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
Wyeth Research, Chemical and Screening Sciences, Department of Infectious Disease and Biological Technologies, 401 N. Middletown Road, Pearl River, New York 10965, USA.
J Med Chem. 2006 Jul 27;49(15):4623-37. doi: 10.1021/jm060021p.
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.
描述了一系列含有[6,5]稠合双环（噻吩、咪唑或吡唑稠合体系）的6-亚甲基青霉烯类化合物的设计与合成，这些化合物作为新型的A、B和C类β-内酰胺酶抑制剂。这些青霉烯类化合物被证明是TEM-1（A类）和AmpC（C类）β-内酰胺酶的有效抑制剂，而对B类金属β-内酰胺酶CcrA的抑制作用较弱。讨论了它们与哌拉西林联合使用时的体外和体内活性。基于化合物2与SHV-1（A类）和GC1（C类）酶的丝氨酸结合反应中间体的晶体结构，设计并合成了化合物14a-l。青霉烯类化合物被认为在A类和C类β-内酰胺酶中均形成七元1,4-噻氮杂环。对酶结合中间体的相互作用能计算表明，在两种β-内酰胺酶中，1,4-噻氮杂环的C7 R对映体比S对映体更有利于形成，这与化合物2与SHV-1和GC1的晶体结构结果一致。
