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, Klebsiellapneumoniae 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 beta-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 C(2)=C(3) of carbapenems upon reaction with transpeptidases or beta-lactamases.
Hakimelahi
G H
GH
Institute of Chemistry and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 115, Republic of China. hosein@chem.sinica.edu.tw
Moosavi-Movahedi
A A
AA
Tsay
S C
SC
Tsai
F Y
FY
Wright
J D
JD
Dudev
T
T
Hakimelahi
S
S
Lim
C
C
D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015169:Colony Count, Microbial; D004352:Drug Resistance, Microbial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D020615:Stenotrophomonas maltophilia / Q000737:chemistry* / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000737:chemistry*
D015780:Carbapenems; D004791:Enzyme Inhibitors; C415153:oxyiminocephalosporinase type II; D001618:beta-Lactamases