Novel pyrazole-containing compounds active against mycobacterium tuberculosis
01 Pubblicazione su rivista
Poce Giovanna, Consalvi Sara, Venditti Giulia, Alfonso Salvatore, Desideri Nicoletta, Fernandez-Menendez Raquel, Bates Robert H., Ballell Lluis, Barros Aguirre David, Rullas Joaquin, De Logu Alessandro, Gardner Michelle, Ioerger Thomas R., Rubin Eric J., Biava Mariangela
ISSN: 1948-5875
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.