STRUCTURE-ACTIVITY STUDIES OF THE INHIBITION OF SERINE BETA-LACTAMASES BY PHOSPHONATE MONOESTERS

A new series of phosphonyl derivatives has been prepared and tested fo r inhibition of serine (class A and C) beta-lactamases. Variations of the leaving group in a series of methyl phosphonates showed that leavi ng groups better than the previously employed p-nitrophenoxide could g ive more effective inhibitors. Inclusion of a negative charge in the l eaving group did not, per se, lead to better inhibitors. Aryl phosphon ates appeared more effective than those with electronically comparable but smaller leaving groups. The combination of a good leaving group, 2,4-dinitrophenoxide, with an phenylmethylsulfonamido-the latter rathe r than phenylacetamido in order. to increase the stability of the comp ound with respect to intramolecular nucleophilic catalysis of hydrolys is by the amide group-did not yield overall a better inhibitor than pr eviously employed p-nitrophenyl phosphonates. These results give the f irst indication of specific interactions between a beta-lactamase and the leaving group of a phosphonate inhibitor. Only one enantiomer of a chiral thiophosphonate, presumably the R-p isomer, was an effective i nhibitor. Addition of either a D- or a L-methyl group to the methylene group of a p-nitrophenyl amidomethylphosphonate did not enhance the i nhibitory ability of the phosphonate. Class A beta-lactamases remain r efractory to phosphonates. (C) 1997 Elsevier Science Ltd.