Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum β-lactamase inhibitors: Crystallographic structures show unexpected binding of 1,4-thiazepine intermediates

Aranapakam M. Venkatesan, Yansong Gu, Osvaldo Dos Santos, Takao Abe, Atul Agarwal, Youjun Yang, Peter J. Petersen, William J. Weiss, Tarek S. Mansour, Michiyoshi Nukaga, Andrea M. Hujer, Robert A. Bonomo, James R. Knox

Research output: Contribution to journalArticle

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Abstract

The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine β-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC β-lactamases and less so against the class B metallo-β-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 Å, respectively, and refined to R-factors equal 0.163 and 0.145. In both β-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.

Original languageEnglish
Pages (from-to)6556-6568
Number of pages13
JournalJournal of Medicinal Chemistry
Volume47
Issue number26
DOIs
StatePublished - 16 Dec 2004

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