title: Substituted aryl malonamates as new serine beta-lactamase substrates: structure-activity studies.
abstract: 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 These compounds are analogues of aryl phenaceturates where the amido side chain has been replaced by a retro-amide.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.
authors.affiliation: Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Adediran
authors.forename: D
authors.initials: D
authors.lastname: Cabaret
authors.forename: J-F
authors.initials: JF
authors.lastname: Lohier
authors.forename: M
authors.initials: M
authors.lastname: Wakselman
authors.forename: R F
authors.initials: RF
authors.lastname: Pratt
mesh_terms: 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*
chemical_list: D008314:Malonates; D065093:beta-Lactamase Inhibitors; C013098:malonamic acid; D001618:beta-Lactamases