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Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross-Linking Activity of a Transpeptidase of l,d Specificity
Authors:Saidbakhrom Saidjalolov  Dr. Zainab Edoo  Dr. Matthieu Fonvielle  Louis Mayer  Dr. Laura Iannazzo  Dr. Michel Arthur  Prof. Dr. Mélanie Etheve-Quelquejeu  Dr. Emmanuelle Braud
Affiliation:1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université de Paris, 45, rue des saints-pères, Paris, 75006 France;2. INSERM UMRS 1138, Sorbonne Universités, UPMC Univ Paris 06, Sorbonne Paris Cité, Université de Paris, Centre de recherche des Cordeliers, Paris, 75006 France
Abstract:The carbapenem class of β-lactams has been optimized against Gram-negative bacteria producing extended-spectrum β-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 β-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.
Keywords:carbapenem  esterification  peptidoglycan  peptidomimetics  transpeptidase
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