Antimalarial activity of quinoline thiosemicarbazones: synthesis and antiplasmodial evaluation
- Nqeno, Lukhanyiso Khanyisile
- Authors: Nqeno, Lukhanyiso Khanyisile
- Date: 2022-04-06
- Subjects: Antimalarials , Quinoline , Thiosemicarbazones , Malaria Chemotherapy , Plasmodium falciparum , Malaria Africa, Sub-Saharan , Iron chelates Therapeutic use
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/291292 , vital:56841
- Description: Africa is one of the regions that is most affected by malaria, as 90% of all malaria deaths occur in sub-saharan Africa. Malaria is a life threatening disease responsible for an estimated 800000 deaths each year, the majority of these deaths occurred in children under the age of five. The disease is a mosquito-borne, and it is transmitted to humans by the female Anopheles mosquito. The parasite responsible for this disease belong to the Plasmodium genus with Plasmodium falciparum causing the most severe cases of the disease in humans. The most widely available anti-malarials were designed to specifically target the pathogenic blood stage in humans, however, in order to completely eradicate malaria there is a need for the development of medicines that not only target the pathogenic blood stage of the parasite but also block parasite transmission and eliminate asymptomatic and cryptic hepatic forms of the parasite. Iron chelators have recently gained importance as potent antimalarials, to cause infection nearly all protozoa obtain growth essential iron from their hosts. Iron is required for the development of the parasite. Deprivation of utilizable iron by chelation is a proficient approach to arrest parasite growth and associated infection. Thiosemicarbazones are known iron chelating agents by bonding through the sulfur and azomethine nitrogen atoms. This study is aimed at the identification of thiosemicarbazone based derivatives as possible antimalarial agents. Due to their iron chelation abilities there has been increasing interest in the investigation of thiosemicarbazones as possible antimalarials. During the course of this project, several thiosemicarbazone derivatives were synthesized and their structure confirmed using routine analytical techniques (NMR, FTIR, and HRMS). The synthesized compounds were evaluated in vitro against the chloroquine sensitive strain (3D7) of P. falciparum for antimarial activity. The compounds were also evaluated agsinst Hela cells for overt cytotoxicity. The compounds generally showed poor antimalarial activity. One compound (LKN11) was identified to possess intrinsic and moderate antimalarial activity of 6.6 μM. The compounds were generally not cytotoxic against Hela cell at concentrations of up to 20 μM, with only compound LKN10 showing modest cytotoxic activity of 9.5 μM. This research went on to identify two thiosemicarbazone based derivatives which had a significant effect on HeLa and pLDH cells. , Thesis (MSc) -- Faculty of Science, Chemistry, 2022
- Full Text:
- Authors: Nqeno, Lukhanyiso Khanyisile
- Date: 2022-04-06
- Subjects: Antimalarials , Quinoline , Thiosemicarbazones , Malaria Chemotherapy , Plasmodium falciparum , Malaria Africa, Sub-Saharan , Iron chelates Therapeutic use
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/291292 , vital:56841
- Description: Africa is one of the regions that is most affected by malaria, as 90% of all malaria deaths occur in sub-saharan Africa. Malaria is a life threatening disease responsible for an estimated 800000 deaths each year, the majority of these deaths occurred in children under the age of five. The disease is a mosquito-borne, and it is transmitted to humans by the female Anopheles mosquito. The parasite responsible for this disease belong to the Plasmodium genus with Plasmodium falciparum causing the most severe cases of the disease in humans. The most widely available anti-malarials were designed to specifically target the pathogenic blood stage in humans, however, in order to completely eradicate malaria there is a need for the development of medicines that not only target the pathogenic blood stage of the parasite but also block parasite transmission and eliminate asymptomatic and cryptic hepatic forms of the parasite. Iron chelators have recently gained importance as potent antimalarials, to cause infection nearly all protozoa obtain growth essential iron from their hosts. Iron is required for the development of the parasite. Deprivation of utilizable iron by chelation is a proficient approach to arrest parasite growth and associated infection. Thiosemicarbazones are known iron chelating agents by bonding through the sulfur and azomethine nitrogen atoms. This study is aimed at the identification of thiosemicarbazone based derivatives as possible antimalarial agents. Due to their iron chelation abilities there has been increasing interest in the investigation of thiosemicarbazones as possible antimalarials. During the course of this project, several thiosemicarbazone derivatives were synthesized and their structure confirmed using routine analytical techniques (NMR, FTIR, and HRMS). The synthesized compounds were evaluated in vitro against the chloroquine sensitive strain (3D7) of P. falciparum for antimarial activity. The compounds were also evaluated agsinst Hela cells for overt cytotoxicity. The compounds generally showed poor antimalarial activity. One compound (LKN11) was identified to possess intrinsic and moderate antimalarial activity of 6.6 μM. The compounds were generally not cytotoxic against Hela cell at concentrations of up to 20 μM, with only compound LKN10 showing modest cytotoxic activity of 9.5 μM. This research went on to identify two thiosemicarbazone based derivatives which had a significant effect on HeLa and pLDH cells. , Thesis (MSc) -- Faculty of Science, Chemistry, 2022
- Full Text:
Exploring para-thiophenols to expand the SAR of antimalarial 3-indolylethanones
- Authors: Chisango, Ruramai Lissa
- Date: 2018
- Subjects: Antimalarials , Malaria Chemotherapy , Thiols , Plasmodium falciparum , Blood-brain barrier
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/63515 , vital:28428
- Description: According to the WHO, malaria is responsible for over half a million deaths annually especially in populations from disadvantaged settings. Although there has been a documented improvement in the mortality rates, malaria has proved to be a global emergency. Mostly affecting the poor population, this disease is perpetuating a vicious cycle of poverty in the developing world as current preventive measures are not adequate unless adopted in addition to effective treatment. However, there has been a worldwide increase in resistance to available treatment which presents a need for novel, affordable treatment. A study conducted in our laboratory identified two hit thiophenol containing compounds 2.24 and 2.25. These molecules provided initial insight into the SAR and potential pharmacophore of this class of compounds. We decided to further explore these compounds by making bioisosteric replacements to optimize the structure as we monitor the effect of these modifications on the anti-plasmodial activity. The synthetic pathway to form the target compounds of our study comprised of three steps which were initiated by the Friedel-Crafts acetylation of the indoles resulting in compounds 3.5 - 3.7. A bromination step followed which yielded the -bromo ketones (3.8 - 3.11). Some of the thiophenols (3.14 and 3.16) were not readily available in our laboratory and so were synthesized for the final synthetic step. This step involved the nucleophilic displacement of the -bromine to generate the -aryl substituted 3-indolylethanones (3.17 - 3.27). The thioethers displayed improved antimalarial activity from 2.24 and 2.25 against the chloroquine sensitive 3D7 Plasmodium falciparum strain. In addition, these compounds were non-toxic against HeLa cells which indicated this potential novel class of antimalarials is selective for the malaria parasite as hypothesized in the previous study conducted in our laboratory. In an attempt to predict the bioavailability of some of our compounds, in silico studies were conducted revealing that these compounds could be passively absorbed by the gastrointestinal tract, a positive result for bioavailability purposes. However, results from these studies indicate that modifications of these compounds would be necessary to allow for permeation through the blood brain barrier (BBB) for instances when the patient has cerebral malaria. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Authors: Chisango, Ruramai Lissa
- Date: 2018
- Subjects: Antimalarials , Malaria Chemotherapy , Thiols , Plasmodium falciparum , Blood-brain barrier
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/63515 , vital:28428
- Description: According to the WHO, malaria is responsible for over half a million deaths annually especially in populations from disadvantaged settings. Although there has been a documented improvement in the mortality rates, malaria has proved to be a global emergency. Mostly affecting the poor population, this disease is perpetuating a vicious cycle of poverty in the developing world as current preventive measures are not adequate unless adopted in addition to effective treatment. However, there has been a worldwide increase in resistance to available treatment which presents a need for novel, affordable treatment. A study conducted in our laboratory identified two hit thiophenol containing compounds 2.24 and 2.25. These molecules provided initial insight into the SAR and potential pharmacophore of this class of compounds. We decided to further explore these compounds by making bioisosteric replacements to optimize the structure as we monitor the effect of these modifications on the anti-plasmodial activity. The synthetic pathway to form the target compounds of our study comprised of three steps which were initiated by the Friedel-Crafts acetylation of the indoles resulting in compounds 3.5 - 3.7. A bromination step followed which yielded the -bromo ketones (3.8 - 3.11). Some of the thiophenols (3.14 and 3.16) were not readily available in our laboratory and so were synthesized for the final synthetic step. This step involved the nucleophilic displacement of the -bromine to generate the -aryl substituted 3-indolylethanones (3.17 - 3.27). The thioethers displayed improved antimalarial activity from 2.24 and 2.25 against the chloroquine sensitive 3D7 Plasmodium falciparum strain. In addition, these compounds were non-toxic against HeLa cells which indicated this potential novel class of antimalarials is selective for the malaria parasite as hypothesized in the previous study conducted in our laboratory. In an attempt to predict the bioavailability of some of our compounds, in silico studies were conducted revealing that these compounds could be passively absorbed by the gastrointestinal tract, a positive result for bioavailability purposes. However, results from these studies indicate that modifications of these compounds would be necessary to allow for permeation through the blood brain barrier (BBB) for instances when the patient has cerebral malaria. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
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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:
- 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:
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:
- 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:
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:
- 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:
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