Synthesis and In Vitro Antibacterial Activity of New C-3-Modified Carbapenems

Abstract

New C-3 modified carbapenems have been synthesized by the Ad_NE-substitution of the enol phosphate group of 4-nitrobenzyl (4R)-3-[(diphenylphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylate by the corresponding thiols in acetonitrile in the presence of diisopropylethylamine (DIPEA). Mercaptoacetic acid methyl ester, furan-1-methylthiol, methyl N-(mercaptoacetyl)methioninate, and 2-(4-methylpiperazin-1-yl)-2-oxoethanethiol as thiols have been used. As a result, we have obtained the expected 4-nitrobenzyl esters of 3-[(2-methoxy-2-oxoethyl)thio]-, 3-[(2-furylmethyl)thio], 3-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]thio}, and 3-[((2-(S)-1-methoxy-4-methylthio-1-oxopropan-2-yl)amino)-2-oxoethyl]thio derivatives of (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid in yields of 67–87% after purification by column chromatography. The p-nitrobenzyl (pNb) esters of carbapenems have been converted to the corresponding acids by hydrogenolysis over 10% Pd/C in methanol. The antibacterial activity of the resulting carbapenems and their preceding pNb-esters has been studied against microorganisms of Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Streptococcus oralis. The compounds that have been found exceed in their activity the known drugs Meropenem and Cilapenem.