Design, Synthesis and SAR Evaluation of Novel Antituberculosis Agents

Abstract

There is an urgent need to discover and develop novel therapeutic alternatives for treatment of Mycobacterium tuberculosis (Mtb) infection, especially for infections caused by drug-resistant strains, to mitigate the global burden of tuberculosis disease. Initially within our group, a benzoxa-[2,1,3]-diazole moiety was employed in these investigations; however, the group has recently adopted a scaffold hopping strategy to generate several structurally diverse examples while maintaining antitubercular efficacy, often enhancing antitubercular activity. The pharmacophores imidazo[1,2 a]pyridine and 3,5-dinitrobenzene N-amino acid substituted hydrazides are of particular interest. The results for imidazo[1,2 a]pyridine substituted amino acid hydrazide compounds demonstrated increased activity with unsubstituted side chains on the amino acid and variable activity depending on the position of the halogen in the aromatic hydrazine. Furthermore, compared to the prior series, the results showed a higher level of action against bacteria with the 3,5-dinitrobenzene moiety substituted amino acid hydrazide, indicating the potential utility of these compounds as future antitubercular medications. Furthermore, this research was conducted to explore the coupling of the N-amino acid hydrazide structure with a scaffold comprising a one nitrogenous group in Pretomanid and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl). Unfortunately, these attempts were not successful, but it is worthwhile considering modifications for future endeavours.