- Title
- Synthesis and in vitro biological evaluation of 2,3-substituted quinoline derivatives
- Creator
- Bokosi, Fostino Raphael Bentry
- ThesisAdvisor
- Khanye, Setshaba
- ThesisAdvisor
- Beteck, Richard
- Subject
- Quinoline
- Subject
- Malaria Chemotherapy
- Subject
- Tuberculosis Chemotherapy
- Subject
- African trypanosomiasis Chemotherapy
- Date
- 2020
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10962/163193
- Identifier
- 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.
- Description
- Thesis (MSc) -- Faculty of Science, Chemistry, 2020
- Format
- computer, online resource, application/pdf, 1 online resource (172 pages), pdf
- Publisher
- Rhodes University, Faculty of Science, Chemistry
- Language
- English
- Rights
- Bokosi, Fostino Raphael Bentry
- Rights
- Attribution 4.0 International (CC BY 4.0)
- Rights
- Open Access
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | BOKOSI-MSC-2020.pdf | 4 MB | Adobe Acrobat PDF | View Details Download |