Objectives:

Discovered more than 50 years ago, beta-lactam antibiotics remain of large interest because of their potentially large spectrum and low intrinsic toxicity. A large number of semi-synthetic derivatives have been obtained, but few have explored the possibility to use bulky side chains in an attempt to more fully block the catalytic crevice in PBPs. In this context, we have synthesised penam and cephem derivatives bearing two morpholine rings attached to their side-chains. We report here on two typical compounds (DEMO-Pen and DEMO-Cef; see structures in the Figure) modelled after benzylpenicillin and the corresponding methoxy-acetyl-cephem.

Methods:

DEMO-Pen and DEMO-Cef were formed via the mixed anhydride method. The whole side chain was first obtained by bis-alkylation of methyl 3,5-dihydroxybenzoate with N-chloroethylmorpholine, and made into a pentafluorophenyl ester. The latter was coupled with 6-APA and 7-ACA to give the corresponding penam and cephem derivatives. MIC's were determined by common agar dilution method in comparison with ampicillin and cefadroxil against both collection strains and clinical isolates.

Results:

The structures and stabilities of DEMO-Pen and DEMO-Cef were confirmed by 1H NMR, 13C NMR, IR, and high-resolution mass spectrometry. DEMO-Pen was active against Gram (+) organims (S. aureus, S. pneumoniae, S. pyogenes). DEMO-Cef was more active (8x) than cefadroxil against S. pneumoniae.

Conclusion:

Bulky side-chains do not prevent penams and cephems to reach the active site of PBP's and may provide increased activity. This opens the way to renewed efforts in the synthesis of novel beta-lactam derivatives.