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A thesis submitted in fulfilment of the requirements for the degree of
M. Sc. in Organic Chemistry (Osmania University, India)
Declaration I certify that except where due acknowledgement has been made, this research is that of the author alone; the content of this research submission is the result of work which has been carried out since the official commencement date of the approved research program; any editorial work, paid or unpaid, carried out by a third party is acknowledged; and ethics procedures and guidelines have been followed. In addition, I certify that this submission contains no material previously submitted for award of any qualification at any other university or institution, unless approved for a joint-award with another institution, and acknowledge that no part of this work will, in the future, be used in a submission in my name, for any other qualification in any university or other tertiary institution without the prior approval of the University, and where applicable, any partner institution responsible for the joint-award of this degree. I acknowledge that copyright of any published works contained within this thesis resides with the copyright holder(s) of those works. I give permission for the digital version of my research submission to be made available on the web, via the University’s digital research repository, unless permission has been granted by the University to restrict access for a period of time. I acknowledge the support I have received for my research through the provision of an Australian Government Research Training Program Scholarship. Umadevi Kizhakke Purakkel 30 November 2021
Acknowledgement I express my gratitude to everyone who helped shape me into a person that I am today. My research program would not have been possible without the help, direction, encouragement, and support of many people, and I am grateful to everyone who has contributed to my thesis. I express heartfelt gratitude and deep sense of appreciation to all people mentioned here as well as if any of the person had been missed unintentionally. I would like to thank my supervisors, Dr. Subashani Maniam (RMIT), Dr. Prathama S. Mainkar (IICT) and Prof. Ewan Blanch (RMIT) for providing me the opportunity, to work with them and enhancing my career. Your endless motivation and guidance made my PhD journey bearable. Thanks for the steady support during difficult times and helping me to keep going. Without you all, I would not be able to complete the doctoral research. The experience I gained from you all are adorable. Thanks for your every word which were very inspirational to mould me. I extend my sincere and genuine gratefulness to the director of IICT, Dr. S. Chandrasekhar and vice chancellor of RMIT, Martin Bean, and Prof. Suresh Bhargava (RMIT) for providing me an excellent opportunity to work in both well reputed institutes through RMIT-IICT joint research program. It has been helpful in enriching my knowledge, research, skills and career. Once again, I thank Prof. Suresh Bhargava for the endless support and motivation provided. I express my heartfelt gratitude to Dr. M. Y. Valli for the guidance and support provided during my research. Thank you for your unwavering support. I extend my thanks to D.V. Sai Prasad and Monica (BITS Pilani), Prof. D. Sriram (BITS Pilani), Dr. G. praveena (IICT) and National Mol bank (IICT) for screening samples for biological activity. I thank Dr. Surender Jadav for performing docking studies. I express my gratitude to Stuart Hombsch and Dr. Saeideh Ostovar for their assistance in Raman spectroscopy. I wish to acknowledge Dr. James Tardio, Dr. Rajesh Ramanathan, Prof. Samantha Richardson, Prof. Michelle Spencer, Prof. Gary Bryant, Prof. Lathe Johnes, Dr. Ravi Shukla, Chenglong Xu, Mrs. Zahra Homan, Mrs. Nadia Zakhartchouk, Mr. Bebeto Lay and to the scientists of IICT, Dr. S. Sridhar, Dr. R. S. Prakasham, Dr. Rajendar reddy, Dr. Haridas B. Rode, Dr. Naveen Kumar and Dr. Sriram murthy. I thank Dr. Lisa Dias, Jennifer O'connor,
Dr. Emma Goethals, Mrs. Piyumi Wickramaarachchi, Mrs. Kriti Sharma and Mrs.Jenny from RMIT for making things smooth and comfortable during my candidature at RMIT. I thank for the assistance provided by NMR, Mass, IR, MNRF and other analytical divisions, administration, technical staffs and library of IICT and RMIT. I express warm regards to Dr. S. Nageshwar Rao, Dr. Aditi Danda, Komal Sagu, P. I. Ramesh and M. Preeti, Sulthan, Dr. Ganga Reddy, Y. Barath Kumar for helping in research. I thank my RMIT co-scholars Dr. Hiranya de silva, Jeremy Landry, Patience Shoko, Anthony Dahdah, Timothy Ong, Biserka Lakic, A. K. Hundal, Dr. Poonam Yadav and Roxanne. I would like to extend thanks to my RMIT-IICT co-scholars Dr. Govind Reddy, Dr. G. Pradeep Reddy, Dr. A. Ramaraju, Dr. J. Ranjithkumar, Dr. Tunki Lakshmi, Dr. K. Paramita, Ramesh, Sudhakar, Aparna, Nazia, Chandramohan Reddy for the fun and stimulating discussion during the PhD. My sincere thanks to IICT lab-mates Bharath, Arun, Vishnu, Damaodar, Hemalatha and Sriram. I thank my father (Late. R. K Kutty) without whom I would not be able to reach here. To all my family members, mother (Suja), brother (Sreekanth), spouse (Kurumaiah); thank you for your affection, continuous support and encouragement. I also thank Mr. Sivasankar, Ms. Santha, Ms. Madhavi, Mr. Parameshwar and Ms. Bhudevi for their support.
Chapter III: Design, Synthesis and Biological Evaluation
Chapter V: Characterisation of H127 Analogues using
Table 15 : MIC of compounds 186 - 202 against M. tuberculosis. .......................................... 136 Table 16 : Observed Raman bands for piperidine derivatives of TTz ................................... 157 Table 17 : Observed amide I bands for piperidine derivatives of TTz .................................. 164 Table 18 : Observed PH-I bands and their relative intensity with respect to amide I band for piperidine derivatives of TTz……………………………………………………………… Table 19 : Observed C-N stretching vibration of triazole ...................................................... 166 Table 20 : Observed Raman and IR bands between 1100 - 1600 cm-^1. .................................. 167 Table 21 : Observed C-S stretching vibrations ...................................................................... 168 Table 22: Observed amide I and PH-I vibrations in Raman and IR spectra of TTz based compounds with different N - heterocycles…………….……………………………...…… 172 Table 23: Observed amide I and PH-I bands in Raman spectra of TTz based compounds with different substituents at carbon linker……………….………………………...…………… List of schemes Scheme 1 : Retrosynthetic approach for H127 and its analogues. ........................................... 62 Scheme 2 : Synthesis of compounds 136 - 172. ......................................................................... 63 Scheme 3 : Synthesis of compounds 173 - 175. ......................................................................... 63 Scheme 4 : Retrosynthetic scheme for bedaquiline-H127 hybrids. ....................................... 126 Scheme 5 : Synthetic scheme for bedaquiline-H127 hybrids. ................................................ 127 Scheme 6 : Proposed structural modifications for TTz. ......................................................... 182 Scheme 7 : Proposed bedaquiline-H127 hybrid synthesis ..................................................... 183 Scheme 8 : Proposed bedaquiline-H127 hybrid having an ester linker.................................. 184 List of Abbreviations accptHB Hydrogen bond acceptors
ADMETox Absorption, distribution, metabolism and elimination ATP Adenosine triphosphate BCG Bacille Calmette-Guerin B. subtilis Bacillus subtilis C Carbon C. albicans Candida albicans Calcd. Calculated CD 3 OD Deuterated methanol CDCl 3 Deuterated Chloroform CF 3 Trifluoromethyl CH 3 OH Methanol Compd. Compound Con. concentrated CS 2 Carbon disulphide d Doublet DCM Dichloromethane dd Doublet of doublet DIPEA N,N - Diisopropylethylamine DFT Density functional theory DMF Dimethylformamide DMSO Dimethyl sulfoxide DMSO- d 6 Deuterated dimethyl sulfoxide DNA Deoxyribonucleic acid donorHB Hydrogen bond donors DOTS Directly observed therapy-short course DprE1 Decaprenylphosphoryl-β-d-ribose 2′-epimerase DR-TB Drug resistant TB DS-TB Drug sensitive TB E. coli Escherichia coli EDC.HCl 1 - Ethyl- 3 - (3-dimethylaminopropyl) carbodiimide EtOAc Ethyl acetate EtOH Ethanol
M. canetti Mycobacterium canetti M. microti Mycobacterium microti M. smegmatis Mycobacterium smegmatis M. p. Melting point M. tb Mycobacterium tuberculosis M. tuberculosis Mycobacterium tuberculosis M. tuberculosis H37Rv A strain of Mycobacterium tuberculosis m/z mass-to-charge ratio MABA microplate alamar blue assay mAGP mycolyl-arabinogalactan-peptidoglycan complex MBC Minimum bactericidal concentration MDAMB- 231 Human breast cancer cell line MDR Multidrug-resistance MDR-TB Multidrug-resistant TB MeOH Methanol mg/L Milligram per litre MHz Megahertz MIC Minimun inhibitory concentration mL Millilitre mmol Milli mole MRSA Methicillin-resistant Staphylococcus aureus MTC Mycobacterium tuberculosis complex MTCC Microbial type culture collection and gene Bank MW Molecular weight N Normality Na 2 SO 4 Sodium thiosulphate NAD Nicotinamide adenine dinucleotide NADH Reduced form of Nicotinamide adenine dinucleotide NMR Nuclear Magnetic Resonance OMe methoxy P. falciparum Plasmodium falciparum PANC- 1 Human pancreatic cancer cell line PC- 3 Human prostate cancer cell line
Pd/C Palladium on carbon PDB Protein data bank Phe Phenylalanine ppm parts per million q Quartet RMSD Root-mean-square deviation RNA Ribonucleic acid RR-TB rifampicin-resistant TB RT Room temperature s Singlet S. mutans Streptococcus mutans S. typhi Salmonella typhi SAR Structure-activity-relationship SKOV- 3 Human ovarian cancer cell line TB Tuberculosis t Triplet TI Therapeutic index TLC Thin layer chromatography TMS Tetramethylsilane TTz Thiazololtriazole Tyr Tyrosine UV Ultraviolet Vol. Volume WHO Word health organisation XDR extensive drug resistance XDR-TB extensive drug- resistant TB Y tyrosine μg/mL Microgram per millilitre μM Micromolar °C Degree centigrade Å Angstrom
