Abstract
ABSTRACT
Emergence of drug‐resistant
Mycobacterium tuberculosis
necessitates the development of new drugs. Here, we studied the activity of new piperazine nitrofuranylamides against a collection of clinical strains from an multidrug‐resistant tuberculosis (MDR‐TB) high‐burden country. A series of nitrofuranylamides
9–15
was synthesized and evaluated using a collection of diverse clinical strains representing globally spread genotypes (Beijing, LAM, and Haarlem; susceptible, MDR, and pre‐extensively drug resistant). Minimal inhibitory concentrations (MIC) were determined using a resazurin assay. Whole‐genome sequencing was performed on an Illumina HiSeq platform. Although clinical isolates differed in their MICs, some tested compounds—namely
11
and
12
—showed higher MICs regardless of the clinical strain. In contrast, compounds
13–15
exhibited promising activity (MIC 13
and
14
were previously shown to have low toxicity in JCL:ICR mice and low cytotoxicity against human cell lines. A closer look at structural variation indicated that the presence of a pyridine‐ or quinoline‐type aryl substituent leads to a broader spectrum of activity. The additional nitro group in
14
appears to contribute significantly to its activity. A nonsynonymous mutation in the efflux pump gene
Rv3728
(372 A > V, GCC → GTC) in one of the Haarlem genotype strains may speculatively correlate with its high‐level intrinsic resistance to nitrofurans. Further biological research is warranted to investigate the mechanism of action of the most promising compounds.