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This dissertation describes the progress made in the development of compounds with in vitro potency against the Plasmodium falciparum parasite. Plasmodium is a genus of single-celled parasites that causes malaria after infection of a human host. Three scaffolds will be discussed. Each shows indications of operating through a mechanism of action orthogonal to that of currently available therapeutics.

Chapter 1 details the growing need for new antimalarials as new resistant strains of Plasmodium emerge. The features of an ideal antimalarial are also mentioned.

Chapter 2 introduces the first scaffold, tetrahydroisoquinolines or (THIQs). This series of compounds was developed by the Knapp group in collaboration with St. Jude Research Hospital and has produced a lead candidate known as SJ733. The synthesis of these compounds involves an amidation at a racemizable carboxylic acid. A stereoselective amidation reaction is described that preferentially produces a higher energy cis product. Evidence of a ketene intermediate is presented in the form of IR evidence and the characterization of ketene dimers.

Chapter 3 presents 2-thio thienopyrimidines (TTPs) as a new antimalarial scaffold that has shown efficacy against the parasite. Despite many promising features, these structures contain a diaryl thioether believed to be metabolically labile and the source of poor in vivo stability. A computational study is described that attempts to define an electronic and geometric mimic to a diaryl thioether. A synthetic effort is then presented that aims to create a TTP analogue featuring a thioether isostere.

Chapter 4 describes the scaffold manipulation and initial structure-activity relationship (SAR) studies of our final series, the tetrahydrobenzonapthyridines (TBNs). These compounds initially showed promising activity against the Plasmodium parasite in the double-digit nanomolar range. However, these numbers could not be reproduced in subsequent studies. This was initially hypothesized to be due to the poor solubility of the compounds. An effort was then launched to increase the drug-likeness of the series by making strategic alterations to the scaffold. A general divergent synthesis for TBNs is described as well as several unique syntheses for chemically interesting analogues. Over seventy compounds were synthesized, and a preliminary SAR was developed. The TBN pyrrolinone, an oxidized form of the TBN that features a unique aminal substructure, was discovered. This product, formed from exposure to oxygen, shows potency against P. falciparum in the single-digit nanomolar range. The purposeful synthesis of these compounds is detailed as well as their EC50 against the parasite.

Chapter 5 details attempts to improve the Mitsunobu reaction by the development of imidazolyl phosphines. These compounds show enhanced solubility over traditional Mitsunobu reagents. Discussion includes attempts to optimize phosphine structure to improve yield, as well as synthetic plans for other phosphines.

ETD_10588

Ph.D.

Includes bibliographical references

doi:10.7282/t3-6ew2-6882

ETD doctoral

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