title: Isothiazoloquinolones with enhanced antistaphylococcal activities against multidrug-resistant strains: effects of structural modifications at the 6-, 7-, and 8-positions.
abstract: We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 microg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.
authors.affiliation: Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, Connecticut 06511, USA.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Wang
authors.forename: Edlaine
authors.initials: E
authors.lastname: Lucien
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Godwin C G
authors.initials: GC
authors.lastname: Pais
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Song
authors.forename: Jane A
authors.initials: JA
authors.lastname: Thanassi
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Marlor
authors.forename: Christy L
authors.initials: CL
authors.lastname: Thoma
authors.forename: Jijun
authors.initials: J
authors.lastname: Cheng
authors.forename: Steven D
authors.initials: SD
authors.lastname: Podos
authors.forename: Yangsi
authors.initials: Y
authors.lastname: Ou
authors.forename: Milind
authors.initials: M
authors.lastname: Deshpande
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pucci
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Buechter
authors.forename: Barton J
authors.initials: BJ
authors.lastname: Bradbury
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wiles
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D016106:Methicillin Resistance; D051379:Mice; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: C517801:9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo(5,4-b)quinoline-3,4-dione; D000900:Anti-Bacterial Agents; D015363:Quinolones; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors