The Synthesis and Study of Small Molecule Inhibitors of Bacterial Cell Division Protein FtsZ

FtsZ is a protein that plays a central role in bacterial cell division and is an attractive target for the development of new antibiotics. The objective of this research was to synthesize natural and designed small molecules that inhibit the bacterial cell division protein FtsZ. In Chapter 1, the concise, enantioselective synthesis of (+)-totarol, a diterpenoid natural product, will be described. Chapter 2 delineates a diverted total synthesis strategy where an advanced intermediate is utilized to introduce different functionality on the A-ring of totarol. The structure-activity relationship (SAR) studies showed a para-cyanoindolototarol derivative to be more potent than totarol itself, but did not inhibit FtsZ in vitro. In Chapter 3, small known molecule inhibitors of FtsZ are investigated. This chapter mainly comprises of the effort towards screening these FtsZ inhibitors using an enzyme-coupled GTPase assay. Chapter 3 narrows down the small molecule inhibitors and settles on a new lead compound, zantrin Z3 for further SAR studies.