Synthesis and evaluation of M.tb Glycosyltransferase (MshA) inhibitors

• Main Author: Sehata, Majimi James
• Other Authors: Jardine, Anwar
• Format: Doctoral Thesis
• Language: English
• Published: University of Cape Town 2015
• Subjects: Chemistry
• Online Access: http://hdl.handle.net/11427/12772

Includes bibliographical references === The emergence of multiple drug resistant (MDR) and extremely drug resistant (XDR) strains of Mycobacterium tuberculosis (M.tb) against the known anti-tuberculosis drug regimens has prompted the need to search for new anti-tubercular drugs. In this study we report the design and synthesis of a series of thiazolidinethione derivatives and substrate mimics, aimed at targeting the mycothiol biosynthetic pathway which is specific to mycobacteria. The strategy involved design of molecules that are expected to compete for the UDP-GlcNAc binding site of the glycosyltransferase (MshA) of M.tb. The bioactivity of the designed molecules against M.tb in cell free and whole cell assays serves as a basis for further inhibitor optimisation. Amongst the thiazolidinethione derivatives screened, compounds (Z)-5-(2,4-dichlorobenzylidene)-2-thioxothiazolidin-4-one (MJ3A) and 2-((Z)-5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (MJ7B) were found to be the most potent compounds with a MIC 50 of 10 μg/mL. In addition, substrate mimics were synthesized and screened for anti-tuberculosis activity. Substrate mimics displayed moderate activity, with exception of substrate mimic (4 -34) which displayed th e highest potency. Tunicamycin which is a known glycosyltransferase inhibitor displayed the highest potency against M.tb H37Rv whole cells by inhibiting cell growth with a MIC 50 of 5 μg/mL . Tunicamycin inhibits the transfer of GlcNAc-1-P from UDP-GlcNAc to polyprenyl monophosphates in a variety of organisms including Gram positive bacteria.