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α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment
Author(s) -
Decuyper Lena,
Magdalenić Katarina,
Verstraete Marie,
Jukič Marko,
Sosič Izidor,
Sauvage Eric,
Amoroso Ana Maria,
Verlaine Olivier,
Joris Bernard,
Gobec Stanislav,
D'hooghe Matthias
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201904139
Subject(s) - chemistry , biochemistry , microbiology and biotechnology , stereochemistry , combinatorial chemistry , biology
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.