title: Structure-activity relationships in quinolone antibacterials: design, synthesis and biological activities of novel isothiazoloquinolones.
abstract: Over the past years it was found that modification of the 3-carboxylic acid group of quinolones generally produced compounds with a substantial decrease in antibacterial activity. The 3-carboxylic acid moiety together with the 4-carbonyl function are believed to be the most structurally critical sites for this class of compounds to DNA gyrase. The authors have designed and synthesized a series of quinolone analogues in which the 3-carboxylic acid group has been modified. These compounds, 2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-diones, possess biological activities far superior to their parent counterparts. For example, the MICs (microgram/ml) for A-62824 (ciprofloxacin 3-carboxylic acid modified analogue) and ciprofloxacin against some organisms are as follows: S. aureus ATCC 6538P (0.02, 0.2); S. epidermidis 3519 (0.05, 0.2); E. coli Juhl (0.005, 0.01); P. aeruginosa A5007 (0.05, 0.1) and Acinetobacter sp. CMX 699 (0.05, 0.78). This investigation has produced the first successful modification of the 3-carboxylic acid group of quinolones resulting in a series of extremely potent antibacterials. The design and synthesis as well as the biological activities of these new derivatives are described.
authors.affiliation: Anti-infective Research Division, Abbott Laboratories, Abbott Park, IL 60064.
authors.forename: D T
authors.initials: DT
authors.lastname: Chu
authors.forename: P B
authors.initials: PB
authors.lastname: Fernandes
authors.forename: A K
authors.initials: AK
authors.lastname: Claiborne
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.forename: A G
authors.initials: AG
authors.lastname: Pernet
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004339:Drug Compounding; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D015363:Quinolones; D013844:Thiazoles; D004250:DNA Topoisomerases, Type II