Discovery and initial development of a novel class of antibacterials: inhibitors of Staphylococcus aureus transcription/translation.
The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chemistry. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional solution phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8mug/mL (compound 4l). Subsequent modification of the central aromatic ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a number of potent antibacterials with MICs of 1mug/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one additional mechanism of action is operative.
Larsen
Scott D
SD
Medicinal Chemistry and Infectious Diseases Biology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49001, USA. scott.d.larsen@pfizer.com
Hester
Matthew R
MR
Craig Ruble
J
J
Kamilar
Gregg M
GM
Romero
Donna L
DL
Wakefield
Brian
B
Melchior
Earline P
EP
Sweeney
Michael T
MT
Marotti
Keith R
KR
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D014176:Protein Biosynthesis / Q000187:drug effects*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*
D000900:Anti-Bacterial Agents