title: New fluoroquinolones active against fluoroquinolones-resistant Mycobacterium tuberculosis strains.
abstract: A set of 21 new fluoroquinolones bearing an aromatic or heteroaromatic moiety at C-7 and an alkyl group at N-1 were synthesized based on the lead structure of pirfloxacin and tested in vitro against Mycobacterium tuberculosis (M. tuberculosis) H37Rv by MIC determination in liquid medium. Among the synthesized compounds, 1-(tert-butyl)-6-fluoro-7-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2o) and 1-(tert-butyl)-6-fluoro-7-(pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2n) were found to be the most active ones against M. tuberculosis H37Rv with the same MICs of reference compounds ciprofloxacin (CFX) and levofloxacin (LFX). MICs of 2o and 2n were determined for fluoroquinolone-sensitive and fluoroquinolone-resistant M. tuberculosis clinical isolates and 2o was the most active compound with up 4-fold difference of MIC with respect to CFX. The activity of 2o was also tested at the concentration of 16 μg/mL against M. tuberculosis H37Rv in infected murine macrophages. The results showed a 4-fold decrease in viable count of cell-associated mycobacteria with respect to untreated controls after 48 h of drug incubation.
authors.affiliation: Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico Santa Maria alle Scotte, Viale Bracci 1, 53100 Siena, Italy. guerrini49@unisi.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Guerrini
authors.forename: Maria
authors.initials: M
authors.lastname: De Rosa
authors.forename: Serena
authors.initials: S
authors.lastname: Pasquini
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cuppone
authors.forename: Gianni
authors.initials: G
authors.lastname: Pozzi
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003470:Culture Media; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology*; D005838:Genotype; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D013329:Structure-Activity Relationship
chemical_list: D000904:Antibiotics, Antitubercular; D003470:Culture Media; D024841:Fluoroquinolones