Synthesis, spectroscopic characterisation and biological evaluation of new inhibitors of mycobacterium tuberculosis based on thiazolotriazole and quinoline heterocycles
Creators: name: Kizhakke Purakkel, Umadevi
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 340101
subject: Analytical spectrometry
classificationCode: 340401
subject: Biologically active molecules
classificationCode: 340503
subject: Organic chemical synthesis

description: Tuberculosis (TB) is a highly infectious disease and the pathogen responsible is a bacterium belonging to the mycobacterium species, Mycobacterium tuberculosis. It is among the top ten diseases causing the highest death rates in the world. TB can affect different organs of which pulmonary TB is the most common case with the lungs being the target organ. Different treatment regimens containing combinations of different drugs are currently available for its treatment, as recommended by the World Health Organisation. However, the emergence of drug resistant strains is now a serious issue encountered in treatment and control of TB. Many of these current medications are found to have severe side effects. Additionally, the long duration of treatment lowers patience tolerance. With this in mind, extensive research is on-going in this area. Target based and whole-cell-based phenotypic screening are some of the commonly employed strategies to discover new anti-tubercular agents. The current research is focused on synthesising new TB inhibitors based on two heterocyclic scaffolds: thiazolotriazole and quinoline.

Chapter I provides an insight into the aetiology and epidemiology of the TB disease. Transmission, pathogenesis, types of TB, treatment options and challenges in prevention and control of the disease are discussed. Heterocyclic compounds are of great importance in day-to-day life in which their applications extend up to life-saving medications. The pharmacological significance of nitrogen containing heterocycles - triazole, thiazole, thiazolotriazole and quinoline is focussed upon, and the anti-tubercular and antimicrobial properties of these scaffolds are reviewed and discussed. Chapter II describes the materials and methods employed for performing experiments in this thesis.

Chapter III deals with the design, synthesis and biological evaluation of thiazolotriazole based compounds as antimycobacterial and antimicrobial agents. Phenotypic screening of compounds from an internal database led to the identification of a thiazolotriazole based molecule, herein denoted as H127, as an anti-tubercular lead along with several other scaffolds. The molecule exhibited MIC of 12.5 µM against Mycobacterium tuberculosis H37Rv. Based on the literature reports on pharmacological applications of thiazole, triazole and fused thiazolotriazole, H127 was taken forward for lead optimisation. Thirty-nine analogues of H127 were rationally designed, synthesised, characterised using various spectroscopic techniques 

and screened for antimycobacterial, antibacterial and antifungal activities. The structure-
activity-relationships responsible for activity are discussed based on the screening results. In addition, the anticancer activities of these compounds were assessed. Finally, their drug-like properties and drug targets were determined by in silico techniques. 

Chapter IV discusses the design, synthesis and biological evaluation of bedaquiline-H127 hybrid molecules as anti-tubercular agents. Bedaquiline is an anti-TB medication used for treating drug resistant TB. The bactericidal activity of this drug is triggered by inhibiting energy metabolism of the bacterial cell through inhibition of the proton pump. The drug was found to be effective in treating TB but also has serious side effects. This leads to the question of whether modifications to the structure of such drug molecules can retain their efficacy while reducing unwanted side effects? Hybridisation is a strategy employed in drug design which combines the active pharmacophores from biologically active molecules to design a single drug molecule which might have multiple drug targets. It has been previously shown that many of the disadvantages of parent molecules can be addressed by hybrid drugs. Here, H127 and the quinoline core of bedaquiline were combined through a hybridisation strategy and seventeen analogues were designed, synthesised and screened against Mycobacterium tuberculosis. The structural requirements responsible for their anti-tubercular activity is discussed.

Raman spectroscopy is an important tool for medicinal chemists in various aspects. Chapter V presents the characterisation of the H127 analogues using Raman spectroscopy and also an investigation as to how the vibrational modes, more specifically carbonyl and phenyl vibrations, are being influenced by structural changes. For studying this, three categories of compounds were taken into consideration; i. H127 analogues having different substituents at the phenyl ring attached to the core heterocycle (thiazolotriazole), ii. H127 analogues having different N-heterocycle at the lateral chain, iii. H127 analogues having different substituents at the carbon linker attached between the sulphur and amide groups. This study ultimately aims to establish a library of spectral bands for TTz which can guide for future experiments to be conducted on cells, to investigate the mode of drug action in vivo.

Overall, this thesis covers the design, synthesis and biological evaluation of compounds belonging to two different heterocyclic scaffolds; thiazolotriazole and quinoline. The synthesised compounds were explored as antimycobacterial and antimicrobial agents.

 Chapter VI summarises the overall outcome of the research conducted and discusses the potential for future development of antimicrobial and antimycobacterial agents based on these scaffolds.