Design, synthesis and SAR evaluation of novel benzoxa-[2,1,3]-diazole amino acid hydrazides against Mycobacterium tuberculosis

Abstract

The major challenges of tuberculosis (TB) treatment are the emergence of the drug-resistant strains and the higher risk of hepatotoxicity with prolonged treatment. Therefore, efforts to effectively control TB require the discovery and development of new therapeutic options possessing new mechanisms of action. This project focused on the design and synthesis of novel agents targeting Mycobacterium tuberculosis (Mtb). We have successfully synthesised 170 hydrazides with 40 of those intermediates being converted to benzoxa-[2,1,3]-diazole substituted amino acid hydrazides 65. The resulting compounds were screened against susceptible and resistant Mtb strains utilising a Resazurin Microtiter Assay (REMA). A subsequent structure activity relationship (SAR) strategy investigated the structural modification of the benzo-[2,1,3]-diazole peptidomimetics architecture 65 as the main focus of the research presented in this thesis. The findings from this SAR study indicate that an increased size of the amino acid side chain, incorporation of heavy halogens at the meta position of the aryl hydrazine, the L-configuration of the amino acid and the benzoxa-[2,1,3]-diazole moiety each play a key role in improving the antitubercular activity.