Synthesis and Evaluation of 3-(Dihydroxyboryl)benzoic Acids as d,d-Carboxypeptidase R39 Inhibitors

Penicillin binding proteins (PBPs) catalyze steps in the biosynthesis of bacterial cell walls and are the targets for the β-lactam antibiotics. Non-β-lactam based antibiotics that target PBPs are of interest because bacteria have evolved resistance to the β-lactam antibiotics. Boronic acids have been developed as inhibitors of the mechanistically related serine β-lactamases and serine proteases; however, they have not been explored extensively as PBP inhibitors. Here we report aromatic boronic acid inhibitors of the d,d-carboxypeptidase R39 from Actinomadura sp. strain. Analogues of an initially identified inhibitor [3-(dihydroxyboryl)benzoic acid 1, IC50 400 μM] were prepared via routes involving pinacol boronate esters, which were deprotected via a two-stage procedure involving intermediate trifluorborate salts that were hydrolyzed to provide the free boronic acids. 3-(Dihydroxyboryl)benzoic acid analogues containing an amide substituent in the meta, but not ortho position were up to 17-fold more potent...