title: Isothiazolopyridones: synthesis, structure, and biological activity of a new class of antibacterial agents.
abstract: We report the syntheses of first-generation derivatives of isothiazolopyridones and their in vitro evaluation as antibacterial agents. These compounds, containing a novel heterocyclic nucleus composed of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the quinolizin-4-one), were prepared using a sequence of seven synthetic transformations. The solid-state structure of 7-chloro-9-ethyl-1-thia-2,4a-diazacyclopenta[b]naphthalene-3,4-dione was determined by X-ray diffraction. The prepared derivatives of desfluoroisothiazolopyridones exhibited (a) antibacterial activity against Gram-negative and Gram-positive organisms, (b) inhibitory activities against DNA gyrase and topoisomerase IV, and (c) no inhibitory activity against human topoisomerase II.
authors.affiliation: Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, Connecticut 06511-6653, USA. jwiles@achillion.com
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wiles
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Jane A
authors.initials: JA
authors.lastname: Thanassi
authors.forename: Jijun
authors.initials: J
authors.lastname: Cheng
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Incarvito
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; D018360:Crystallography, X-Ray; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D011728:Pyridones; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV