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

Aranapakam M. Venkatesan, Atul Agarwal, Takao Abe, Hideki Ushirogochi, Itsuka Yamamura, Mihira Ado, Takasaki Tsuyoshi, Osvaldo Dos Santos, Yansong Gu, Fuk Wah Sum, Zhong Li, Gerry Francisco, Yang I. Lin, Peter J. Petersen, Youjun Yang, Toshio Kumagai, William J. Weiss, David M. Shlaes, James R. Knox, Tarek S. Mansour

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Abstract

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.

Original languageEnglish
Pages (from-to)4623-4637
Number of pages15
JournalJournal of Medicinal Chemistry
Volume49
Issue number15
DOIs
StatePublished - 27 Jul 2006

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Venkatesan, A. M., Agarwal, A., Abe, T., Ushirogochi, H., Yamamura, I., Ado, M., Tsuyoshi, T., Dos Santos, O., Gu, Y., Sum, F. W., Li, Z., Francisco, G., Lin, Y. I., Petersen, P. J., Yang, Y., Kumagai, T., Weiss, W. J., Shlaes, D. M., Knox, J. R., & Mansour, T. S. (2006). 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. Journal of Medicinal Chemistry, 49(15), 4623-4637. https://doi.org/10.1021/jm060021p