title: Exploration of the activity of 7-pyrrolidino-8-methoxyisothiazoloquinolones against methicillin-resistant Staphylococcus aureus (MRSA).
abstract: A series of 7-(3'-substituted)pyrrolidino-8-methoxyisothiazoloquinolone (ITQ) analogues were prepared, and their antibacterial potency against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli were compared. Many of these analogues had MIC ≤ 0.25 μg/mL against quinolone-resistant MRSA strains. The stereochemical preference was explored for a series of 1''-methyl-3'-aminomethylpyrrolidine analogues. Antibacterial activity was generally more favorable with 3'-R, 1''-S configuration. Substitution on the 3'-aminomethyl nitrogen tended to decrease activity, while potency was maintained with disubstitution or aryl substitution at the 1''-carbon. The 7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl] analogue (6a(R,S)) and the (R)-7-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl] analogue (7a(R)) were found to be the ITQs with the most promising antibacterial profiles. The MICs of these select ITQs versus a panel of clinical MRSA strains were determined, and the ITQs were found to have 8- to 16-fold greater potency than linezolid. These analogues were also evaluated for inhibition of the target enzymes, topoisomerase IV and DNA gyrase, from both wild-type and multidrug resistant strains. The ITQs were up to >30 times more inhibitory against these targets than the fluoroquinolone moxifloxacin.
authors.affiliation: Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, Connecticut 06511, United States.
authors.forename: Ha Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wiles
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Wang
authors.forename: Godwin C G
authors.initials: GC
authors.lastname: Pais
authors.forename: Edlaine
authors.initials: E
authors.lastname: Lucien
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Jane A
authors.initials: JA
authors.lastname: Thanassi
authors.forename: Steven D
authors.initials: SD
authors.lastname: Podos
authors.forename: Milind
authors.initials: M
authors.lastname: Deshpande
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pucci
authors.forename: Barton J
authors.initials: BJ
authors.lastname: Bradbury
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: C559863:7-(3-(1-aminoethyl)pyrrolidin-1-yl)-9-cyclopropyl-6-fluoro-8-methoxyisothiazolo(5,4-b)quinoline-3,4(2H,9H)-dione; C559864:7-(3-(2-aminopropan-2-yl)pyrrolidin-1-yl)-9-cyclopropyl-6-fluoro-8-methoxyisothiazolo(5,4-b)quinoline-3,4(2H,9H)-dione; D000900:Anti-Bacterial Agents; D011759:Pyrrolidines; D015363:Quinolones; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV