Synthesis and SAR of novel benzoxaboroles as a new class of β-lactamase inhibitors

Yi Xia; Kathy Cao; Yasheen Zhou; M R K Alley; Fernando Rock; Manisha Mohan; Maliwan Meewan; Stephen J Baker; Sarah Lux; Charles Z Ding; Guofeng Jia; Maureen Kully; Jacob J Plattner

doi:10.1016/j.bmcl.2011.02.024

Synthesis and SAR of novel benzoxaboroles as a new class of β-lactamase inhibitors

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2533-6. doi: 10.1016/j.bmcl.2011.02.024. Epub 2011 Feb 12.

Authors

Yi Xia¹, Kathy Cao, Yasheen Zhou, M R K Alley, Fernando Rock, Manisha Mohan, Maliwan Meewan, Stephen J Baker, Sarah Lux, Charles Z Ding, Guofeng Jia, Maureen Kully, Jacob J Plattner

Affiliation

¹ Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA. [email protected]

PMID: 21392987
DOI: 10.1016/j.bmcl.2011.02.024

Abstract

A new class of benzoxaborole β-lactamase inhibitors were designed and synthesized. 6-Aryloxy benzoxaborole 22 inhibited AmpC P99 and CMY-2 with K(i) values in the low nanomolar range. Compound 22 restored antibacterial activity of ceftazidime against Enterobacter cloacae P99 expressing AmpC, a class C β-lactamase enzyme. The SAR around the arylbenzoxaboroles, which included the influence of linker and substitutions was also established.

MeSH terms

Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Benzoxazoles / chemistry*
Boron Compounds / chemical synthesis
Boron Compounds / chemistry*
Boron Compounds / pharmacology
Enterobacter cloacae / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Microbial Sensitivity Tests
Pyrazines / chemical synthesis*
Pyrazines / chemistry
Pyrazines / pharmacology
Structure-Activity Relationship
beta-Lactamase Inhibitors*
beta-Lactamases / metabolism

Substances

Anti-Bacterial Agents
Benzoxazoles
Boron Compounds
Enzyme Inhibitors
Pyrazines
beta-Lactamase Inhibitors
beta-Lactamases