Open AccessNovel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis
Author(s) -
Giovanna Poce,
Sara Consalvi,
Giulia Venditti,
Salvatore Alfonso,
N. Desideri,
Raquel Fernández-Menéndez,
Robert H. Bates,
Lluís Ballell,
David Barros Aguirre,
Joaquín Rullás,
Alessandro De Logu,
Michelle Gardner,
Thomas R. Ioerger,
Eric J. Rubín,
Mariangela Biava
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00204
Subject(s) - mycobacterium tuberculosis , pyrazole , tuberculosis , pyridine , pyrrole , minimum inhibitory concentration , cytotoxic t cell , chemistry , microbiology and biotechnology , stereochemistry , antimicrobial , biology , biochemistry , medicine , organic chemistry , in vitro , pathology
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.