[en] Innovative monocyclic β-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high β-lactamase stability and compact scaffold. α-Benzylidene-substituted 3-amino-1-carboxymethyl-β-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central β-lactam ring. The present study discloses a 12-step synthesis of ten α-arylmethylidenecarboxylates using a microwave-assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced β-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased β-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the β-lactam C4-position. The significance of α-unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron-withdrawing groups. Furthermore, ring cleavage by representative β-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic β-lactams as eligible PBP or β-lactamase inhibitors.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Decuyper, Lena ; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Magdalenić, Katarina; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Verstraete, Marie-Blanche ; Université de Liège - ULiège ; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Jukič, Marko ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
Sosič, Izidor ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
Sauvage, Eric ; Université de Liège - ULiège > Département des sciences de la vie
Amoroso, Ana Maria ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)
Verlaine, Olivier ; Université de Liège - ULiège > Département des sciences de la vie > Centre d'Ingénierie des Protéines (CIP)
Joris, Bernard ; Université de Liège - ULiège > Integrative Biological Sciences (InBioS)
Gobec, Stanislav ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
D'hooghe, Matthias ; SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
Language :
English
Title :
α-Unsaturated 3-Amino-1-carboxymethyl-β-lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment.
The authors are indebted to the Research Foundation—Flanders (FWO), the Slovenian Research Agency (research program P1-0208) and Belspo IAP-Project P44-iPros for financial support.
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