The design and synthesis of heteroatom-containing small molecules for the chemotherapy of infectious diseases
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Organic medicinal chemistry is the science dedicated to the development of new synthetic method and their potential usage in drug discovery. It is becoming increasingly clear that heteroatom chemistry plays an important role in lead discovery and modification. In Chapter 2 the preparation and spectral characteristics of olefins through thermal elimination is reported. The reaction of o-nitro phenyl sulfoxide precursor under toluene reflux is shown to proceed cleanly and quantitatively via a concerted mechanism; the ratio of Z- and E-isomers is altered depending on different α- or β- substitution groups. The use of sulfur chemistry in synthetic transformation is further investigated in Chapter 3. An asymmetrical method to synthesize β-lactams using photochemistry as the key in the synthetic steps has been developed. Photooxidation of L-cysteine thiazolidine hydroxamate esters afforded C-5 hydroxylated products which when cyclized and deprotected gave the corresponding 3R, 4R monocyclic β-lactam platforms. The investigation on a unique antimicrobial platform is next followed in Chapter 4. A group of phosphonium salts were made using atovaquone as lead compound to treat parasitic disease (i.e., malaria). Compound 28k exhibited moderate in vitro antimalarial activity (17 ± 4 nM) against chloroquine resistant (W2) Plasmodium falciparum. The results demonstrate the advantage of attaching a triphenylphosphonium-based mitochondriotropic group to increase subcellular concentration in the plasmodial mitochondria, within which the drug target is located. Preliminary toxicity and a structure-activity relationship studies of interested compounds are also included.