Advisor

David H. Peyton

Date of Award

Fall 12-11-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry

Department

Chemistry

Physical Description

1 online resource (xii, 348 pages)

Subjects

Quinoline, Chloroquine, Plasmodium falciparum, Antimalarials -- Therapeutic use -- History

DOI

10.15760/etd.2112

Abstract

Intermittent fevers caused by Plasmodium parasites have been known for millennia, and have caused untold human suffering. Today, millions of people are afflicted by malaria each year, and hundreds of thousands die. Historically, the most successful synthetic antimalarial drug was chloroquine, as it was safe, inexpensive, and highly efficacious. However, plasmodial resistance to chloroquine now greatly limits its utility. Previously in our laboratories it has been shown that attachment of a "reversal agent moiety" to the side chain of chloroquine can result in the restoration of activity against chloroquine-resistant strains of P. falciparum malaria. In the first part of the work presented here, a study has been made of the importance of the quinoline ring substitution pattern to the activity of such reversed chloroquines. The compounds presented here include those bearing a substituent in the 2-, 5, 6-, 7-, and/or 8- position, and include those with chloro, bromo, iodo, fluoro, nitro, trifluoromethyl, methyl, and methoxy substituents. For reversed chloroquines, 2-, 5-, and 8- substituents have been found to decrease in vitro antiplasmodial activity against P. falciparum relative to 7-chloro substitution, whereas 6- and 7- substituted compounds with various substituents have in many cases similar activity to that of 7-chloro substituted compounds. Little difference has been observed between 6- and 7- substitution, or between chlorine and a methyl group in position 6. In most cases these effects on activity are directionally similar to those observed for chloroquine analogs without an attached reversal agent, but the magnitude of the effect is generally smaller, suggesting that the activities of reversed chloroquines are less affected by modifications to the quinoline ring system than is true for chloroquine analogs without an attached reversal agent.

The second portion of this work presents an asymmetrical bis-quinoline (PL241) that is highly active against P. falciparum malaria, with an IC50 of less than 0.1 nM for all strains tested. Mechanistic studies have been performed in which the substitution patterns of the two quinoline rings of PL241 are modified in ways that indicate that either ring system is equally capable of participating in the antimalarial activity of these compounds. The excellent in vitro antiplasmodial activity of PL241 makes this a compound of great interest for further development as a potential antimalarial drug.

In the third part of this work, a survey has been made of antimalarial treatments recommended in the European medical literature from the time of Pliny the Elder (active in the first century A.D.) through the advent of modern malaria chemotherapy in the early twentieth century. In the fifteen primary sources utilized in this study, 251 distinct substances - primarily plants - were identified as having likely been used in the treatment of malaria. Of the 38 substances that were described in three or more sources, at least fifteen have been examined by other workers for antiplasmodial activity; in many cases, they were found to have antiplasmodial activity in vitro or in vivo. However, the majority of the phytotherapies for malaria identified in this project have not yet been tested against Plasmodium species, and may provide valuable leads in the search for new compounds active against drug-resistant malaria.

Persistent Identifier

http://archives.pdx.edu/ds/psu/13247

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