STRUCTURE-ACTIVITY-RELATIONSHIPS IN THE INHIBITION OF SERINE BETA-LACTAMASES BY PHOSPHONIC ACID-DERIVATIVES

A new series of phosphonyl derivatives has been prepared and tested fo r inhibition of serine (classes A and C) beta-lactamases. The results were compared with those previously acquired with aryl phosphonate mon oesters and with alkaline hydrolysis rates. A methyl p-nitrophenyl pho sphate monoanion was markedly poorer as an inhibitor of the class C be ta-lactamase of Enterobacter cloacae P99 than a comparable p-nitrophen yl phosphonate. Phosphonyl fluorides, thiophenyl esters, N-phenylphosp honamidates and a p-nitrophenyl thionophosphonate were, in general, co mparable with p-nitrophenyl phosphonates in inhibitory power. The inco rporation of a specific amido side chain led to an increase in the rat es of inhibition of around 10(4)-fold. Apparently unresponsive to the addition of the side chain to the enzyme was N-phenyl methylphosphonam idate, where binding of the side chain may interfere with access of th e leaving group to a proton which is necessary to active-site phosphon ylation and inhibition. Typical class A beta-lactamases were significa ntly more refractory than the class C enzyme to all of these reagents.