Lactamases Acidic Dihydrocoumarins

A new series of unfunctionalized (17) and functionalized (18) 3,4-dihydrocoumarins (Fig. 11.11) was synthesized. These new benzopyranones differ from the previous neutral dihydrocoumarins, which are suicide substrates of proteinases (Section 11.4, in that they have a carboxy substituent on their aromatic ring and a side chain phenylacetamido group at the 3-position of the heterocycle instead of a benzyl one in compound 3. 

All these 3,4-dihydro-2H-1 -benzopyran-2-ones 17 and 18 are substrates of class A and class C (3-lactamases. They are thus the first 8-lactones that are hydrolyzed by [3-lactamases. The kcat values for these substrates are generally smaller than those of the analogous acyclic phenaceturates suggesting that the tethered leaving group obstructs the attack of water on the acyl-enzyme. Despite the apparent advantage of the long-lived acyl-enzymes, the irreversible inhibition by the functionalized compounds is no better than that of acyclic molecules 16. Thus, even the tethered QM cannot efficiently trap a second nucleophile at the [3-lactamase active site, at least as placed as dictated by the structure of compounds 18.70 

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