Document Type


Publication Date

Fall 12-10-2010


Roman Manetsch

Advisor Email


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.