4.6 Article

Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross-Linking Activity of a Transpeptidase of l,d Specificity

Journal

CHEMISTRY-A EUROPEAN JOURNAL
Volume 27, Issue 10, Pages 3542-3551

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202004831

Keywords

carbapenem; esterification; peptidoglycan; peptidomimetics; transpeptidase

Funding

  1. Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation

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Carbapenems have been optimized to target Gram-negative bacteria producing extended-spectrum beta-lactamases for the treatment of tuberculosis. The introduction of substituents at position C2 has shown to increase drug efficacy. Synthesizing peptido-carbapenems with a phenethylthio substituent at C2 demonstrated improved activity compared to the reference drug meropenem.
The carbapenem class of beta-lactams has been optimized against Gram-negative bacteria producing extended-spectrum beta-lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of L,D-transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As beta-lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido-carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems.

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