Studies in the thiophenol mediated substitution and reductive dehalogenation of 3 bromoacetylcoumarins
- Authors: Magwenzi, Faith N
- Date: 2017
- Subjects: 3-bromoacetylcoumarins , Coumarins , Halogens -- Decontamination , Thiols , Plasmodium falciparum , Malaria -- Chemotherapy
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/45769 , vital:25546
- Description: A previous study conducted by our group identified indolyl-3-ethanone-a-thioethers (2.1a and 2.1b) as non-toxic, nanomolar, in vitro inhibitors of Plasmodium falciparum. Since the coumarin scaffold is associated with numerous biologically active compounds including antiprotozoal, anti-viral, anti-bacterial, and anti-inflammatory agents we were prompted to investigate coumaryl-3-ethanone-a-thioethers (2.1c) inspired by the activity of 2.1a and 2.1b against P. falciparum. We proposed a three-step synthesis of our target compounds 2.1c. The first step involved the Knoevenagel synthesis of 3-acetyl coumarins (2.3.1a - e) followed by a selective a-bromination to yield 3-bromoacetyl coumarin (2.2a). The final proposed step involved the nucleophilic displacement of the bromine by appropriately substituted thiophenols in either the presence or absence of base (K2CO3). Our initial findings revealed an unexpected major reductive dehalogenation of 2.2a into 2.3.1a. Further investigation revealed a close relationship between the electron withdrawing or donating nature of the thiophenol substituents and the relative formation of nucleophilic substitution or reductive dehalogenation products. Desired thioether products were obtained in higher yields when thiophenol was substituted with electron donating groups i.e. more nucleophilic thiophenols, while conversely, electron withdrawing substituents (i.e. lowered nucleophilicity) resulted in an increase of reductive dehalogenation. Furthermore, these results were consistent when experiments were conducted using either 2 or 1.2 equivalents of thiophenols which was an important observation in the context of two previous studies, by Oki et. al. and Israel et. al. Oki proposed that dehalogenation of a-chloro carbonyls occurs via sequential nucleophilic displacement of a-thioethers, while the study of Israel concluded that the dehalogenation of a-iodo carbonyls occurred in a single discreet step. Finally, in an effort to enhance nucleophilic substitution through the addition of K2CO3, we observed a Robinson annulation resulting in previously undescribed C-8 thiophenol functionalised dibenzo[b,d]pyran-6-ones (3.4a - e). In the introduction to this thesis, we briefly summarise the utility of coumarins in medicinal chemistry and related fields. Chapter two describes the rationalisation of our original research question and a retrosynthetic analysis of our desired compounds, followed by an initial description of the unexpected reductive dehalogenation. Chapter 3, begins with a brief review of reductive dehalogenation of a-halocarbonyls, and is followed by an analysis and discussion of our results in the context of the studies by Israel et. al. and Oki et. al.
- Full Text:
- Date Issued: 2017
- Authors: Magwenzi, Faith N
- Date: 2017
- Subjects: 3-bromoacetylcoumarins , Coumarins , Halogens -- Decontamination , Thiols , Plasmodium falciparum , Malaria -- Chemotherapy
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/45769 , vital:25546
- Description: A previous study conducted by our group identified indolyl-3-ethanone-a-thioethers (2.1a and 2.1b) as non-toxic, nanomolar, in vitro inhibitors of Plasmodium falciparum. Since the coumarin scaffold is associated with numerous biologically active compounds including antiprotozoal, anti-viral, anti-bacterial, and anti-inflammatory agents we were prompted to investigate coumaryl-3-ethanone-a-thioethers (2.1c) inspired by the activity of 2.1a and 2.1b against P. falciparum. We proposed a three-step synthesis of our target compounds 2.1c. The first step involved the Knoevenagel synthesis of 3-acetyl coumarins (2.3.1a - e) followed by a selective a-bromination to yield 3-bromoacetyl coumarin (2.2a). The final proposed step involved the nucleophilic displacement of the bromine by appropriately substituted thiophenols in either the presence or absence of base (K2CO3). Our initial findings revealed an unexpected major reductive dehalogenation of 2.2a into 2.3.1a. Further investigation revealed a close relationship between the electron withdrawing or donating nature of the thiophenol substituents and the relative formation of nucleophilic substitution or reductive dehalogenation products. Desired thioether products were obtained in higher yields when thiophenol was substituted with electron donating groups i.e. more nucleophilic thiophenols, while conversely, electron withdrawing substituents (i.e. lowered nucleophilicity) resulted in an increase of reductive dehalogenation. Furthermore, these results were consistent when experiments were conducted using either 2 or 1.2 equivalents of thiophenols which was an important observation in the context of two previous studies, by Oki et. al. and Israel et. al. Oki proposed that dehalogenation of a-chloro carbonyls occurs via sequential nucleophilic displacement of a-thioethers, while the study of Israel concluded that the dehalogenation of a-iodo carbonyls occurred in a single discreet step. Finally, in an effort to enhance nucleophilic substitution through the addition of K2CO3, we observed a Robinson annulation resulting in previously undescribed C-8 thiophenol functionalised dibenzo[b,d]pyran-6-ones (3.4a - e). In the introduction to this thesis, we briefly summarise the utility of coumarins in medicinal chemistry and related fields. Chapter two describes the rationalisation of our original research question and a retrosynthetic analysis of our desired compounds, followed by an initial description of the unexpected reductive dehalogenation. Chapter 3, begins with a brief review of reductive dehalogenation of a-halocarbonyls, and is followed by an analysis and discussion of our results in the context of the studies by Israel et. al. and Oki et. al.
- Full Text:
- Date Issued: 2017
Synthesis, characterisation and evaluation of benzoxaborole-based hybrids as antiplasmodial agents
- Authors: Gumbo, Maureen
- Date: 2017
- Subjects: Malaria Chemotherapy , Antimalarials , Boron compounds , Drug resistance , Plasmodium falciparum , Drug development
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/59193 , vital:27456
- Description: Malaria is a mosquito-borne disease, which continues to pose a threat to the entire humanity. About 40% of the world population is estimated to be at risk of infections by malaria. Despite efforts undertaken by scientific community, government entities and international organizations, malaria is still rampant. The major problem is drug resistance, where the Plasmodium spp have over the past decades developed drug resistance against available drugs. In order to counter this problem, novel antimalarial drugs that are efficacious and with novel mode of action are of great necessity. Benzoxaborole derivatives have been shown to exhibit promising antimalarial activity against Plasmodium falciparum strains. Previous studies reported on the compounds such as 6-(2- (alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles, which showed good antimalarial activity against both W7 and 3D7 strains without significant toxicity. On the other hand, chloroquine (CQ) and cinnamic acids have a wide variety of biological activity including antimalarial activity. Herein, a hybridisation strategy was employed to synthesise new CQ-benzoxaborole and cinnamoyl-benzoxaborole hybrids. CQ-Benzoxaborole 2.12a-c and cinnamoylbenzoxaborole 2.11a-g hydrid molecules were synthesised in low to good yields. Their structural identities were confirmed using conventional spectroscopic techniques (1H and 13C NMR, and mass spectrometry). CQ-benzoxaborole compounds, however, showed instability, and only 2.12b was used for in vitro biological assay and showed activity comparable to CQ. Furthermore, in vitro biological assay revealed that compounds 2.11a-g poorly inhibited the growth of P. falciparum parasites. Interestingly, these compounds, however, exhibited satisfactory activity against Trypanosoma brucei with IC50 = 0.052 μM for compound 2.11g. The cell cytotoxicity assay of all final compounds confirmed that all CQ-benzoxaborole 2.12b and cinnamoyl-benzoxaborole 2.11a-g hybrids were non-toxic against HeLa cell lines. However, efforts to further expand the structure-activity relationship (SAR) of CQbenzoxaborole by increasing the length of the linker with one extra carbon (Scheme 2.10) were not possible as an important precursor 6-formylbenzoxaborole 2.29 could not be synthesized in sufficient yields. , Thesis (MSc) -- Faculty of Faculty of Science, Chemistry, 2017
- Full Text:
- Date Issued: 2017
- Authors: Gumbo, Maureen
- Date: 2017
- Subjects: Malaria Chemotherapy , Antimalarials , Boron compounds , Drug resistance , Plasmodium falciparum , Drug development
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/59193 , vital:27456
- Description: Malaria is a mosquito-borne disease, which continues to pose a threat to the entire humanity. About 40% of the world population is estimated to be at risk of infections by malaria. Despite efforts undertaken by scientific community, government entities and international organizations, malaria is still rampant. The major problem is drug resistance, where the Plasmodium spp have over the past decades developed drug resistance against available drugs. In order to counter this problem, novel antimalarial drugs that are efficacious and with novel mode of action are of great necessity. Benzoxaborole derivatives have been shown to exhibit promising antimalarial activity against Plasmodium falciparum strains. Previous studies reported on the compounds such as 6-(2- (alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles, which showed good antimalarial activity against both W7 and 3D7 strains without significant toxicity. On the other hand, chloroquine (CQ) and cinnamic acids have a wide variety of biological activity including antimalarial activity. Herein, a hybridisation strategy was employed to synthesise new CQ-benzoxaborole and cinnamoyl-benzoxaborole hybrids. CQ-Benzoxaborole 2.12a-c and cinnamoylbenzoxaborole 2.11a-g hydrid molecules were synthesised in low to good yields. Their structural identities were confirmed using conventional spectroscopic techniques (1H and 13C NMR, and mass spectrometry). CQ-benzoxaborole compounds, however, showed instability, and only 2.12b was used for in vitro biological assay and showed activity comparable to CQ. Furthermore, in vitro biological assay revealed that compounds 2.11a-g poorly inhibited the growth of P. falciparum parasites. Interestingly, these compounds, however, exhibited satisfactory activity against Trypanosoma brucei with IC50 = 0.052 μM for compound 2.11g. The cell cytotoxicity assay of all final compounds confirmed that all CQ-benzoxaborole 2.12b and cinnamoyl-benzoxaborole 2.11a-g hybrids were non-toxic against HeLa cell lines. However, efforts to further expand the structure-activity relationship (SAR) of CQbenzoxaborole by increasing the length of the linker with one extra carbon (Scheme 2.10) were not possible as an important precursor 6-formylbenzoxaborole 2.29 could not be synthesized in sufficient yields. , Thesis (MSc) -- Faculty of Faculty of Science, Chemistry, 2017
- Full Text:
- Date Issued: 2017
Synthesis, characterisation and evaluation of novel ferrocene-thiazole derivatives as antiplasmodial agents
- Authors: Hakizimana, Emmanuel Victor
- Date: 2017
- Subjects: Plasmodium , Malaria -- Chemotherapy , Plasmodium falciparum , Plasmodium -- Inhibitors , Drug resistance in microorganisms , Thiaszoles
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/5304 , vital:20807
- Description: Malaria is mosquito-transmitted disease which continues to pose threat to humanity, despite the efforts undertaken by the scientific community, government entities and international organizations. The major problem is that Plasmodium species have developed resistance against available drugs. In order to counter this problem, antimalarial drugs that are efficacious and with novel mode of action are of great necessity. Thiazole derivatives, in particular aminomethylthiazole analogues, have been shown to exhibit promising antimalarial activity against Plasmodium falciparum strains. Previous studies reported the hit compound MMV010539, which showed good antimalarial activity against both K1 (CQ and multidrug resistant strains) and NF54 (CQ sensitive strain). In this study, MMV010539 was deemed to be as an attractive compound to generate novel analogues by addition of ferrocenyl organometallic unit. The ferrocene based compounds have shown biological activity; and with ferroquine currently in clinical trials there has been increasing research into identifying new ferrocenyl-containing molecules as potential antimalarial agents. Herein, thiazole ferrocene based molecules 3.22a-e were synthesised in low to good yields. Their structural identities were confirmed using conventional spectroscopic techniques (¹H and ¹³C NMR, FT-IR spectroscopy and mass spectrometry). The cell cytotoxicity assay of all final compounds confirmed that all ferrocene-thiazole blends 3.22a-e were non-toxic against HeLa cell lines. However, the in vitro biological assay revealed that despite the absence of cell cytotoxicity these compounds poorly inhibited the growth of Plasmodium falciparum parasite. As the aim was to expand further the structure-activity relationship (SAR) of MMV010539, this study confirmed the previous findings that there is a limited structural modification that could be accommodated as indicated in Figure 3.3 (Panel C). Moreover, the combination of ferrocenyl moiety and various alkylamines resulted in compounds with poor antiplasmodial potency, further suggesting that the free amine (Panel A, Figure 3.3) is important for activity.
- Full Text:
- Date Issued: 2017
- Authors: Hakizimana, Emmanuel Victor
- Date: 2017
- Subjects: Plasmodium , Malaria -- Chemotherapy , Plasmodium falciparum , Plasmodium -- Inhibitors , Drug resistance in microorganisms , Thiaszoles
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/5304 , vital:20807
- Description: Malaria is mosquito-transmitted disease which continues to pose threat to humanity, despite the efforts undertaken by the scientific community, government entities and international organizations. The major problem is that Plasmodium species have developed resistance against available drugs. In order to counter this problem, antimalarial drugs that are efficacious and with novel mode of action are of great necessity. Thiazole derivatives, in particular aminomethylthiazole analogues, have been shown to exhibit promising antimalarial activity against Plasmodium falciparum strains. Previous studies reported the hit compound MMV010539, which showed good antimalarial activity against both K1 (CQ and multidrug resistant strains) and NF54 (CQ sensitive strain). In this study, MMV010539 was deemed to be as an attractive compound to generate novel analogues by addition of ferrocenyl organometallic unit. The ferrocene based compounds have shown biological activity; and with ferroquine currently in clinical trials there has been increasing research into identifying new ferrocenyl-containing molecules as potential antimalarial agents. Herein, thiazole ferrocene based molecules 3.22a-e were synthesised in low to good yields. Their structural identities were confirmed using conventional spectroscopic techniques (¹H and ¹³C NMR, FT-IR spectroscopy and mass spectrometry). The cell cytotoxicity assay of all final compounds confirmed that all ferrocene-thiazole blends 3.22a-e were non-toxic against HeLa cell lines. However, the in vitro biological assay revealed that despite the absence of cell cytotoxicity these compounds poorly inhibited the growth of Plasmodium falciparum parasite. As the aim was to expand further the structure-activity relationship (SAR) of MMV010539, this study confirmed the previous findings that there is a limited structural modification that could be accommodated as indicated in Figure 3.3 (Panel C). Moreover, the combination of ferrocenyl moiety and various alkylamines resulted in compounds with poor antiplasmodial potency, further suggesting that the free amine (Panel A, Figure 3.3) is important for activity.
- Full Text:
- Date Issued: 2017
Synthesis, characterisation and evaluation of novel ferrocene-thiazole derivatives as antiplasmodial agents
- Authors: Hakizimana, Emmanuel Victor
- Date: 2017
- Subjects: Plasmodium , Malaria -- Chemotherapy , Plasmodium falciparum , Plasmodium -- Inhibitors , Drug resistance in microorganisms , Thiaszoles
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/96068 , vital:31232
- Description: Malaria is mosquito-transmitted disease which continues to pose threat to humanity, despite the efforts undertaken by the scientific community, government entities and international organizations. The major problem is that Plasmodium species have developed resistance against available drugs. In order to counter this problem, antimalarial drugs that are efficacious and with novel mode of action are of great necessity. Thiazole derivatives, in particular aminomethylthiazole analogues, have been shown to exhibit promising antimalarial activity against Plasmodium falciparum strains. Previous studies reported the hit compound MMV010539, which showed good antimalarial activity against both K1 (CQ and multidrug resistant strains) and NF54 (CQ sensitive strain). In this study, MMV010539 was deemed to be as an attractive compound to generate novel analogues by addition of ferrocenyl organometallic unit. The ferrocene based compounds have shown biological activity; and with ferroquine currently in clinical trials there has been increasing research into identifying new ferrocenyl-containing molecules as potential antimalarial agents. Herein, thiazole ferrocene based molecules 3.22a-e were synthesised in low to good yields. Their structural identities were confirmed using conventional spectroscopic techniques (¹H and ¹³C NMR, FT-IR spectroscopy and mass spectrometry). The cell cytotoxicity assay of all final compounds confirmed that all ferrocene-thiazole blends 3.22a-e were non-toxic against HeLa cell lines. However, the in vitro biological assay revealed that despite the absence of cell cytotoxicity these compounds poorly inhibited the growth of Plasmodium falciparum parasite. As the aim was to expand further the structure-activity relationship (SAR) of MMV010539, this study confirmed the previous findings that there is a limited structural modification that could be accommodated as indicated in Figure 3.3 (Panel C). Moreover, the combination of ferrocenyl moiety and various alkylamines resulted in compounds with poor antiplasmodial potency, further suggesting that the free amine (Panel A, Figure 3.3) is important for activity.
- Full Text:
- Date Issued: 2017
- Authors: Hakizimana, Emmanuel Victor
- Date: 2017
- Subjects: Plasmodium , Malaria -- Chemotherapy , Plasmodium falciparum , Plasmodium -- Inhibitors , Drug resistance in microorganisms , Thiaszoles
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/96068 , vital:31232
- Description: Malaria is mosquito-transmitted disease which continues to pose threat to humanity, despite the efforts undertaken by the scientific community, government entities and international organizations. The major problem is that Plasmodium species have developed resistance against available drugs. In order to counter this problem, antimalarial drugs that are efficacious and with novel mode of action are of great necessity. Thiazole derivatives, in particular aminomethylthiazole analogues, have been shown to exhibit promising antimalarial activity against Plasmodium falciparum strains. Previous studies reported the hit compound MMV010539, which showed good antimalarial activity against both K1 (CQ and multidrug resistant strains) and NF54 (CQ sensitive strain). In this study, MMV010539 was deemed to be as an attractive compound to generate novel analogues by addition of ferrocenyl organometallic unit. The ferrocene based compounds have shown biological activity; and with ferroquine currently in clinical trials there has been increasing research into identifying new ferrocenyl-containing molecules as potential antimalarial agents. Herein, thiazole ferrocene based molecules 3.22a-e were synthesised in low to good yields. Their structural identities were confirmed using conventional spectroscopic techniques (¹H and ¹³C NMR, FT-IR spectroscopy and mass spectrometry). The cell cytotoxicity assay of all final compounds confirmed that all ferrocene-thiazole blends 3.22a-e were non-toxic against HeLa cell lines. However, the in vitro biological assay revealed that despite the absence of cell cytotoxicity these compounds poorly inhibited the growth of Plasmodium falciparum parasite. As the aim was to expand further the structure-activity relationship (SAR) of MMV010539, this study confirmed the previous findings that there is a limited structural modification that could be accommodated as indicated in Figure 3.3 (Panel C). Moreover, the combination of ferrocenyl moiety and various alkylamines resulted in compounds with poor antiplasmodial potency, further suggesting that the free amine (Panel A, Figure 3.3) is important for activity.
- Full Text:
- Date Issued: 2017
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