Design, synthesis, and evaluation of alpha-ketoheterocycles as class C beta-lactamase inhibitors.
A series of specific alpha-ketoheterocycles (benzoxazole, thiazole, imidazole, tetrazole, and thiazole-4-carboxylate) has been synthesized in order to assess their potential as beta-lactamase inhibitors. The syntheses were achieved either by construction of the heterocycle (benzoxazole) from an appropriate alpha-hydroxyimidate, followed by oxidation of the alcohol, or by direct reaction of methyl phenaceturate with a lithiated heterocycle. The properties of these compounds in aqueous solution are described and their inhibitory activity against beta-lactamases assessed. They did inhibit the class C beta-lactamase of Enterobacter cloacae P99 but not the TEM beta-lactamase. The most effective inhibitor of the former enzyme (K(i)=0.11 mM) was 5-(phenylacetylglycyl) tetrazole, probably because it is an anion at neutral pH. Interpretation of the results was aided by computational models of the tetrahedral adducts. Most of the compounds also inhibited alpha-chymotrypsin but not porcine pancreatic elastase.
Kumar
S
S
Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Pearson
A L
AL
Pratt
R F
RF
D015195:Drug Design; D004754:Enterobacter / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D013379:Substrate Specificity; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors
D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D007093:Imidazoles; D013777:Tetrazoles; D013844:Thiazoles; D065093:beta-Lactamase Inhibitors