Development of berberine-based derivatives as novel antimicrobial agents PDF
Preview Development of berberine-based derivatives as novel antimicrobial agents
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 i 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. ii 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 iii 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. iv 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 vi 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 vii
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