Novel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis

Poce G.;Consalvi S.;Venditti G.;Alfonso S.;Desideri N.;Fernandez-Menendez R.;Bates R. H.;Ballell L.;Barros Aguirre D.;Rullas J.;De Logu A.;Gardner M.;Ioerger T. R.;Rubin E. J.;Biava M.

2019-01-01

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Abstract

In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5-49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome sequencing revealed mutations in the mmpL3 gene.