ray crystallography , Antimalarials
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4562 , http://hdl.handle.net/10962/d1020868
- Description: A series of 31 sulfur-nitrogen donor ligands and 64 metal(II) complexes have been investigated. The thiomethylated aniline ligands 2–(methylthiomethyl)aniline 2MT and 2–(methylthio)aniline 2MA were synthesized with their substituted derivatives (-Me, -MeO, -Cl, -Br, -NO2) to serve as chelating agents. These ligands behave as bidentate ligands with SN donor group with Co(II), Ni(II) and Cu(II). The Co(II) and Ni(II) complexes have the ML2Cl2 molecular formula while the Cu(II) complexes formed with MLCl2 stoichiometry where L is the bidentate ligand. The ligands and their metal(II) complexes have been characterized by elemental analysis and with spectroscopic techniques. The trend observed in the NMR spectra and IR frequencies of the thiomethylated compounds shows there is a significant difference between the 2MT and 2MA series as a result of sulfur lone pairs extending the conjugation of the aromatic ring in the case of the latter. The effect of the position and electronic nature of ring substituent on the NMR shifts of the amine protons is discussed. The 6- and 5-membered chelate complexes formed by the 2MT and 2MA ligands respectively do not show significant diversity in their spectroscopic properties. From the elemental analysis for the Co(II) and Ni(II) complexes, their compositions reveal 1:2 M:L stoichiometry with 2 chlorine atoms from the respective metal salts. In addition, the spectroscopic data are largely indicative of tetragonally distorted structures for these solid complexes. The X-ray crystallography data reveal the Cu(II) complexes exist as square pyramidal dimers and with long Cu–Cl equitorial bonds fit into the tetragonally distorted octahedral structure. The electrolytic nature of Co(II) and Cu(II) complexes in DMF were found to be similar, they behave as non electrolytes in contrast to Ni(II) complexes which are 1:1 electrolytes. The electronic spectra of these metal(II) complexes were found to be different for both their solid forms and in solutions of DMF and DMSO and this has been discussed. The thiomethylated aniline ligands possess the amine and thioether groups which are present in many known biologically active compounds, hence the biological activity of the ligands and their metal complexes were tested against three strains of bacteria and one fungus. The methoxy-substituted derivatives were found to possess better inhibitory activity and this was similarly reflected in the metal(II) complexes. The activity of the complexes can be said to be in the order, Cu(II) > Co(II) > Ni(II). The Schiff-base derivatives were prepared from the ligands and para-methoxysalicylaldehyde and their Cu(II) complexes were synthesized in order to determine their biological activity. The Schiff-base ligands were found to be less active than their parent ligands. The Cu(II) complexes are not soluble in water, DMSO or DMF, as a result and could not be evaluated for their biological activity. Based on the good results from the antimicrobial evaluation, the antiplasmodial activity of some of the Co(II), Ni(II) and Cu(II) complexes of the thiomethylated ligands against Plasmodium falciparum (FCR-3) was determined. At 50 μM concentration level, the Cu(II) complexes show activity equal or better than the prophylactic chloroquine. The Cu(II) complexes with the methoxy-substituted demonstrated exceptional activity but their Co(II) and Ni(II) analogues did not show any activity. The cytotoxicity of the active Cu(II) complexes at 50 μM concentration was determined against the breast cancer cell line (MDA-MB-231). The compounds destroyed the cancer cell in the range of 28–40%, thus showing their preferred activity against the parasitic cell instead of the cancer cell. The selectivity demonstrated by these compounds have shown them to be potential antimalarial agents and this could be further investigated.
- Full Text:
The isolation, quantification and synthetic modification of antiplasmodial natural products from sargassum heterophyllum
- Authors: Munedzimwe, Tatenda Carol
- Date: 2012
- Subjects: Malaria -- Developing countries -- Prevention , Antimalarials
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3871 , http://hdl.handle.net/10962/d1018252
- Description: Malaria is one of the most deadly parasitic diseases known to man. Although the number of malaria cases reported each year is decreasing, this disease continues to pose health and economic problems mainly in developing countries. Significant progress has been made in the fight against this disease. This includes the discovery and development of potent antimalarial agents. However, the development of resistance to most of these potent antimalarials has made the development of new antiplasmodial agents of paramount importance. Several promising antiplasmodial agents have been found from the marine environment. Amongst these are the tetraprenylated toluquinols from the brown alga: Sargassum heterophyllum. These metabolites have been reported to exhibit a range of antiplasmodial activity; however, the mechanisms by which these compounds bring about their antiplasmodial activity and the pharmacophoric groups responsible for such activity are unknown. Two species of Sargassum algae were encountered during the course of this project. From the investigation of the geographical and seasonal variation of metabolites of S. heterophyllum and S. elegans we established that there were no significant intra and inter site variations amongst metabolite profiles of both species both within and between the sampled seasons. These results enabled us to establish that the collection of both species from three different sites on the eastern coast of South Africa namely; Kenton on Sea, Port Alfred and Noordhoek in autumn, winter or spring would qualitatively yield the same metabolites. A comparison of metabolite profiles of both species also revealed no qualitative differences between metabolites of S. heterophyllum and S. elegans. The quantities of selected prenylated metabolites extracted from S. heterophyllum using four different extraction techniques was also assessed using qNMR as the method of quantification. This led to the identification of optimal extraction techniques and conditions for the extraction of sargahydroquinoic acid (1.38), sargaquinoic aid (1.39) and sargachromenol (2.10) from S. heterophyllum. From this study, the extraction of algae by soxhlet extraction using EtOH as the extraction solvent led to the extraction of the highest quantities of sargahydroquinoic acid. The potential of other extraction techniques such as microwave assisted extraction, to yield high quantities of the selected metabolites were also identified. With gram quantities of sargahydroquinoic acid (1.38) in hand, this compound was modified by oxidation, reduction, acetylation, methylation and cyclization reactions to yield nine derivatives. The derivatives and four naturally occurring prenylated toluquinols were assessed for antiplasmodial and cytotoxic activity against the FCR-3 Gambian Chloroquine resistant strain of P. falciparum and the MDA-MB-231 breast carcinoma cell line respectively. Comparison of antiplasmodial data for all twelve compounds showed that the hydroquinone moeity of sargahydroquinoic acid (1.38) is important for antiplasmodial activity while esterification of the carboxylic acid group in 1.38 resulted in more potent antiplasmodial compounds. Of all twelve compounds, compound 5.2, the hydroquinone methyl ester of 1.38 was found to be the most potent antiplasmodial compound with an IC₅₀ value of 1.94 μM and a selectivity index of 22.68.
- Full Text:
- Authors: Munedzimwe, Tatenda Carol
- Date: 2012
- Subjects: Malaria -- Developing countries -- Prevention , Antimalarials
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3871 , http://hdl.handle.net/10962/d1018252
- Description: Malaria is one of the most deadly parasitic diseases known to man. Although the number of malaria cases reported each year is decreasing, this disease continues to pose health and economic problems mainly in developing countries. Significant progress has been made in the fight against this disease. This includes the discovery and development of potent antimalarial agents. However, the development of resistance to most of these potent antimalarials has made the development of new antiplasmodial agents of paramount importance. Several promising antiplasmodial agents have been found from the marine environment. Amongst these are the tetraprenylated toluquinols from the brown alga: Sargassum heterophyllum. These metabolites have been reported to exhibit a range of antiplasmodial activity; however, the mechanisms by which these compounds bring about their antiplasmodial activity and the pharmacophoric groups responsible for such activity are unknown. Two species of Sargassum algae were encountered during the course of this project. From the investigation of the geographical and seasonal variation of metabolites of S. heterophyllum and S. elegans we established that there were no significant intra and inter site variations amongst metabolite profiles of both species both within and between the sampled seasons. These results enabled us to establish that the collection of both species from three different sites on the eastern coast of South Africa namely; Kenton on Sea, Port Alfred and Noordhoek in autumn, winter or spring would qualitatively yield the same metabolites. A comparison of metabolite profiles of both species also revealed no qualitative differences between metabolites of S. heterophyllum and S. elegans. The quantities of selected prenylated metabolites extracted from S. heterophyllum using four different extraction techniques was also assessed using qNMR as the method of quantification. This led to the identification of optimal extraction techniques and conditions for the extraction of sargahydroquinoic acid (1.38), sargaquinoic aid (1.39) and sargachromenol (2.10) from S. heterophyllum. From this study, the extraction of algae by soxhlet extraction using EtOH as the extraction solvent led to the extraction of the highest quantities of sargahydroquinoic acid. The potential of other extraction techniques such as microwave assisted extraction, to yield high quantities of the selected metabolites were also identified. With gram quantities of sargahydroquinoic acid (1.38) in hand, this compound was modified by oxidation, reduction, acetylation, methylation and cyclization reactions to yield nine derivatives. The derivatives and four naturally occurring prenylated toluquinols were assessed for antiplasmodial and cytotoxic activity against the FCR-3 Gambian Chloroquine resistant strain of P. falciparum and the MDA-MB-231 breast carcinoma cell line respectively. Comparison of antiplasmodial data for all twelve compounds showed that the hydroquinone moeity of sargahydroquinoic acid (1.38) is important for antiplasmodial activity while esterification of the carboxylic acid group in 1.38 resulted in more potent antiplasmodial compounds. Of all twelve compounds, compound 5.2, the hydroquinone methyl ester of 1.38 was found to be the most potent antiplasmodial compound with an IC₅₀ value of 1.94 μM and a selectivity index of 22.68.
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