Design, synthesis, and SAR of novel carbapenem antibiotics with high stability to Xanthomonas maltophilia oxyiminocephalosporinase type II

Racemic cis-6-(phenylacetamido)carbapenem (21), 2-hydroxycarbonyl-cis-6-(phenylacetamido)-carbapenem (22), 2-methoxycarbonyl-cis-6-(phenylacetamido)carbapenem (30), 2-methoxycarbomethyl-cis-6-(phenylacetamido)carbapenem (33), 2-hydroxyethyl-cis-6-(phenylacetamido)carbapenem (34), and 2-acetoxyethyl-cis-6-(phenylacetamido)carbapenem (35) were synthesized. Formation of the carbapenem nuclei in 21, 22, and 30 involved dehydrophosphonation of the corresponding 2-diphenylphosphono-6-(phenylacetamido)carbapenam precursors 14, 15, and 28 using trimethylsilyl triflate and 1,8-diazabicyclo[5.4.0]undec-7-ene in THF. Syntheses of carbapenems 33-35 involved a Wittig reaction of carbapenam 14 with methyl glyoxylate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. For the antibacterial activities against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiella pneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, and P. aeruginosa 18S-H, carbapenems (±)-21, (±)-22, (±)-30, and (±)-33-35 were found comparable with imipenem ((+)-3), yet they were notably more potent than (+)-3 against Xanthomonas maltophilia GN 12873. On the other hand, unlike (+)-3, carbapenems (±)-21, (±)-22, (±)-30, and (±)-33-35 were stable to X. maltophilia oxyiminocephalosporinase type II. Their β-lactamase inhibitory properties, however, were found to be more comparable with those of penicillin G ((+)-4) than to those of imipenem ((+)-3). A combination of imipenem ((+)-3) with (±)-21, (±)-22, (±)-30, and (±)-33-35 resulted in synergistic antibacterial activity against X. maltophilia GN 12873. Results from the biological tests were correlated with the distribution of the electron density at C₂=C₃ of carbapenems upon reaction with transpeptidases or β-lactamases.