623906-34-3Relevant articles and documents
Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum β-lactamase inhibitors: Evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods
Venkatesan, Aranapakam M.,Agarwal, Atul,Abe, Takao,Ushirogochi, Hideki,Yamamura, Itsuka,Ado, Mihira,Tsuyoshi, Takasaki,Dos Santos, Osvaldo,Gu, Yansong,Sum, Fuk-Wah,Li, Zhong,Francisco, Gerry,Lin, Yang-I.,Petersen, Peter J.,Yang, Youjun,Kumagai, Toshio,Weiss, William J.,Shlaes, David M.,Knox, James R.,Mansour, Tarek S.
, p. 4623 - 4637 (2007/10/03)
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 β-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) β-lactamases and less so against the class B metallo-β-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-1 were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C β-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 β-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
