Synthetic Efforts Towards Creating New Analogs of Zantrin Z3, A Selective Inhibitor of FtsZ, and, Efforts Towards the Total Syntheses of Chrysophaentin E

Antibiotic resistance has been increasing within the past few decades and has developed into a bigger issue for our society today. Currently we are running out of therapeutics to combat antibiotic resistance, yet the need for novel small molecules that target bacterial infection increases. This thesis describes two efforts toward synthesizing small molecules, both of which could lead to a new antibiotic. Zantrin 3 (also known as Z3), a small molecule found in a high-throughput-screening assay, is a selective inhibitor of the filamenting temperature-sensitive mutant Z protein (FtsZ)--- a protein responsible for cell division. This lead molecule has a half-maximal inhibitory concentration (IC50) of 20 micro molar; in FtsZ Bacillus subtilis (referred to subsequently as BsFtsZ). Zantrin 3 is suggested to target FtsZ in vitro by inhibiting GTPase hydrolysis. The first chapter describes the process of making several analogs to further study the structure-activity relationship (SAR) of zantrin 3 in order to produce a better inhibitor of FtsZ.;Similarly, a class of natural products called chrysophaentins has also been found to inhibit FtsZ with a half-maximal minimum inhibitory concentration (MIC50) as low as 1.8 micro molar in strains of Staphylococcus aureus FtsZ (referred to later as SaFtsZ). Given that these natural products were isolated in milligram quantities only, a synthetic route is needed to confirm their biological activity as well as their structure identity, including both the absolute and relative stereochemistry. The second chapter of this thesis details the progress made toward chrysophaentin E, one of the chrysophaentin derivatives. The synthesis of chrysophaentin E includes joining two bisdiaryl units by an aromatic ether linkage and an unusual E-chloroalkene moiety that have not been seen previously in any known natural products.