Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum beta-lactamase inhibitors: evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods.
The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C beta-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C beta-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both beta-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
Venkatesan
Aranapakam M
AM
Wyeth Research, Chemical and Screening Sciences, Department of Infectious Disease and Biological Technologies, 401 N. Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com
Agarwal
Atul
A
Abe
Takao
T
Ushirogochi
Hideki
H
Yamamura
Itsuka
I
Ado
Mihira
M
Tsuyoshi
Takasaki
T
Dos Santos
Osvaldo
O
Gu
Yansong
Y
Sum
Fuk-Wah
FW
Li
Zhong
Z
Francisco
Gerry
G
Lin
Yang-I
YI
Petersen
Peter J
PJ
Yang
Youjun
Y
Kumagai
Toshio
T
Weiss
William J
WJ
Shlaes
David M
DM
Knox
James R
JR
Mansour
Tarek S
TS
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021902:Enterobacter aerogenes; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000401:mortality; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000401:mortality; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000737:chemistry*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
D000447:Aldehydes; D000900:Anti-Bacterial Agents; D006574:Heterocyclic Compounds, 2-Ring; D007093:Imidazoles; D011720:Pyrazoles; D013841:Thiazepines; D013876:Thiophenes; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases