title: Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis.
abstract: Novel 3'-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by (1)H, (13)C and (19)F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC(50)), or inducing 25% DNA cleavage by DNA gyrase (CC(25)). Compound 4 (with a methoxy in R(8) and a secondary carbamate in R(3)') and compound 5 (with a hydrogen in R(8) and an ethyl ester in R(3)') displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R(3)' substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR CNRS 7086, 15 rue J-A de Baïf, 75205 Paris Cedex 13, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gomez
authors.forename: Prishila
authors.initials: P
authors.lastname: Ponien
authors.forename: Nawal
authors.initials: N
authors.lastname: Serradji
authors.forename: Aazdine
authors.initials: A
authors.lastname: Lamouri
authors.forename: Alix
authors.initials: A
authors.lastname: Pantel
authors.forename: Estelle
authors.initials: E
authors.lastname: Capton
authors.forename: Vincent
authors.initials: V
authors.lastname: Jarlier
authors.forename: Guillaume
authors.initials: G
authors.lastname: Anquetin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aubry
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology; D053837:DNA Cleavage / Q000187:drug effects; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D024841:Fluoroquinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000077734:Gatifloxacin; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D009166:Mycobacterium leprae / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase; D000077734:Gatifloxacin; D000077266:Moxifloxacin