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:
- Date Issued: 2022-04-06
- 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:
- Date Issued: 2022-04-06
Exploring Quinolinyl-Thiazolidinedione hybrid compounds as potential anti-tubercular agents
- Authors: Mtshare, Thanduxolo Elihle
- Date: 2020
- Subjects: Quinoline , Mycobacterium tuberculosis , Tuberculosis -- Chemotherapy , Plasmodium falciparum , Thiazolidinedione
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/143314 , vital:38232
- Description: Tuberculosis (TB) is an infectious disease caused by the pathogen, Mycobacterium tuberculosis. According to the World Health Organization, TB is the ninth leading cause of death worldwide ranking above HIV/AIDS. This high mortality rate of TB begs the questions about the efficiency of the current therapy and raises an urgent need to create novel anti-tuberculosis agents which will aid in curbing this burden. Quinoline containing compounds have remarkable biological activities across a wide spectrum of diseases including anti-tuberculosis. On the other hand, thiazolidinedione containing compounds possess a broad spectrum of biological properties. In this study, we rationally designed compounds containing these pharmacophoric units and investigated them for their potential biological activity against Mycobacterium tuberculosis. Considering antimalarial activity of quinoline-based compounds, the compounds achieved were also cross-screened for their activity against the Plasmodium falciparum parasite, a causative agent of malaria. In all the synthesized compounds, compound 2.6a, 2.6b and 2.7b emerged as most active compounds against the H37Rv strain with MIC₉₀ values ranging in between of 1.08 – 17.1 μM. In addition, none of the compounds showed any inhibitory activities against the 3D7 strain of P. falciparum parasite. All the compounds prepared in this study showed no significant human cytotoxic effects as measured by HeLa cell line.
- Full Text:
- Date Issued: 2020
- Authors: Mtshare, Thanduxolo Elihle
- Date: 2020
- Subjects: Quinoline , Mycobacterium tuberculosis , Tuberculosis -- Chemotherapy , Plasmodium falciparum , Thiazolidinedione
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/143314 , vital:38232
- Description: Tuberculosis (TB) is an infectious disease caused by the pathogen, Mycobacterium tuberculosis. According to the World Health Organization, TB is the ninth leading cause of death worldwide ranking above HIV/AIDS. This high mortality rate of TB begs the questions about the efficiency of the current therapy and raises an urgent need to create novel anti-tuberculosis agents which will aid in curbing this burden. Quinoline containing compounds have remarkable biological activities across a wide spectrum of diseases including anti-tuberculosis. On the other hand, thiazolidinedione containing compounds possess a broad spectrum of biological properties. In this study, we rationally designed compounds containing these pharmacophoric units and investigated them for their potential biological activity against Mycobacterium tuberculosis. Considering antimalarial activity of quinoline-based compounds, the compounds achieved were also cross-screened for their activity against the Plasmodium falciparum parasite, a causative agent of malaria. In all the synthesized compounds, compound 2.6a, 2.6b and 2.7b emerged as most active compounds against the H37Rv strain with MIC₉₀ values ranging in between of 1.08 – 17.1 μM. In addition, none of the compounds showed any inhibitory activities against the 3D7 strain of P. falciparum parasite. All the compounds prepared in this study showed no significant human cytotoxic effects as measured by HeLa cell line.
- Full Text:
- Date Issued: 2020
Synthesis and in vitro biological evaluation of 2,3-substituted quinoline derivatives
- Bokosi, Fostino Raphael Bentry
- Authors: Bokosi, Fostino Raphael Bentry
- Date: 2020
- Subjects: Quinoline , Malaria Chemotherapy , Tuberculosis Chemotherapy , African trypanosomiasis Chemotherapy
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/163193 , vital:41017
- Description: The urgent need for new systemic pharmacological entities prompted us to report a library of 2,3-substituted quinoline derivatives. Considering the ubiquity of quinoline-containing compounds in pharmacologically active small molecules, synthesized 2,3-substituted quinoline derivatives were in vitro biologically evaluated for their potential antitubercular, antimalarial and antitrypanosomal activities. Quinoline scaffold was achieved by the Vilsmeier-Haack methodology, affording synthetically useful chloro and formyl substituents on C-2 and C-3 respectively. These two substituents acted as handles in expanding the chemical space around the quinoline ring. Target compounds were synthesized in six to seven steps, employing conventional synthetic organic protocols adapted from various literature. The final compounds were accessed in moderate to good yields. The structural identity of each compound was confirmed by common spectroscopic techniques. Aryl quinoline carboxamide derivatives 3.113 – 3.126 were isolated as rotamers, hence, Variable-Temperature Nuclear Magnetic Resonance (VT-NMR) was employed in resolving 1H splitting. At elevated temperature (~328 K); N-methylene carbons were not visible on 13C NMR due to signal line broadening effects. The presence of these nuclei in such cases was, however, supported by 2-dimensional NMR and high-resolution MS data. Most of the compounds achieved in this study displayed promising antimalarial activity against chloroquine-sensitive 3D7 strain of Plasmodium falciparum compared to antitrypanosomal activity against Trypanosoma brucei brucei 427 strain. In particular, compounds 3.80 and 3.108 showed superior activity against chloroquine-sensitive 3D7 P. falciparum strain with IC50 values < 1 μM. More importantly, most of the compounds were non-toxic as determined by HeLa cells, indicating their selectivity towards the parasites. Exploring the space provided on the quinoline scaffold revealed that methoxy incorporation on C-2 is very critical in enhancing antimalarial activity of this class of quinoline compounds. The preliminary SAR of compounds 3.57 – 3.72 showed that compounds containing the 3-cinnamate exhibited enhanced antimalarial activity compared to 2 and 4-cinnamates. Finally, benzamide compounds 3.113 − 3.126 showed poor activity against Mycobacterium tuberculosis H37Rv strain with only compounds 3.113, 3.117 – 3.120 and 3.126 showing appreciable MIC90 values in the range of 40 – 85 μM. , Thesis (MSc) -- Faculty of Science, Chemistry, 2020
- Full Text:
- Date Issued: 2020
- Authors: Bokosi, Fostino Raphael Bentry
- Date: 2020
- Subjects: Quinoline , Malaria Chemotherapy , Tuberculosis Chemotherapy , African trypanosomiasis Chemotherapy
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/163193 , vital:41017
- Description: The urgent need for new systemic pharmacological entities prompted us to report a library of 2,3-substituted quinoline derivatives. Considering the ubiquity of quinoline-containing compounds in pharmacologically active small molecules, synthesized 2,3-substituted quinoline derivatives were in vitro biologically evaluated for their potential antitubercular, antimalarial and antitrypanosomal activities. Quinoline scaffold was achieved by the Vilsmeier-Haack methodology, affording synthetically useful chloro and formyl substituents on C-2 and C-3 respectively. These two substituents acted as handles in expanding the chemical space around the quinoline ring. Target compounds were synthesized in six to seven steps, employing conventional synthetic organic protocols adapted from various literature. The final compounds were accessed in moderate to good yields. The structural identity of each compound was confirmed by common spectroscopic techniques. Aryl quinoline carboxamide derivatives 3.113 – 3.126 were isolated as rotamers, hence, Variable-Temperature Nuclear Magnetic Resonance (VT-NMR) was employed in resolving 1H splitting. At elevated temperature (~328 K); N-methylene carbons were not visible on 13C NMR due to signal line broadening effects. The presence of these nuclei in such cases was, however, supported by 2-dimensional NMR and high-resolution MS data. Most of the compounds achieved in this study displayed promising antimalarial activity against chloroquine-sensitive 3D7 strain of Plasmodium falciparum compared to antitrypanosomal activity against Trypanosoma brucei brucei 427 strain. In particular, compounds 3.80 and 3.108 showed superior activity against chloroquine-sensitive 3D7 P. falciparum strain with IC50 values < 1 μM. More importantly, most of the compounds were non-toxic as determined by HeLa cells, indicating their selectivity towards the parasites. Exploring the space provided on the quinoline scaffold revealed that methoxy incorporation on C-2 is very critical in enhancing antimalarial activity of this class of quinoline compounds. The preliminary SAR of compounds 3.57 – 3.72 showed that compounds containing the 3-cinnamate exhibited enhanced antimalarial activity compared to 2 and 4-cinnamates. Finally, benzamide compounds 3.113 − 3.126 showed poor activity against Mycobacterium tuberculosis H37Rv strain with only compounds 3.113, 3.117 – 3.120 and 3.126 showing appreciable MIC90 values in the range of 40 – 85 μM. , Thesis (MSc) -- Faculty of Science, Chemistry, 2020
- Full Text:
- Date Issued: 2020
- «
- ‹
- 1
- ›
- »