The synthesis and evaluation of benzofuranones as β-Lactamase substrates

• Published in: Bioorganic & medicinal chemistry 2001-05, Vol.9 (5), p.1175-1183
• Main Authors: Adediran, S.A, Cabaret, D, Drouillat, B, Pratt, R.F, Wakselman, M
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Benzofurans - chemical synthesis; Benzofurans - metabolism; Benzofurans - pharmacology; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Biological and medical sciences; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrogen-Ion Concentration; Hydrolases; Hydrolysis - drug effects; Kinetics; Lactones - chemistry; Lactones - metabolism; Medical sciences; Pharmacology. Drug treatments; Substrate Specificity - physiology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00345-X

6- and 7-Carboxy-3-phenylacetamido-3 H-1-benzofuran-2-one have been synthesized as potential β-lactamase substrates and/or inhibitors. These compounds were prepared by lactonization of the corresponding, appropriately substituted phenylglycines. The latter compounds were prepared by either the Strecker or the Bücherer–Berg method. The benzofuran-2-ones were less stable in aqueous solution than the analogous acyclic phenaceturate esters but comparably stable to analogous benzopyran-2-ones. They differed from the latter compounds however in that the C-3 hydrogen of the furan-2-ones, adjacent to the lactone carbonyl group, was distinctly acidic; 7-carboxy-3-phenylacetamido-3 H-1-benzofuran-2-one exists largely as an enolate at pH 7.5. The furan-2-ones were β-lactamase substrates with reactivity very similar to the analogous acyclic phenaceturates. They were not, however, dd-peptidase inhibitors and are thus unlikely to have antibiotic activity. The structural basis for these observations is discussed. Graphic