Carbapenem-based prodrugs. Design, synthesis, and biological evaluation of carbapenems.
Syntheses of racemic trans-3-hydroxycarbonyl-6-(phenylacetamido)carbapenem (13), trans-3-phosphono-6-(phenylacetamido)carbapenem (17), and beta-lactam based prodrugs 19 and 22 were accomplished. Carbapenem 13 was found to possess antibacterial activity, comparable with imipenem (+)-3, against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiella pneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, P. aeruginosa 18S-H, and Xanthomonas maltophilia GN 12873. Like imipenem ((+)-3), carbapenem 13 was not stable to X. maltophilia oxyiminocephalosporinase type II. Its phosphonate analog 17, however, was neither a significant antibacterial agent nor a good beta-lactamase inhibitor. Chemical combinations of trans carbapenem 13 with cis carbapenem 6 (compound 19) as well as clavulanic acid (20) with cis carbapenem 6 (compound 22) via a tetrachloroethane linker exhibited remarkable activity against beta-lactamase producing microorganisms in vitro.
Hakimelahi
Gholam Hossein
GH
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. hosein@chem.sinica.edu.tw
Moosavi-Movahedi
Ali Akbar
AA
Saboury
Ali Akbar
AA
Osetrov
Valeriy
V
Khodarahmi
Ghadam Ali
GA
Shia
Kak-Shan
KS
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D004791:Enzyme Inhibitors; D011355:Prodrugs; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases