Nanomolar beta-lactamase inhibitors

New .alpha.-boronated N-alkylamides, R1C(O)NHCHR2B(OH)2 (R1 = H, organyl, excluding R1 = Me, Ph; R2 = heterocyclyl, cycloalkenyl, alkenyl, alkyl), preferably N-acyl-3-aminomethylbenzoates (.alpha.R)-RC(O)NHCH[B(OH)2]-1,3-C6H4X [15-17; X = CO2H, R = Me, 2-thienylmethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl; 21, X = H, R = 2-thienylmethyl], designed as transition-state analog inhibitors effective against class C .beta.-lactamase AmpC, were prepd. by one-pot procedure comprising stereoselective dichlorocarbene insertion into B-C-bond of (+)-pinanediol 3-(4,4-dimethyl-2-oxazolinyl)phenylboronate (7), amination of the resulting QO2BCHCl-1,3-C6H4R3 [8; Q = (+)-pinanediyl, R3 = 4,4-dimethyl-2-oxazolinyl] and subsequent acylation. The new compds. improve inhibition by over two-orders of magnitude compared to analogous glycylboronic acids, with Ki values as low as 1 nM. In an example, (+)-pinanediol (1R)-1-(2-thienylacetylamino)-1-[3-(4,4-dimethyl-4,5-dihydro-2-oxazolyl)phenyl]methylboronate (11) was prepd. from 7 by reaction with LiCHCl2 at -80, followed by amination by LiN(TMS)2, desilylation, and acylation by Ac2O with 24% overall yield. In another example, compd. 10 was deprotected to give 3-[(R)-(borono)(2-thienylacetylamino)methyl]benzoic acid (16). Compd. 16 exhibited binding const. with AmpC .beta.-lactamase of 0.001 .mu.M, and synergic inhibiting effect on E.coli growth at min. inhibition concn. (MIC) of 1.mu.g/mL in combination with antibiotic ceftazidime; in the absence of 16 the MIC of ceftazidime was 32 .mu.g/mL.