Carboxylic acid isosteres improve the activity of ring-fused 2-pyridones that inhibit pilus biogenesis in E. coli.
Ring-fused 2-pyridones, termed pilicides, are small synthetic compounds that inhibit pilus assembly in uropathogenic Escherichia coli. Their biological activity is clearly dependent upon a carboxylic acid functionality. Here, we present the synthesis and biological evaluation of carboxylic acid isosteres, including, for example, tetrazoles, acyl sulfonamides, and hydroxamic acids of two lead 2-pyridones. Two independent biological evaluations show that acyl sulfonamides and tetrazoles significantly improve pilicide activity against uropathogenic E. coli.
Berg
Veronica
V
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Das
Pralay
P
Chorell
Erik
E
Hedenström
Mattias
M
Pinkner
Jerome S
JS
Hultgren
Scott J
SJ
Almqvist
Fredrik
F
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D010861:Fimbriae, Bacterial / Q000187:drug effects* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011728:Pyridones / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D011728:Pyridones; C017679:2-hydroxypyridine