Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2008. / Includes bibliographical references. Also available in electronic version.

Thesis (M.S.)--Brigham Young University. Dept. of Chemistry and Biochemistry, 2007. / Includes bibliographical references (p. 117-122).

In spite of great effort aimed at eradication, the malaria epidemic still claims over 600,000 lives each year, and 50% of the world is at risk of contracting the disease. The most deadly form of malaria is caused by Plasmodium falciparum, which is spread from human to human via the female Anopheles mosquito. P. falciparum's lifecycle, which includes both sexual and asexual reproduction, facilitates rapid evolution in response to drug pressure, resulting in the emergence of resistant strains against every antimalarial medication that has been deployed. There is a great need for new antimalarial drugs. Chloroquine (CQ), an aminoquinoline drug deployed in the 1940s, was an inexpensive, effective and safe drug but now has been rendered ineffective throughout much of the tropical regions due to the emergence of CQ-resistant strains of P. falciparum. A new class of hybrid drugs, called Reversed-CQs, has been developed by linking a molecule with a CQ-like moiety to a molecule with a reversal agent (RA) moiety; an RA is a chemosensitizer that can reverse CQ-resistance. The prototype Reversed-CQ, PL01, was shown to be effective in vitro against sensitive and resistant P. falciparum cell cultures, with IC50 values of 2.9 and 5.3 nM, respectively, in comparison to IC50 values for CQ which were 6.9 and 102 nM, respectively. In the course of the Reversed-CQ research, PL74 was synthesized with a pyridine ring replacing the quinoline ring. It was expected that PL74 would display reversal agent activity but would not display antimalarial activity. However PL74 showed antimalarialactivity with IC50 values of 185 and 169 nM in vitro against CQ-sensitive and CQ-resistant strains, respectively. In the investigation of PL74 it has been found that this molecule has a pyridinium salt structure, novel to the Reversed-CQ compounds, and through a structure-activity relationship (SAR) study, it was shown to have activity that may indicate a mode of action different from the Reversed-CQ compounds. A study of the literature revealed that pyridinium salt compounds, with some similarity to PL74, were found to operate as choline analogs inhibiting the biosynthesis of phosphatidylcholine as their main antimalarial mode of action.

It has been observed by Kröhnke, that certain N-substituted pyridinum compunds possess both pressor and ergot-like activity. It has also been reported that both N-phenacylpiperidinium hydrochloride and the corresponding carbinol have some value as local anaesthetics.

Utilizing primary amines as alkyl coupling partners has garnered attention in recent years due to their widespread availability, facile preparation and purification, and presence in a variety of common building blocks. The reemergence of Katritzky salts has enabled deaminative alkylation and arylation of alpha primary and alpha secondary amines. The Rovis group has developed deaminative conditions for alpha tertiary amines utilizing redox-active imines to generate tertiary carbon-centered radicals. Herein, we couple this tertiary alkyl radical to haloarenes to generate benzylic quaternary centers, a common motif in pharmaceuticals and natural products. We then applied this methodology in the realm of isotopic exchange to generate 15N-primary amines from their naturally occurring 14N-analogues. By activating alpha primary and alpha secondary amines to Katritzky pyridinium salts and alpha tertiary amines to redox-active imines, we can engage primary alkyl amines in a late-stage isotopic exchange with complete and selective isotopic labeling.

No description available.

2-Benzyloxy-1-methylpyridinium trifluoromethanesulfonate (commonly referred to as benzyloxypyridinium triflate or Dudley’s salt) is a novel protecting reagent for the conversion of an alcohol functional group into a benzyl ether. This novel protecting reagent allows for protection of an alcohols, carboxylic acids, and other nucleophiles under mild conditions. The two traditional methods of forming this benzyl ether rely on either basic (Williamson ether synthesis) or acidic (coupling via trichloroacetimidate with a strong acid) conditions which may potentially decompose sensitive substrates. This research will investigate the mechanism by which benzyloxypyridinium triflate decomposes. Investigation of benzyloxypyridinium triflate will require two aspects, synthesis of various derivatives and a rate study. The synthesis of benzyloxypyridinium triflate derivatives (broadly named benzyloxypyridinium salts) will result in a series of new compounds, along with new synthetic routes to make them. Testing the derivatives to ensure they form the expected benzyl ether or ester then allows for investigation of the rate for each derivative as they form the benzyl ether. Among the various techniques that may be employed to study the mechanism, rate studies will be a significant portion of data used to draw a conclusion. Each derivative of the benzyloxypyridinium triflate is designed to affect the rate of decomposition thereby changing the rate of benzyl ether formation by either promoting or impeding the formation of a carbocation. Monitoring the rate of each derivative and comparing that rate to the rate of the benzyloxy- pyridinium triflate will give insight to a mechanistic pathway, indicating whether the pathway is more unimolecular or bimolecular. An immediate application of a known mechanism could lead to more desirable conditions for the benzyloxypyridinim triflate when forming the benzyl ether. In addition, having an understanding of the mechanism allows for the utility of arylmethylpyridinium salts to be expanded by allowing the pyridinium salt to deliver a variety of different electrophiles. The mechanism will also allow for different nucleophiles to trap the corresponding electrophile from the pyridinium salt. / No title page or introductory pages in thesis body PDF. / Department of Chemistry

Because of the structural analogies between these compounds and several other physiologically active compounds, such as chloroamphenicol, 4,4'-diaminodiphenyl sulfone, and 2,2-bis-(p-aminophenyl)-1,1,1-trichloroethane, a more complete study of the reduction products and the sequence of catalytic reduction of N-(4-nitrophenacyl)-4-(1-hexyl)pyridinium bromide was made in this investigation.