Side chain SAR of bicyclic β-lactamase inhibitors (BLIs). 2. N-Alkylated and open chain analogs of MK-8712

The bridged monobactam β-lactamase inhibitor MK-8712 ( 1) effectively inhibits class C β-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C β-lactamase mediated resistance. Although some analogs were more pote...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-07, Vol.21 (14), p.4267-4270
Hauptverfasser:	Chen, Helen, Blizzard, Timothy A., Kim, Seongkon, Wu, Jane, Young, Katherine, Park, Young-Whan, Ogawa, Aimie M., Raghoobar, Susan, Painter, Ronald E., Wisniewski, Doug, Hairston, Nichelle, Fitzgerald, Paula, Sharma, Nandini, Scapin, Giovanna, Lu, Jun, Hermes, Jeff, Hammond, Milton L.
Format:	Artikel
Sprache:	eng
Schlagworte:	Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents beta-lactamase beta-Lactamase Inhibitors beta-Lactamases - metabolism Binding Sites Biological and medical sciences Carbapenem chemistry Computer Simulation Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Imipenem Imipenem - pharmacology Inhibitor Medical sciences Microbial Sensitivity Tests Monobactams - chemical synthesis Monobactams - pharmacology Pharmacology. Drug treatments Protein Structure, Tertiary Structure-Activity Relationship β-Lactamase
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Zusammenfassung:	The bridged monobactam β-lactamase inhibitor MK-8712 ( 1) effectively inhibits class C β-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C β-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1. The bridged monobactam β-lactamase inhibitor MK-8712 ( 1) effectively inhibits class C β-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C β-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.05.065