Design and Synthesis of some Anti-tubercular compounds & Studies in C-C bond forming reactions

Abstract

It is now widely appreciated that bacterial resistance to antibiotics has grown to very serious proportions. Many formerly controlled infectious diseases are no longer readily treatable with contemporary antibiotics, requiring other measures for therapeutic intervention. Tuberculosis is one of these diseases. In the last decade, the resurgence of tuberculosis and increase in the resistance of Mycobacterium tuberculosis to antimycobacterial agents has emphasized the importance of implementing and maintaining effective public health approaches to prevent transmission of the disease. Thus, there is an urgent demand for new anti-TB drugs possessing novel modes of action, not only to shorten the long treatment regimen by targeting nonreplicating persistent Mtb phenotype (NRP-TB) but also to battle resistant Mtb strains. Among the new anti-TB drugs, the quinoline class of compounds has shown promising activity against resistant TB. Amongst these, diarylquinoline based molecule R207910 (TMC207) inhibits TB with very high potency with new mechanism of action based on the interaction with the enzyme adenosine triphosphate (ATP) synthase, which is the energy source for the bacterium. The work embodied in this thesis comprises of five chapters distributed into two parts namely Part A and Part B. Part A of the thesis consists of two chapters (1 and 2) which deal with a brief review on tuberculosis and the development of novel analogs of TMC207. Part B of the thesis consists of three chapters (3, 4 and 5) dealing with the studies towards the synthesis of carbon-carbon bond formation. Chapter-1 In order to provide insight, chapter 1 of the dissertation presents a brief review on tuberculosis – its pathogenesis, current status, drugs in pipeline for the treatment along with drug classes with novel mode of action and new chemical entities has been discussed. Chapter 2 narrates our efforts towards the design, synthesis and anti-mycobacterial activities of conformationally-constrained analogs of TMC207 against Mycobacterium tuberculosis H37Rv. Chapter 3 The chiral synthesis of natural products has always been an area of active research interest. Chapter 3 describes the detailed account of the short steroselective approach to Penmacric acid, an unusual amino acid, by utilizing the reaction of Li and Ti enolates of pyroglutamate with various imines. Chapter 4 encompasses our attempts to develop the Aza variant of intramolecular catalytic, asymmetric nucleophile-catalyzed, aldol lactonization (NCAL) reaction to synthesize -lactone fused nitrogen hetrocyclics as aza-sugars precursors by employing achiral amino acids. Chapter 5 Endocyclic N-acyliminium ions have been involved in an impressive number of synthetic applications, mainly devoted to the synthesis of biologically important nitrogen-containing cyclic compounds. Chapter 5, therefore, describes our attempt to explore the aza-Baylis-Hillman reaction of in situ generated N-acyliminium ions. Each chapter is followed by the bibliography, experimental data and selected spectra supporting the information presented in the chapter. The compound numbers, figure numbers, scheme numbers and bibliography numbers are separate for each data. The list of abbreviations used is presented at the beginning of the dissertation for referring.