Spirocyclopropyl beta-lactams as mechanism-based inhibitors of serine beta-lactamases. Synthesis by rhodium-catalyzed cyclopropanation of 6-diazopenicillanate sulfone.
Class A-class C mechanism-based beta-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin against class A and class C producing organisms showed improvement over clinically used tazobactam.
Sandanayaka
Vincent P
VP
Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
Prashad
Amar S
AS
Yang
Youjun
Y
Williamson
R Thomas
RT
Lin
Yang I
YI
Mansour
Tarek S
TS
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins; D002384:Catalysis; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003979:Diazonium Compounds / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012238:Rhodium; D012694:Serine / Q000737:chemistry*; D012706:Serratia marcescens / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013407:Sulbactam / Q000031:analogs & derivatives / Q000737:chemistry*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C475513:6-diazopenicillanate sulfone; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003521:Cyclopropanes; D003979:Diazonium Compounds; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D012694:Serine; D012238:Rhodium; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1; D013407:Sulbactam