- Title
- A medicinal chemistry study in nitrogen containing heterocycles
- Creator
- Lunga, Mayibongwe Junior
- Subject
- Indole
- Subject
- Tetrazoles
- Subject
- Antimalarials
- Subject
- Heat shock proteins
- Subject
- Plasmodium falciparum
- Date Issued
- 2018
- Date
- 2018
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10962/63521
- Identifier
- vital:28430
- Description
- Heterocyclic structures have found extensive utility in the field of medicinal chemistry, as prominent regions of pharmacophores resulting in numerous drug treatments for many diseases. Accordingly, in this project we explored the respective antimalarial and anticancer activity exhibited by compounds featuring nitrogen containing indole and tetrazole heterocycles respectively. This thesis therefore comprises of two distinct parts. Part 1. Following the development of resistance towards traditional antimalarial therapy such as chloroquine and emerging resistance towards artemisinin combination therapies, the WHO reported the urgent need for new, effective drugs and identification of new drug targets to combat the Plasmodium falciparum parasite. In 2015 the parasite was the cause of 429 000 deaths, the majority occurring in the sub-Saharan region of Africa. This highlights the failing effectiveness of vector control strategies, reiterating the need to develop alternative control and treatment strategies. In response to this need we wanted to expand and further describe the SAR of the indole based series, indolyl-3-ethanone-α- thioethers, previously synthesized in our laboratory. These compounds were found to exhibit antimalarial activity with compounds 2.26 and 2.27 exhibiting activity against P. falciparum 3D7 in the nanomolar range. Based on these compounds we synthesized compounds 3.21 and 3.24 – 3.32 following a three step reaction pathway. Our results in this study, indicate that compound 3.28, a pnitrothiophenol analogue of 2.27 was the most active of the compounds we synthesized and furthermore was superior in activity against Plasmodium compared to 2.27. This result indicated that the presence of p-NO2 is important in enhancing anti-plasmodial activity. Comparing compounds 3.25 and 3.26 with an oxygen on the ether bridge to compounds 3.29 and 3.30 with a sulfur, we observed an increase in hydrophilicity coupled to a decrease in anti-plasmodial activity in the compounds, thus, highlighting the importance of sulfur for enhanced activity. Furthermore, we investigated bioisosteric replacement of the 5-chloro substituent present in hit compounds 2.27 and 3.28, with an electron withdrawing nitrile (3.27) and electron donating methyl (3.29) and methoxy (3.31) substituents. These substituents decreased anti-plasmodial activity, confirming that a chlorine substituent is optimal for biological activity. This study furthered our understanding of the SAR of indolyl-3-ethanone-α- thioethers for the development of potent anti-plasmodial lead compounds. Part 2. Triple negative breast cancer (TNBC), which disproportionately affects women of sub-Saharan Africa, is unresponsive to hormone-based therapies. This emergence presents a population of patients devoid of effective drug treatment, signaling the urgent need to develop new effective therapies with novel drug targets. Therefore, we identified our target in TNBC cells as the protein-protein interaction between the co-chaperones HOP and HSP90. We reasoned that a disruption of this interaction would ultimately result in cancer cell death via the degradation of essential oncogenic client proteins. Following a fragment screening campaign, which identified several acid and tetrazole containing hits (4.56 – 4.58) which bound to HOP, with low anticancer activity, we sought to develop synthetic methodology to elaborate our fragment hits synthesizing tetrazole containing fragments to target TNBC cell lines. We therefore proceeded to synthesize a range of multi substituted fragments (4.59 – 4.63), utilizing a nitrile (4.66) to access tetrazoles via 1,3-cycloaddition and an acid by nitrile hydrolysis. We successfully synthesized the tetrazole and acid fragments which are currently undergoing characterization for activity against TNBC.
- Description
- Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2018
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (124 pages)
- Format
- Publisher
- Rhodes University
- Publisher
- Faculty of Pharmacy, Pharmacy
- Language
- English
- Rights
- Lunga, Mayibongwe Junior
- Rights
- Attribution 4.0 International (CC BY 4.0)
- Rights
- Open Access
- Hits: 4744
- Visitors: 4935
- Downloads: 261
Collections
RU Department of Pharmacy
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | Adobe Acrobat PDF | 5 MB | Adobe Acrobat PDF | View Details Download |