Synthesis and Evaluation of New Nitrofuranylamides With Collection of Mycobacterium tuberculosis Clinical Strains From Multidrug‐Resistant Tuberculosis High‐Burden Country

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 < 0.1 µg/mL) against the majority of strains. Moreover, 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.