Peripherally substituted monocyclic beta-lactams
The invention provides monobactams that can be used as antibacterial agents or intermediates for the preparation of other useful compounds such as antibacterial agents.
1. An N-sulfonyloxy β-lactam compound of Formula (I):
wherein R is an optionally substituted aryl with the proviso that R is not tolyl, or an optionally substituted alkenyl(aryl), and the bromine is optionally replaced by a sulfur-containing side chain; and Formula (I) has an optional aminothiazole methoxime (ATMO) containing side chain at C3.
2. The compound of claim 1 wherein R is selected from the group consisting of:
3. A compound selected from the group consisting of 41, 43, 44, and 48, or a pharmaceutically acceptable salt thereof:
4. The compound of claim 1 wherein the bromine moiety of Formula (I) is replaced with a sulfur-containing side chain.
5. The compound of claim 1 wherein Formula (I) has an aminothiazole methoxime (ATMO) containing side chain at the C3 position.
6. A method of inhibiting β-lactamase activity comprising contacting a β-lactamase enzyme with a compound of claim 1 .
7. The method of claim 6 , wherein the β-lactamase enzyme is a β-lactamase enzyme isolated from a pathogenic bacterium.
8. The method of claim 6 , wherein the β-lactamase enzyme is naturally occurring in a pathogenic bacterium.
9. The method of claim 8 , wherein the pathogenic bacterium is selected from the group consisting of gram positive bacteria and gram negative bacteria.
10. A method of inhibiting β-lactamase activity comprising contacting an N-sulfonyloxy β-lactam of claim 1 with a β-lactamase enzyme that is naturally occurring in a pathogenic bacterium selected from the group consisting of gram positive bacteria and gram negative bacteria, wherein the gram positive bacteria are selected from the group consisting of B. subtilis and M. vaccae.
11. The method of claim 9 , wherein the gram negative bacteria are selected from the group consisting of A. baumannii, P. aeruginosa and E. coli.
12. A method of inhibiting β-lactamase activity comprising contacting a β-lactamase enzyme with a compound of claim 2 .
13. A method of treating a bacterial infection comprising administering to a subject in need thereof an effective antibacterial amount of a compound of claim 3 , or a pharmaceutically acceptable salt thereof.
14. A method of treating a bacterial infection comprising administering to a subject in need thereof an effective antibacterial amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. A method of treating a bacterial infection comprising administering to a subject in need thereof an effective antibacterial amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
16. A method of treating a bacterial infection comprising administering to a subject in need thereof an effective antibacterial amount of a compound of claim 4 , or a pharmaceutically acceptable salt thereof.
17. A method of treating a bacterial infection comprising administering to a subject in need thereof an effective antibacterial amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
18. A method of inhibiting β-lactamase activity comprising contacting a β-lactamase enzyme with a compound of claim 3 .
19. A method of inhibiting β-lactamase activity comprising contacting a β-lactamase enzyme with a compound of claim 4 .
20. A method of inhibiting β-lactamase activity comprising contacting a β-lactamase enzyme with a compound of claim 5 .