Carbapenem-Based Prodrugs. Design, Synthesis, and Biological Evaluation of Carbapenems Publisher Pubmed



Hakimelahi GH^{1, 2, 3, 5} ; Moosavimovahedi AA¹ ; Saboury AA¹ ; Osetrov V² ; Khodarahmi GA³ ; Shia KS⁴
Source: European Journal of Medicinal Chemistry Published:2005

Abstract

Syntheses of racemic trans-3-hydroxycarbonyl-6-(phenylacetamido)carbapenem (13), trans-3-phosphono-6-(phenylacetamido)carbapenem (17), and β-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 β-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 β-lactamase producing microorganisms in vitro. © 2005 Elsevier SAS. All rights reserved.