Year

2002

Degree Name

Doctor of Philosophy

Department

Department of Chemistry

Abstract

Research on the development of novel, carbazole-based peptoids as potential new antibacterial agents is presented in this thesis. The series of macrocyclic peptoid compounds were designed to act as vancomycin mimics, and possessed many of the structural features believed to be necessary for antibacterial activity. Being less conformationally restricted than vancomycin, these compounds have the potential to be active against both vancomycin-resistant and vancomycin-susceptible strains of enterococci, and other Gram-positive species.

Chapter 2 describes the synthesis of a number of structurally variant cyclized and uncyclized peptoid derivatives, which were produced from a multi-step (15) synthetic route, in overall yields of around 11%. The basic synthetic strategy involved the initial formation of an appropriately derivatised carbazole scaffold, to which a dipeptide moiety was attached, followed by cyclization through a ring-closing metathesis reaction. In preparation for this key metathesis reaction, two remote ally] substituents were incorporated into the peptoid structure during earlier steps in the synthetic route. The incorporation of a racemic constituent into the synthetic route resulted in the formation of diastereoisomer mixtures. Consequently, the spectral data for the peptoid derivatives was considerably complex, arising from the presence of diastereoisomers, amide rotamers and cis/trans isomers (alkene derivatives). Detailed 2D NMR analysis was required to characterize these diastereoisomers.

In chapter 3, the results from the antibacterial testing assays, against Staphylococcus aureus, are discussed and potential structure-activity trends highlighted. The activities obtained for a smaller set of uncyclized target compounds suggested that cyclization is probably not necessary for activity, as these derivatives were seen to have a similar efficacy to the most active cyclized peptoids. Additionally, the carbazole N-Boc peptoids were found to have the best antibacterial activity (MIC 15 µg/mL against Staphylococcus aureus for one such derivative), implying the N-Boc substituent is an important feature for activity, together with the inclusion of a basic amino acid residue (bearing a protonated terminus).

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.