A thesis submitted to the Faculty of Science University of the Witwatersrand
Johannesburg in fulfillment for the requirements of the degree of Master of Science.
14 May 2015. / Peptidomimetic compounds have been shown to exhibit both anti-HIV and anti-malarial activity. A multicomponent reaction was used to create a library of peptidomimetic compounds with an α-hydroxy-β-amino acid unit. The Passerini reaction between an aldehyde, carboxylic acid and isocyanide was used to prepare compounds containing both ester and amide functionalities. These compounds were then subjected to a deprotection-acyl migration strategy giving rise to the target compounds. This approach, known as the Passerini Amine Deprotection Acyl Migration (PADAM) sequence was successfully used to create a library of novel peptidomimetic compounds. From this library, 22 compounds were tested for activity against HIV and malaria.
The Passerini reaction gives rise to a product containing a new stereogenic centre, and as the starting aldehyde used (N-Boc-phenylalaninal) has a stereogenic centre, the products were isolated as a mixture of diastereomers. Our research was also focused on finding ways of influencing the stereoselectivity of the reaction and the separation of the resulting diastereomers. The diastereomeric ratio of the Passerini products was found to be approximately 2:1 for all the reactions performed. This ratio could be modified slightly when using certain carboxylic acids and isocyanides that were either very bulky or had a stereogenic centre.
Attempts to enzymatically resolve the diastereomeric products were not successful after trials using a library of 25 lipase enzymes. However, use of preparative HPLC enabled the successful separation of most of the diastereomeric mixtures, affording compounds with high purity. X-ray crystallography enabled us to identify the major diastereomers as having the R,S configuration, whilst the minor diastereomers had the S,S configuration at the two stereogenic centres.
A possible explanation for the observed stereoselectivity is based on the Felkin-Anh chelation control model. It suggests that mono-protected amino aldehydes follow a chelation controlled mechanism in nucleophilic addition reactions. Chelation occurs, albeit in the form of hydrogen bonding, between the NH and carbonyl oxygen.
The library of compounds was tested for activity against both HIV-1 and malaria. Only three compounds showed moderate activity against the malaria parasite, inhibiting parasitic growth by 37-42% at 5 μM respectively. Significantly, all of the active compounds contained an adamantyl moiety. Unfortunately no anti-HIV activity was seen for any of the compounds tested in the HIV-assay.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/18565 |
| Date | 14 May 2015 |
| Creators | Zimuwandeyi, Memory |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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