Design, synthesis and SAR of antitubercular benzylpiperazine ureas

N -furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to molecule ( I ) with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC 50 ~ 80 μM), good DMPK properties and specificity for Mtb . With the aim of delineating the SAR associated with ( I ), fifty-five analogs were synthesized and screened against Mtb . The SAR suggests that the piperazine ring, benzyl urea and piperonyl moieties are essential signatures of this series. Active compounds in this series are metabolically stable, have low cellular toxicity and are valuable leads for optimization. Molecular docking suggests these molecules occupy the Q0 site of QcrB like Q203. Graphic Abstract Bioisosteric replacement of N -furfuryl piperazine-1-carboxamides yielded molecule (I) a novel lead with satisfactory PD, metabolism, and toxicity profiles.