Design and synthesis of novel cationic peptide antibiotics

The results of the research on the development of novel cationic peptoids as potential new antibacterial agents is presented in this thesis. The series of macrocyclic peptoids prepared in this study arises from a previously identified lead which was designed to act as a vancomycin mimic, and possessed many of the features believed to be necessary for antibacterial activity. Chapters 2 and 4 describe the design and synthesis of a number of structurally different cyclised and linear peptoids, which were produced from a multi-step synthetic pathway. The basic strategy involved the synthesis of a hydrophobic scaffold, to which a cationic peptide was attached. Compounds described in Chapter 2 contained two remote allyl substituents which were utilized in the reliable ring-closing metathesis reaction to produce the desired macrocycles. Subsequent removal of the amino acid residue protecting groups yielded the desired targets for antibacterial testing. A total of 163 compounds were synthesized, including 146 new compounds. In Chapters 3 and 5, the results from the antibacterial testing assays against Staphylococcus aureus (Chapters 3 and 5) and several vancomycin-resistant enterococci (VRE) strains (Chapter 5), are discussed and structure-activity trends are highlighted. It was found that for antibacterial activity against both Staphylococcus aureus and VRE strains, a (S)-1,1’-binaphthyl hydrophobic scaffold must be present (MIC 3.9 g/mL against Staphylococcus aureus and 15.6 g/mL against the VRE for one such derivative). Chapter 6 reports the screening of several peptoids against the HIV integrase enzyme. From the screening, key structure activity trends were observed and a preliminary computational model indicating the mechanism of binding and inhibition is proposed. Four target compounds were prepared to justify the preliminary model.