Substituted aryl malonamates as new serine beta-lactamase substrates: structure-activity studies.
A series of substituted aryl malonamates have been prepared. These compounds are analogues of aryl phenaceturates where the amido side chain has been replaced by a retro-amide. Like the phenaceturates, these compounds are substrates of typical class A and class C beta-lactamases, particularly of the latter, and of soluble DD-peptidases. The effect of substituents alpha to the ester carbonyl group on turnover by these enzymes is similar to that in the phenaceturates. On the other hand, N-alkylation of the side chain amide of malonamates, but not of phenaceturates, retains the susceptibility of the compounds to hydrolysis by beta-lactamases. This reactivity is not enhanced, however, by bridging the amide nitrogen and Calpha atoms. A phosphonate analogue of the malonamates was found to be an irreversible inhibitor of the beta-lactamases. These results, therefore, provide further evidence for the covalent access of compounds bearing retro-amide side chains to the active sites of beta-lactam-recognizing enzymes.
Adediran
S A
SA
Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Cabaret
D
D
Lohier
J-F
JF
Wakselman
M
M
Pratt
R F
RF
D004754:Enterobacter / Q000201:enzymology*; D008314:Malonates / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
D008314:Malonates; D065093:beta-Lactamase Inhibitors; C013098:malonamic acid; D001618:beta-Lactamases