Preparation of novel anthranilic acids as antibacterial agents. Extensive evaluation of alternative amide bioisosteres connecting the A- and the B-rings.
In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently described the identification of an anthranilic acid lead 1 and the optimization resulting in the advanced lead 2. In this report, we describe the preparation of several selected amide bioisosteres connecting the A- and the B-rings. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element rather acts as an appropriate spatial linker of the two important aryl A and B rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity.
Thorarensen
Atli
A
Medicinal Chemistry and Infectious Diseases Biology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49001, USA. atli.thorarensen@pfizer.com
Wakefield
Brian D
BD
Romero
Donna L
DL
Marotti
Keith R
KR
Sweeney
Michael T
MT
Zurenko
Gary E
GE
Rohrer
Douglas C
DC
Han
Fusen
F
Bryant
Garold L
GL
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D062367:ortho-Aminobenzoates; C031385:anthranilic acid