Document Type

Thesis

Publication Date

Fall 12-10-2010

Advisor

Roman Manetsch

Advisor Email

manetsch@cas.usf.edu

Abstract

Malaria is one of the most significant parasitic diseases affecting mankind today, exceeding 200 million annual cases worldwide1. This disease has been a serious issue due to developed resistance to commonly available antimalarial drugs including atovaquone and artemisinin2, the most relevant modern treatment (figure 1.1). This project focuses on the preparation of 1,2,3,4- tetrahydroacridones (figure 1.2) that can be tested for their activity against P. falciparum isolates TM90-C2B (an atovaquone-resistant parasitic strain) and W2 (an atovaquone-susceptible parasite). In the past, studies have shown that endochins (4(1H)-quinolones) 3 and acridines (figure 1.1) have been found to exhibit antimalarial activity4. The research aims to create tetrahydroacridone derivatives as a hybrid of endochins and acridines by utilizing structureactivity relationship (SAR) studies of the benzenoid ring of the 1,2,3,4-tetrahydroyacridone scaffold by following the Topliss operational scheme. 1,2,3,4-tetrahydroacridones are generated through a linear synthesis that involves the cyclization of substituted anthranilic acids by refluxing in phosphorus oxychloride (POCl3) with cycloalkanones to produce various 9-chloro- 1,2,3,4-tetrahydrohydroacridines. Subsequent hydrolysis in acetic acid gives the respective 1,2,3,4-tetrahydroacridone. Since 1,2,3,4-tetrahydroacridones contain some similar structural properties to naphthoquinolone and ubiquinone5 (an important feature in the parasite’s energy generation), it is hypothesized that 1,2,3,4-tetrahydroacridones are potential inhibitors of the parasite’s respiration at the site of the bc1 complex. Once compounds are synthesized they are screened in vitro against blood stage P. falciparum.

Comments

Chemistry

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