The development of novel carbazole-based peptoid antibacterials to challenge the deadly superbugs

394 Pages·2013·5.22 MB·English

University of Wollongong
Research Online
University of Wollongong Thesis Collection University of Wollongong Thesis Collections
2002
The development of novel carbazole-based peptoid
antibacterials to challenge the deadly superbugs
Helen M. Witchard
University of Wollongong
Recommended Citation
Witchard, Helen M., The development of novel carbazole-based peptoid antibacterials to challenge the deadly superbugs, Doctor of
Philosophy thesis, Department of Chemistry, University of Wollongong, 2002. http://ro.uow.edu.au/theses/1203
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The Development of Novel Carbazole-
Based Peptoid Antibaeterials to
Challenge the Deadly Superbugs
Helen M. Witchard, B.Med.Chem (Hons)
A thesis submitted in fulfilment of the requirements for
the degree of Doctor of Philosophy
Department of Chemistry
University of Wollongong
Wollongong, AUSTRALIA
March 2002
1
Declaration
The work described in this thesis does not contain any material that has been
submitted for the award of any higher degree in this or any other University, and to the
best of my knowledge and belief contains no material previously published by any other
person, except where due reference has been acknowledged.
Helen M. Witchard
March 2002
11
Publications
Sections of the work described in this thesis have been reported in the following
publications:
1 Bremner, J. B.; Coates, J. C; Keller, P. A.; Pyne, S. G.; Witchard, H. M. "The
Synthesis of a Novel Carbazole-linked Cyclic Peptoid with Antibacterial
Activity." Synlett 2002, 2, 219-222.
2 Bremner, J. B.; Coates, J. C; Coghlan, D.; David, D.; Keller, P. A.; Pyne, S. G.;
Witchard, H. M. "Peptoid Compounds." The Australian Provisional Patent
Application No. PR6044/01. Filed June 29, 2001.
Ill
Acknowledgements
Sincere thanks must be offered to the many people who have guided and assisted
me throughout the past three years. I will be forever grateful for their kindness, help
and encouragement, as I know this thesis would not have been possible without them. I
would like to express my gratitude to the following people
To my supervisors John, Steve and Paul for their guidance, tolerance and
encouragement throughout the three years of this PhD project. There were a few
occasions where I thought my project had 'hit the wall' or gone as far as it could, but
they managed to find a way out of these difficult situations. I feel very lucky to have had
the benefit of their experience and extensive knowledge, especially in the area of
synthetic organic chemistry.
To Dr Jonathan Coates (AMRAD) for his genuine interest in my work and for
carrying out all of the antibacterial testing assays for this project. Many days would
have been devoted to the testing of my compounds, and for that, I am sincerely grateful.
To the computer genius Tien Pham — you have no idea how much I appreciate
your generous assistance, which I pursued on many occasions, and the many hours you
spent setting up my home computer. With virtually no computer knowledge of my own, I
have been very dependent on the help you have given so readily - THANKS TIEN!!
To Larry Hick, Roger Kanitz and John Korthfor running numerous MS samples
over the past three years, and for letting me loose on their Quattro spectrometer, so I
was able to run my own LRMS samples, as frequently as was required, during the
difficult stages of the project.
IV
To Sandra, Ellen, Graham Ball (UNSW) and Hilda Stender (UNSW), thanks for
your patience and kind assistance with the running and processing of NMR
experiments. Thanks especially to Graham for his helpful spectra interpretations.
To all the members of the Pyne group, for their friendship and the fun times, and
for being tolerant of my sometimes eccentric nature.
To Alison Ung, for always being prepared to give helpful advice and assistance
whenever it was required, and for keeping the Pyne lab and its members in good order.
To those people who have been supportive and helpful over the years: Sue, Jody,
Dan and Tim, thanks for all the good advice and the fun conversations we had.
To my parents, for their continuing support and encouragement, which has
been, and I know always will be, unconditional.
To my good friend Tien Luu, for all those interesting little 'hypothetical
situation' discussions we had in the years past, and for always being prepared to listen
when I needed her support. Thanks also for those terribly long and expensive phone
calls you made from Cambridge in the UK - / will forever feel guilty over these.
And finally, to my good buddy Steve Ralph, thank you for making the rough
times bearable, and for always being prepared to listen when I needed to vent my
frustrations. No doubt, your friendship has been a source of motivation over the past
few years, and I hope it will continue to be in the years to come.
V
List of Abbreviations
Ac acetyl
AIBN 2,2'-azobisisobutyronitrile
Ala alanine
Anal analysis
Ar aryl
Arg arginine
atm atmosphere(s)
Boc tert-butox yc arbon yl
br broad (spectral)
C cytosine
°C degrees Celcius
calcd calculated
CC1 carbon tetrachloride
4
C D deuterio benzene
6 6
CDC1 deuterio chloroform
3
CD C1 deuterio dichloromethane
2 2
CD3CN deuterio acetonitrile
(CD ) CO deuterio acetone
3 2
CD3OD deuterio methanol
(CD ) SO deuterio dimethyl sulfoxide
3 2
CH3CN acetonitrile
p-Chloranil 2,3,5,6-tetrachloro-1,4-ben:
CI chemical ionization (in mas
chloride
CNS
coagulase-negative staphylococci
COSY
correlation spectroscopy
5
chemical shift in parts per million downfield from TMS
d
doublet (spectral)
ID
one-dimensional (in NMR)
2D
two-dimensional (in NMR)
DCC
N,./V-dicyclohexylcarbodiimide
DCM
dichloromethane
DCU
Af,iV-dicyclohexylurea
DDQ
2,3-dichloro-5,6-dicyano-l,4-benzoquinone
DEPT
distortionless enhancement by polarization transfer
DMAP
4-(dimethylamino)pyridine
DMF
dimethylformamide
DMSO dimethyl sulfoxide
EDCI
1 -[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
EI
electron impact (in mass spectrometry)
eq equivalent(s)
ES electrospray (in mass spectrometry)
ESI-MS electrospray ionization mass spectrometry
Et ethyl
EtOAc ethyl acetate
EtOH ethanol
FDA
Food and Drug Administration
Fmoc
9-fluorenylmethoxycarbonyl
Vll
g gram(s)
G guanine
h
hour(s)
HC1
hydrochloric acid
HMBC
heteronuclear multiple bond coherence
HOBT
1-hydroxy-l//-benzotriazole
HRMS
high-resolution mass spectrometry
HSQC
heteronuclear single quantum coherence
Hz
hertz
IR
infrared
J
coupling constant (in NMR)
L
litre(s)
Lac
lactate
Lys
lysine
micro
m
multiplet (spectral), milli
M moles per litre
Me methyl
MeOH methanol
MHz megahertz
MIC
minimum inhibitory concentration
min minute(s)
mol mole(s)
mp melting point
MRSA
methicillin-resistant Staphylococcus aureus