Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum beta-lactamase inhibitors: crystallographic structures show unexpected binding of 1,4-thiazepine intermediates.
The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine beta-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of 17 with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 A, respectively, and refined to R-factors equal 0.163 and 0.145. In both beta-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has the R configuration in the SHV-1 intermediate and has both R and S configurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a 7-endo-trig cyclization.
Venkatesan
Aranapakam M
AM
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA.
Gu
Yansong
Y
Dos Santos
Osvaldo
O
Abe
Takao
T
Agarwal
Atul
A
Yang
Youjun
Y
Petersen
Peter J
PJ
Weiss
William J
WJ
Mansour
Tarek S
TS
Nukaga
Michiyoshi
M
Hujer
Andrea M
AM
Bonomo
Robert A
RA
Knox
James R
JR
D001665:Binding Sites; D018360:Crystallography, X-Ray; D016972:Enterobacter cloacae / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006868:Hydrolysis; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012706:Serratia marcescens / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry*; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D006574:Heterocyclic Compounds, 2-Ring; D006575:Heterocyclic Compounds, 3-Ring; D013841:Thiazepines; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C054882:beta-lactamase PIT-2; D001618:beta-Lactamases