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Synthesis and Preliminary Biological Evaluation of 3′‐Substituted Cephem Sulfones as Potential β‐Lactamase Inhibitors
Author(s) -
De Angelis Francesco,
Attorrese Giuseppe,
Cavicchio Giancarlo,
Ciampa Sabatino,
Di Tullio Alessandra,
Fattori Daniela,
Nicoletti Rosario,
Domenici Enrico
Publication year - 2001
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200108)2001:16<3075::aid-ejoc3075>3.0.co;2-a
Subject(s) - chemistry , enterobacter cloacae , cephem , sulfone , sulbactam , enzyme , stereochemistry , nucleophile , beta lactamase inhibitors , medicinal chemistry , combinatorial chemistry , organic chemistry , escherichia coli , enterobacteriaceae , biochemistry , carboxylic acid , antibiotics , catalysis , antibiotic resistance , imipenem , gene
3′‐Substituted cephem sulfones, as well as the unsubstituted congener, were synthesized and biologically evaluated as β‐lactamase inhibitors. Sodium 3′‐substituted cephalosporanate sulfones 4 and 5 were prepared starting from 7‐aminodeacetoxycephalosporanic acid (7‐ADCA, 6 ) by a bromodeamination reaction, followed by reduction of the 7‐halo derivative. Selective, radical bromination at C‐3′ on the Δ 3 ‐isomer, followed by nucleophilic substitution and then retroisomerization at Δ 2 , afforded the required derivatives. 3′‐Unsubstituted and 3′‐acetoxycephem sulfones 2 and 3 were prepared using routine chemistry. The 3′‐substituted cephem sulfone derivatives, evaluated as β‐lactamase inhibitors by IC 50 determinations, behave as weak inhibitors of the class D “oxacillinase” OXA1 from Escherichia coli and the class C β‐lactamase of Enterobacter cloacae P99. Conversely, the 3′‐unsubstituted cephem sulfone 2 was shown to be comparable to sulbactam and even more active than clavulanic acid against the latter enzyme. The activity of 2 against E. cloacae P99 was also greatly enhanced by prolonging the pre‐incubation time. Considerations as to the mechanism of inhibition are also put forward.