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

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.