Synthesis of Pyrrolo[1,3]-Diazepines and Potential Poxvirus Resolvase Inhibitors

This thesis describes our efforts toward the development of a dynamic combinatorial library using pyrrolo[1,3]-diazepines. During our work, I have demonstrated the ability to hydrolyze and recyclize the diazepine core via the condensation of several different aldehydes to afford novel diazepine derivatives. Additionally, I have been able to modulate the electronic and steric properties of the diazepine scaffold through substitution on the pyrrole core. My work towards finding suitable conditions for a thermodynamically controlled dynamic exchange reaction have shown that while hydrolysis of the diazepine scaffold seems to be favored, recyclization of the resulting amine intermediate appears to be disfavored. As a second project I describe our efforts toward the development of a library of pyrimidinone-based potential poxvirus resolvase inhibitors. Utilizing the multi-component Biginelli reaction, I have synthesized a small library of pyrimidinones attached to potential chelating functionalities, including the di-keto acid moiety. Biological testing has resulted in the discovery of a carboxylic acid containing pyrimidinone (MAL1-265) that possesses moderate fowlpox resolvase inhibitory activity (IC50 16 μM)