LC-MS based characterization of Mycobacterium tuberculosis shikimate kinase inhibitors containing oxadiazole-amide and aminobenzothiazole rings
Type of DegreeMaster's Thesis
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The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has increased the demand for the discovery of new antitubercular drugs. The shikimate pathway is essential for the survival of Mycobacterium tuberculosis (Mtb), due to the production of choris¬mate, a precursor for aromatic amino acids but is absent from mammals. Shikimate kinase (SK) the fifth enzyme in the shikimate pathway in Mtb that catalyzes a phosphate transfer from ATP to shikimate, producing shikimate-3-phosphate (S3P) and ADP, and has been considered a promising drug target for tuberculosis drug discovery. The goal of this thesis is to understand the inhibitory mechanism of the most active compounds from a set of 14 oxadiazole-amide and 2-aminobenzothiazole containing synthetic compounds with IC50 values <50 µM against Mycobacterium tuberculosis shikimate kinase (MtSK) using an LC-MS based approach. Chapter one is an overview of tuberculosis pathogenesis and statistics, and it describes the role of the shikimate pathway in M. tuberculosis (Mtb). Additionally, this chapter describes a short revision of specific and non-specific binding to drug targets, Mtb cell wall permeability, and antibacterial activity of 1,3,4-oxadiazole, and 2-aminobenzothiazole scaffolds. Chapter two describes the experimental characterization of M. tuberculosis shikimate kinase inhibitors containing oxadiazole-amide and aminobenzothiazole rings by using LC-MS and other orthogonal confirmatory assays. Chapter three describes the results, discussion and conclusions. Our findings by the use of LC-MS, 1H-NMR, DLS, TEM, and centrifugation assays suggested that these compounds are non-specific inhibitors of MtSK by aggregate formation.