Nitrogen-containing heterocycles are commonly seen both in the pharmacophores of drug molecules and also in the cores of natural products. This dissertation explores the functionalization of nitrogen-containing heteroaromatic rings to access the highly substituted scaffolds of bioactive molecules within two distinct projects. Part I features medicinal chemistry efforts in the synthesis and derivatization of functionalized quinolines, indoles, pyridines, and pyrroles as novel HIV allosteric integrase inhibitors. Alternatively, part II involves synthetic efforts towards the indole subunit of the bioactive natural product, sespendole.
HIV integrase (IN) plays a crucial role in the replication of the HIV virus as it catalyzes the transfer of the viral genetic code into the host genome. Raltegravir (Merck & Co) is the first FDA drug targeting this strand transfer catalytic activity; however, rapid viral mutation has since led to drug-resistance and a renewed interest in developing new integrase inhibitors. In this regard, the host enzyme lens-epithelium derived growth factor (LEDGF)-integrase interaction served as new targets for generating novel integrase inhibitors. Recently, independent studies by other groups resulted in the identification of 2-(quinolin-3-yl)acetic acid derivatives as allosteric integrase inhibitors (ALLINIs). Development of synthetic routes to these inhibitors and a series of structural analogues have facilitated elucidation of the novel multifunctional mechanism of action for this class of compounds. Additionally, the design of novel scaffolds as ALLINIs was investigated through a scaffold hopping technique, the derivatization of leads from an in silico screen, and a fragment-based drug design approach. These drug discovery methods have resulted in the syntheses of a structurally diverse class of compounds that have provided an insight on the structural and functional requirements of the binding pocket.
Sespendole, an indolosesquiterpene alkaloid isolated from the fungus Pseudobotrytis terrestris FKA-25, was reported as a potent inhibitor of lipid droplet synthesis. The proposed biosynthesis of sespendole, which involves a carbocation induced cyclization/rearrangement cascade, initially intrigued our group and spurred our interest in the synthesis of this complex molecule. This dissertation focuses on the synthesis of the highly substituted indole subunit of sespendole. Direct functionalization of the indole nucleus at the C4 and C5 positions via application of Bartoli's Grignard addition and halogen-metal exchange chemistry resulted in the successful synthesis of the fully substituted indole subunit of sespendole.