Development of berberine-based derivatives as novel antimicrobial agents

236 Pages·2005·1.32 MB·English

University of Wollongong Thesis Collections
University of Wollongong Thesis Collection
University of Wollongong Year 
Development of berberine-based
derivatives as novel antimicrobial agents
Siritron Samosorn
University of Wollongong
Samosorn, Siritron, Development of berberine-based derivatives as novel antimicro-
bial agents, PhD thesis, Department od Chemistry, University of Wollongong, 2005.
http://ro.uow.edu.au/theses/281
ThispaperispostedatResearchOnline.
http://ro.uow.edu.au/theses/281

DEVELOPMENT OF BERBERINE-BASED DERIVATIVES
AS NOVEL ANTIMICROBIAL AGENTS

A thesis submitted in fulfillment of the requirements of the award of
the degree
DOCTOR OF PHILOSOPHY
from

UNIVERSITY OF WOLLONGONG

by
Siritron Samosorn, M.S. (Applied Chemistry)

Department of Chemistry
University of Wollongong
Wollongong, Australia
June 2005
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.

Siritron Samosorn
8th June 2005

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Publications

Sections of the work described in this thesis have been reported in the following
publications:
1. Bremner, J. B.; Samosorn, S. “8-Allyldihydroberberine as an Alternative
Precursor for the Synthesis of 13-Substituted Berberine Derivatives.” Aust. J.
Chem. 2003, 56, 871-873.
2. Bremner, J. B.; Samosorn, S.; Ambrus, J. I. “N-Acylation of 5-Substituted
Indoles with Carboxylic Acids via DCC Coupling.” Synthesis, 2004, 16, 2653-
2658.
3. Samosorn, S.; Bremner, J. B.; Ball, A.; Lewis, K. “Synthesis of Functionalised
2-Aryl-5-nitro-1H-indoles and their Activity as NorA Efflux Pump Inhibitors”
Biorg. Med. Chem. to be submitted.

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Acknowledgements
My sincere thanks go to everyone who has assisted and supported me throughout
the four years of this PhD project.
To the following financial support: The University of Wollongong, Australia and
Srinakarinwirot University, Thailand for providing me scholarships.
To my supervisor, Prof. John Bremner, for your encouragement and guidance
throughout the difficult situations. I am very grateful and appreciative for your
tremendous academic and personal support, without you this work would not be
possible.
To Dr. Kirsten Benkendorff and Dr. Carey Rogers for providing me your
microbiology skills and teaching me how to manipulate and undertake the antibacterial
testing.
To Prof. Kim Lewis and Anthony Ball, Northeastern Universisty, USA for your
microbiological specialist aspect, and carrying out the bacterial multidrug resistance
pump inhibitory testing together with antibacterial testing; Dr. Sumalee
Kamchonwongpaisan, National Science and Technology Development Agency,
Thailand for conducting antimalarial testing; Avexa, Ltd., Australia for performing the
antibacterial testing; and Ms. Kara Vine for operating cytotoxicity testing for my
samples.
To my ‘English teacher’ and ‘Chemistry son’, Joseph Ambrus, for teaching me all
those English words, correcting and proof-reading my thesis. I will miss answering you
all those chemistry questions.
To the Bremner research group: Hadi, Jo, Johana, Julie, Montra, Neal, Pat,
Phurpa, Tom, Waya, and Zinka for your friendships. Special thanks go to Dr. Colette
Godfrey, Ms. Jane Faragalla and Dr. Susan McGinty, who guided and helped me in the
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lab through the beginning of my experimental work, which I really impress and
appreciate.
To spectroscopy technical staff of the Chemistry Department: Dr. Wilford Lie,
Ms. Sandra Chapman, Dr. John Korth, Mr. Larry Hick, Ms. Karin Maxwell, and Mr.
Roger Kanitz for providing assistance, undertaking and training IR, NMR, and Mass
Spectrometry.
To my wonderful parents for your love and unconditional support in everything I
have required throughout my life. I am everlastingly grateful for all your love and
support.
To my lovely husband, Ong, who has greatly cared, constantly supported, and
been next to me no matter what circumstances.

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List of Abbreviations
ABC ATP-binding cassette
AcOH acetic acid
ArCH CH in aromatic ring
ArH aromatic proton
ATP adenosine triphosphate
ax axial
Boc tert-butoxycarbonyl
(Boc) O di-tert-butyl dicarbonate
2
br.d broad doublet
br.m broad multiplet
br.s broad singlet
br.t broad triplet
Bu butyl
tBuOH tert-butanol
oC degree celcius
C carbon
C. albicans Candida albicans
CI chemical ionization
13-CPTC 13-cyclopentylthio-5-hydroxy tetracycline
d doublet
DCC dicyclohexylcarbodiimide
DCM dichloromethane
dd doublet of doublets
v
ddd doublet of doublet of doublets
decomp. decomposition
DEPT distortionless enhancement by polarization transfer
DHU dicyclohexylurea
DMAP dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DNA deoxyribose nucleic acid
dt doublet of triplet
E. coli Escherichia coli
EDCI 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
E. faecalis Enterococcus faecalis
E. faecium Enterococcus faecium
EI electron impact
eq (molar) equivalent/equatorial
ES electrospray
Et ethyl
EtOAc ethyl acetate
EtOH ethanol
FDA food and drug administration
g gram/s
gCOSY gradient correlation spectroscopy
gHMBC gradient heteronuclear multiple bond correlation
gHSQC gradient heteronuclear single quantum correlation
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H hydrogen/proton
HOBt 1-hydroxybenzotriazole
HPLC high performance liquid chromatography
HRMS high resolution mass spectrometry
HRP horseradish peroxide
Hz Hertz
IC inhibitory concentration 50%
50
J coupling constant
Lit. literature
m multiplet
M molar (moles per litre)
m.p. melting point
m/z mass to charge ratio
MATE multidrug and toxic compound extrusion
MDR multidrug resistance
Me methyl
MeOH methanol
MFS major facilitator superfamily
5'-MHC 5'-methoxyhydnocarpin
MHz mekahertz
MIC minimum inhibitory concentration
min minute/s
mL milliliters
µM micromolar
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