Design, Synthesis and Biological Evaluation of Sulfenimine Cephalosporin Analogues as β-Lactamase Inhibitors

doi:10.1007/s40242-015-4413-y

Chemical Research in Chinese Universities ›› 2015, Vol. 31 ›› Issue (3): 388-393.doi: 10.1007/s40242-015-4413-y

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Design, Synthesis and Biological Evaluation of Sulfenimine Cephalosporin Analogues as β-Lactamase Inhibitors

ZHANG Kai¹, DING Huaiwei¹, SHI Ailong¹, HUANG Qi¹, SONG Hongrui¹, FU Decai²

1. Key Laboratory of Structure-based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China;
2. College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, P. R. China

Received:2014-10-31 Revised:2015-01-28 Online:2015-06-01 Published:2015-03-16
Contact: SONG Hongrui, FU Decai E-mail:hongruisong@163.com;dc6310@sina.com

Abstract

Abstract:

A series of sulfenimine cephalosporin derivatives(6a-6t) was designed, synthesized and evaluated for their inhibitory activity against class A β-lactamase(TEM-1) derived from E. coli, and class C β-lactamase (cephalosporinase) derived from wild Bacillus subtilis in cell-free systems. Most of the tested compounds showed enhanced inhibitory activity against class C β-lactamase(cephalosporinase) compared with tazobactam. The most promising compounds 6c and 6o in combination with cefradine(IC₅₀=1.80 and 1.59 μmol/L, respectively) were further investigated against a series of clinical isolated β-lactamase-producing bacterial strains. The results reveal that compounds 6c and 6o in combination with cefradine show two to four times more activity than cefradine alone against methicillin-sensitive Staphylococcus aureus(MSSA) and Klebsiella pneumoniae. The data suggest that the sulfenimine moiety may be beneficial to the activity and selectivity of inhibitors.

Key words: β-Lactamase-inhibitor, Sulfenimine, Cephalosporins

ZHANG Kai, DING Huaiwei, SHI Ailong, HUANG Qi, SONG Hongrui, FU Decai. Design, Synthesis and Biological Evaluation of Sulfenimine Cephalosporin Analogues as β-Lactamase Inhibitors[J]. Chemical Research in Chinese Universities, 2015, 31(3): 388-393.

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Design, Synthesis and Biological Evaluation of Sulfenimine Cephalosporin Analogues as β-Lactamase Inhibitors

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